A Review of African Medicinal Plants and Functional Foods for the Management of Alzheimer's Disease-related Phenotypes,Treatment of HSV-1 Infection and/or Improvement of Gut Microbiota

Abstract

Alzheimer's disease (AD), which is a progressive neurodegenerative disorder is the most common form of dementia globally. Several studies have suggested alteration in the gut microbiota and HSV-1 infection as contributing factors to the development of the disease. As at now, there are no AD attenuating agents and AD pharmacotherapy is focused on managing symptoms while plants used in ethnomedicine remain potential sources of drugs for the treatment of the condition. Here, we reviewed published databases for African ethnomedicinal plants and functional foods of African origin that are used in the management of AD-related phenotypes, treatment of herpes simplex virus −1 (HSV-1) and/or improvement of gut microbiota. A total of 101 unique plant species and 24 different types of traditionally prepared African functional foodstuff were identified. Of the 101 identified plant species, 50 species serve as functional foodstuffs. Twenty-three (23) of the ethnomedicinal plant families were successfully identified for the treatment and management of AD-related phenotypes and age-related dementia. Eighteen (18) African plant species from 15 families were also identified as potent remedies for HSV-1; while many African wild fruits (3 species), roots and tubers (7 species), leafy vegetables (14 species), and seaweeds (26 species) were functional foods for modifying AD-related phenotypes. It was concluded that African medicinal plants are potential sources of both AD attenuating agents and phytocompounds that may be used against HSV-1 infection and alteration of gut microbiota. Additionally, a number of African functional foods are important sources of prebiotics and probiotics.

Keywords

Alzheimer’s disease HSV-1 infection ethnomedicinal plants and functional foods

Introduction

Alzheimer's disease (AD) described by Alois Alzheimer in 1906,¹ is now the most common form of dementia globally.² AD results in memory loss and erosion of several cognitive and emotional functions. Age is often considered the most central risk factor for AD, with an estimated 14-fold increase in risk in people over 85 years of age compared to people between the ages of 65 and 69.^1–7 Globally, it is estimated that between 7–10% of individuals over 65 years of age and approximately 50–60% of persons over 85 years of age suffer from AD.⁵ The disease condition occurs as a result of the aggregation of misfolded β-amyloid and hyperphosphorylated tau peptides in selective regions of the central nervous system (CNS).^8–14

Several studies have suggested alteration of the gut microbiota and HSV-1 infection as contributing factors to the development of the disease,^15–17 while other studies have implicated dysbiosis in the intestinal microbiota and neurotropic infectious agents as triggers.^18–20 Using polymerase chain reaction (PCR) in the studies of the human brain of elderly normal and AD patients have led to the detection of the viral DNA signal of human simplex virus type 1 (HSV-1) in the regions that are mostly affected by AD.^21–23 These findings were confirmed by other studies that have also detected viral DNA signals in the brain.^24–26 A study by Itzhaki et al (1993) has demonstrated by reverse transcription (RT) PCR that the infection was latent by the presence of latency-associated transcripts in favor of thymidine kinase transcripts.^23,27 According to Jamieson and colleagues (1992), the viral DNA of HSV-1 was detected in only a very small percentage of brains in younger people compared to the aged,²² suggesting that the virus is able to cross the blood-brain barrier in the aged possibly as a result of declined immunity.^23,28 From both cell culture and brain studies, it is evident that HSV-1 cause neuronal damage directly or through inflammation when reactivated.²⁹

Gut microbiota induced immuno-modulation has emerged as an important pathway in the pathogenesis of AD.³⁰ The human gut microbiota is diverse, large, dynamic and made up of more than 100 trillion microorganisms that come from more than 1000 different bacteria species with evidence of the interplay between the intestinal mucosal immune system and intestinal microbiota.^31,32 Numerous studies have generated compelling evidence suggesting that the human gut microbiota may play a key role in AD neuroinflammation³³ such that the gut flora can influence the brain in several ways through the immune system. Thus, signifying that the gut and the CNS engage in crosstalk.^18,33–35

Currently, there is no AD attenuating agent^36,37 and AD pharmacotherapy is focused on managing symptoms without disease attenuation.³⁸ The neuroprotective capabilities of natural phenolic compounds from plants used in ethnomedicine have been reported and they remain the preferred primary treatment choice. It is estimated that over 60% of the global population and approximately 80% of the population in developing countries rely on herbal medicine.^37,39,40 According to Fabricant and Farnsworth (2001), a total of some 122 isolated compounds from 94 plant species have been identified.⁴¹ Of these, 80% were employed for the same or related ethnomedicinal uses.⁴¹ Considering the fact that these isolated plant compounds were derived from only 94 plant species out of an estimated 250 000 plant species, Mahapatra and colleagues argued that the plethora of active drug compounds that remains to be identified in plants is unlimited.⁴² The use of prebiotics and probiotics has also been shown to help restore or at least improve the density and diversity of healthy human gut flora. This is achieved by consuming probiotic foodstuffs that provide healthy food microbes to the gut or indigestible polysaccharides known as prebiotics that are essential for the growth of healthy gut flora.⁴³ This study therefore reviewed published records on African ethnomedicinal plants that are used in the management of the above-stated disease conditions and those that are used as functional foodstuffs.

Methodology

This study reviewed electronic databases (Science Direct, Google Scholar, ResearchGate, and PubMed) and the Ghana Herbal Pharmacopoeia for African ethnomedicinal plants that have been used in the treatment of AD-related phenotypes, the treatment of HSV-1, and the enhancement and restoration of the gut microbiota, to determine their therapeutic efficacy and functional food use. The search was performed using specific search terms for the various disease conditions, and functional food usage.

Traditional Use of Plants

Ethnomedicinal Plants for the Management of AD-Related Phenotypes

The current AD management therapeutics are only focused on slowing disease progression and alleviating the symptoms.^38,44 However, since time immemorial, mankind has always relied on ethnomedicine for the treatment and management of diseases related to the CNS.^37,44 One plant from which successful ethnopharmaceutical have been developed for the treatment of dementia is Ginkgo biloba with a good safety profile.^44,45 One of such efficacious remedies from Ginkgo biloba is EGb 761 (a standardized extract marketed by Wilmar Schwabe GmbH), which is very effective in the treatment of AD-related dementia in clinical trials.^44,46 The drug discovery and development pipeline have always started with ethnomedicinal knowhow and it is now more important than ever to profile ethnomedicinal plants that can attenuate AD-related pathophysiology. This section is a compilation of some African ethnomedicinal plants that are traditionally used in the treatment and management of AD-related phenotypes. The compilation considers the (i) traditional use of the plants in humans; (ii) its uses on animals:—of which both (i) and (ii) are categorized as in vivo use; and (iii) its uses on cell-line(s), which is categorized as in vitro use.

The list of ethnomedicinal plants credited with attenuating capacity in AD-related phenotypes consists of plants belonging to the family Agapanthaceae to family Zingiberaceae (Table 1). Plants from the following families were identified Agapanthaceae, Aizoaceae, Amaryllidaceae, Apocynaceae, Araceae, Asteraceae, Combretaceae, Euphorbiaceae, Fabaceae, Gelidiaceae, Gracilariaceae, Hydrophilaceae, Lessoniaceae, Moringaceae, Myristicaceae, Orchidaceae, Piperaceae, Polygalaceae, Rhamnaceae, Scrophulariaceae, Sterculiaceae, Ulvaceae and Zingiberaceae, making a total of 23 plant families in all. Majority of the plants were from the family Amaryllidaceae, followed by an equal proportion of members from the following families:—Combretaceae, Euphorbiaceae, Piperaceae, Rhamnaceae and Zingiberaceae. Photographs of some of the members of plants listed in Table 1 are provided.

Table 1.

List of African Medicinal Plants Used for Memory and Cognition Enhancement, and Management of Other Alzheimer's Disease Related Phenotypes.

Botanical name (Family)	in vivo	in vitro	Part(s) used/reference
Crinum glaucum A. Chev. (Amaryllidaceae) Compounds/Phytochemicals : Hamayne Lycorine Mechanism : Active against AChE	Memory enhancer		Bulb⁴⁷
Crinum jagus C. (Amaryllidaceae) Compounds/Phytochemicals : Hamayne Lycorine Mechanism : Active against AChE	Memory enhancer		Bulb⁴⁷
Hydrolea glabra Schum. (Hydrophilaceae) Compounds/Phytochemicals : Steroids Mechanism : Acts on GABA receptor	Memory enhancer and alleviates anxiety in mice		Leaves^48,49
Pistia stratiotes L. (Araceae) Compounds/Phytochemicals : Stratioside II Mechanism : Anti-inflammatory and nociceptor sensitization	Relieves dementia		Roots / Leaves^50,51
Boophone disticha (L.f.) Herb. (Amaryllidaceae) Compounds/Phytochemicals : 6-hydroxycrinamine Mechanism : Inhibits AChE		Inhibits AChE and potentially neuroprotective	Leaves / Bulb^52,53
Croton sylvaticus Hochst. (Euphorbiaceae) Compounds/Phytochemicals : Quercetin Kaempferol Mechanism : Inhibits AChE		Inhibits AChE and potentially neuroprotective	Leaves⁵⁴
Ziziphus mucronata Willd. (Rhamnaceae) Compounds/Phytochemicals : Galantamine Mechanism : Inhibits AChE		Inhibits Aβ in SH-SY5Y cells	Leaves^55,56
Cola nitida (Vent.) Schott & Endl. (Sterculiaceae) Compounds/Phytochemicals : 9-Octadecenamide Augustamine Undulatine Mechanism : Inhibits AChE and BuChE	CNS stimulant/anti-depressant		Seed^57,58
Lannea schweinfurthii (Engl.) Engl. (Anacardiaceae) Compounds/Phytochemicals : Epicatechin Sitosterol Mechanism : Inhibits AChE		Inhibits A-beta in SH-SY5Y cells	Roots^55,59
Terminalia sericea Burch. ex DC. (Combretaceae) Compounds/Phytochemicals : Sericic acid Sericoside Mechanism : Inhibits AChE and A-beta		Inhibits A-beta in SH-SY5Y cells	Roots^55,60
Piper capense L.f. (Piperaceae) Compounds/Phytochemicals : Piperine 4,5-dihydropiperine Mechanism : Inhibits AChE, and antioxidant activity		Inhibits AChE and potentially neuroprotective	Roots⁵⁶
Piper nigrum L (Piperaceae) Compounds/Phytochemicals : Allyl isothiocyanate Zingerone Mechanism : Inhibits cellular production of TNF-α and nitric oxide		Enhanced memory in Wistar rat	Fruits^61,62
Terminalia sericea Burch. ex DC. (Combretaceae) Compounds/Phytochemicals : Anolignan B Sericic acid Mechanism : Anti-inflammatory, and inhibits AChE		Inhibits AChE and potentially neuroprotective	Roots^56,63,64
Ziziphus mucronate Willd. (Rhamnaceae) Compounds/Phytochemicals : Sanjoinine A Sanjoinine B Mechanism : Inhibits AChE, and antioxidant activity		Inhibits AChE and potentially neuroprotective	Roots^56,65
Rauwolfia vomitoria Afz. (Apocynaceae) Compounds/Phytochemicals : Yohimbine Ajmaline Reserpine Mechanism : Inhibits AChE	Antipsychotic		Roots^57,66
Jatropha curcas L. (Euphorbiaceae) Compounds/Phytochemicals : Curcin Sitosterol Mechanism : Anti-inflammatory effect	Antipsychotic		Fruits^67,68
Peltophoru africanum Sond. (Fabaceae) Compounds/Phytochemicals : Coumarins Gallic acid Mechanism : Anti-depressant, anti-inflammatory effect		Anti-oxidant and potentially neuroprotective	Roots/Bark⁶⁹
Ammocharis coranica (Ker-Gawl.) Herb. (Amaryllidaceae) Compounds/Phytochemicals : Lycorine Mechanism : Inhibits AChE	Antipsychotic	Inhibits AChE and potentially neuroprotective	Bulb⁷⁰
Carpolobia lutea G. Don (Polygalaceae) Compounds/Phytochemicals : Flavones Isoflavones Mechanism : Antioxidant and anti-AChE effect	Enhanced cognition in mice (CD 1)		Roots^71,72
Crinum macowanii (Amaryllidaceae) Compounds/Phytochemicals : Lycorine Mechanism : Anti-AChE effect	Enhanced memory in BALB/c mice		Bulb⁷³
Agapanthus africanus (Agapanthaceae) Compounds/Phytochemicals : Alkaloids Flavonoids Mechanism : Anti-AChE effect	Memory enhancer		Whole plant⁷⁴
Aptosimum decumbens Schinz (Scrophulariaceae) Compounds/Phytochemicals : Alkaloids Flavonoids Mechanism : Anti-AChE effect	Memory enhancer		Whole plant^74,75
Tithonia diversifolia (Hemsl.) (Asteraceae) Compounds/Phytochemicals : Gallic acid Chlorogenic acid Mechanism : Antioxidant and anti-cholinesterase		Inhibits AChE and potentially neuroprotective	Leaves⁷⁶
Pycnanthus angolensis (Welw) Warb. (Myristicaceae) Compounds/Phytochemicals : Omifoate A Mechanism : Anti-cholinesterase	Enhanced memory in mice		Bark^77,78
Carpobrotus edulis L. (Aizoaceae) Compounds/Phytochemicals : Coumaric acid Epicatechin Mechanism : Anti-neuroinflammatory and anti-AChE		Inhibits AChE and BuChE and potentially neuroprotective	Leaves⁷⁹
Angraecum eichlerianum Bory. (Orchidaceae) Compounds/Phytochemicals : Alkaloids Flavonoids Mechanism : Antioxidant effect	Memory enhancer		Leaves⁸⁰
Aframomum melegueta K. Schum. (Zingiberaceae) Compounds/Phytochemicals : Gingerols Paradols Mechanism : Antioxidant effect and anti-neuroinflammatory	Memory enhancer		Seeds^80,81
Moringa Oleifera (Moringaceae) Compounds/Phytochemicals : Alkaloids Flavonoids Mechanism : Antioxidant effect	Memory enhancer		Leaves^57,72,82
Ecklonia maxima (Lessoniaceae) Compounds/Phytochemicals : Dibenzo [1,4]dioxine-2,4,7,9-tetratol Eckmaxol Mechanism : Anti-AChE effect, and decreases Reactive Oxygen Species		Inhibits Cholin., β-sec., Aβ aggregation and potentially neuroprotective	Whole plant^83–85
Gelidium pristoides (Gelidiaceae) Compounds/Phytochemicals : 35,7-trimethoxy flavone Biochanin A Mechanism : Anti-BChE, anti-AChE, and anti-amyloidogenic		Inhibits Cholin., β-sec., Aβ aggregation and potentially neuroprotective	Whole plant⁸³
Gracilaria gracilis (Gracilariaceae) Compounds/Phytochemicals : Alpha-tocopherol Beta-sitosterol Mechanism : Anti-BChE, anti-AChE, and anti-amyloidogenic		Inhibits Cholin., β-sec., Aβ aggregation and potentially neuroprotective	Whole plant⁸³
Ulva lactuca (Ulvaceae) Compounds/Phytochemicals : Beta-D-Galactofuranoside Arabinose Mechanism : Anti-BChE, anti-AChE, and anti-amyloidogenic		Inhibits Cholin., β-sec., Aβ aggregation and potentially neuroprotective	Whole plant⁸³
Zingiber officinale (Zingiberaceae) Compounds/Phytochemicals : α-Zingiberene Camphene Mechanism : Antioxidant effect, and anti-inflammatory		Inhibits AChE andpotentially neuroprotective	Rhizomes^86,87

*** Cholin. = Cholinesterases; β-sec. = β-secretase; ***BuChE = Butyrylcholinesterase; *** AChE = Acetylcholinesterase; Aβ = β-amyloid; CNS = Central Nervous System; Compounds/Phytochemicals = Already identified plant compounds or phytochemicals; Mechanism = Mechanism of action of the plant extract(s).

Whole plant extract of Agapanthus africanus (Figure 1A) belonging to the Agapanthaceae family is known to have memory-enhancing capability and has been used to enhance memory in ethnomedicine.⁷⁴ The leaf extract of Carpobrotus edulis (Figure 1B) from the family Aizoaceae has been reported to have neuroprotective capacity and shown to inhibit AChE and BuChE in vitro.⁷⁹ The bulb extract of Crinum glaucum (Figure 1C),⁴⁷ Crinum jagus (Figure 1D),⁴⁷ and Crinum macowanii (Figure 1E)⁷³ have all demonstrated their capacity as memory enhancers in vivo whiles the in vitro assessment of the leaves and bulb extracts of Boophone disticha (Figure 1F) have both demonstrated the plant's neuroprotective potential and the capacity to inhibit AChE.⁵² Furthermore, the bulb extract of Ammocharis coranica (Figure 1G), which is used ethnomedicinally as an antipsychotic, has also been reported to have neuroprotective capacity and ability to inhibit AChE in vitro.⁷⁰ The root extract of Rauwolfia vomitoria (family: Apocynaceae) (Figure 1I) was reported to be a potent antipsychotic agent used in ethnomedicine around the African continent.^57,66

Figure 1.

Photographs of some of the plants listed in Table 1.

Leave and root extracts of Pistia stratiotes (family: Araceae) (Figure 1H) are known to exhibit the capacity to relieve dementia in ethnomedicine.⁵⁰ The leaf extract of Tithonia diversifolia (family: Asteraceae) (Figure 1J) has demonstrated the capacity as both a neuroprotective agent and an inhibitor of AChE in vitro,⁷⁶ whereas root extract of Terminalia sericea (Figure 1L) belonging to the Family Combretaceae exhibited neuroprotective capacity and the ability to inhibit AChE in vitro.⁵⁶ The capacity of the root extract of Terminalia sericea to inhibit the formation of beta-amyloid was also demonstrated in the SH-SY5Y cell line.⁵⁶

Two plant species Jatropha curcas (Figure 1M) and Croton sylvaticus (Figure 1N), were identified from the Euphorbiaceae family. While the fruits of Jatropha curcas has antipsychotic properties,⁶⁷ the leaf extract of Croton sylvaticus have been reported to both inhibit AChE and protect neuron cells.⁵⁴ The root and bark extracts of Peltophorum africanum (family: Fabaceae) (Figure 1O) demonstrated a strong antioxidant capacity and neuroprotective potential in vitro.⁶⁹ Gelidium pristoides (Figure 1P), Gracilaria gracilis (Figure 1K), Ecklonia maxima (Figure 1Q), and Ulva lactuca (Figure 1R) were identified from Gelidiaceae, Gracilariaceae, Lessoniaceae, and Ulvaceae families respectively. Whole plant extracts from these plants have demonstrated their neuroprotective capacity, as well as their ability to inhibit cholinesterase, beta-secretase, and beta-amyloid aggregation in vitro.⁸³

Ethnomedicinal plants with the capacity to enhance memory were identified from the plant families: Moringaceae (Moringa Oleifera) (Figure 1S), Orchidaceae (Angraecum eichlerianum) (Figure 1T), Scrophulariaceae (Aptosimum decumbens) (Figure 1U), and Zingiberaceae (Aframomum melegueta) (Figure 1V). The leave extracts of Moringa Oleifera^57,72 and Angraecum eichlerianum⁸⁰ have been shown to demonstrate the capacity to enhance memory, while the whole plant extract of Aptosimum decumbens demonstrated its ability to enhance memory.⁷⁴ Also, the seeds of Aframomum melegueta have been traditionally reported to enhance memory.⁸⁰ Another member identified from the Zingiberaceae family is Zingiber officinale (Figure 1W). The rhizome of Zingiber officinale had been identified as having neuroprotective capacity and the ability to inhibit AChE in vitro.⁸⁶ Pycnanthus angolensis is the plant that was identified as representative of the family Myristicaceae. Pycnanthus angolensis (Figure 1X) bark extract demonstrated its ability to enhance memory in mice.⁷⁷ The root extract of Carpolobia lutea (Figure 1Y) of the family Polygalaceae had successfully demonstrated cognition enhancement in CD1 mice.⁷⁹

The leave extract of Hydrolea glabra (Figure 1Z) of the family Hydrophilaceae has been shown to be a potent memory enhancer with the capacity to alleviate anxiety in mice.^48,49 From the family Piperaceae were identified plant species; Piper capense (Figure 1AA) and Piper nigrum (Figure 1BB). The roots of Piper capense are known to be neuroprotective with the ability to inhibit AChE in vitro,⁵⁶ while the fruits of Piper nigrum have demonstrated memory enhancing capacity in the Wistar rat.⁶¹

The root extract of Ziziphus mucronata (family: Rhamnaceae) (Figure 1CC) has been shown to possess neuroprotective capacity and AChE inhibitory effect,⁵⁶ while the leaf extract has been shown to inhibit beta-amyloid.⁵⁵ The seeds of Cola nitida (Figure 1DD) belonging to the Sterculiaceae family have been identified as having antidepressant properties and the ability to stimulate the CNS.⁵⁷

Ethnomedicinal Plants for the Treatment of Herpes Simplex Virus Type 1 (HSV-1)

The Herpes Simplex Virus

In essence, there are eight types of herpesviruses in a large family called Herpesviridae, which consist of viral particles made up of a single double-stranded DNA molecule contained in a viral envelope.⁸⁸ The large family of herpesviruses has been classified into 3 basic groups, (i) group alpha: made up of herpes simplex virus type-1 and −2 (HSV-1/HSV-2), and varicella-zoster virus (VZV); (ii) group beta: includes human herpesvirus type-6 and −7 (HHV-6/HHV-7), and human cytomegalovirus (HCMV); as well as (iii) group gamma: which has human herpesvirus type-8 (HHV-8) and Epstein-Barr virus (EBV) as members of the group.

Herpesviruses have the characteristic of persisting throughout the host's lifetime and can be reactivated from latency.⁸⁹ Herpesviruses are common pathogens that cause varying types of diseases ranging from infections of the skin, oral cavity, eye, esophagus, pharynx up to the genitalia.⁹⁰ HSV-1 is a neurotropic virus that causes lifelong infection and can enter latency in infected neuronal cells⁹¹ with the possibility of reactivation resulting in recurrent and acute infections.⁹⁰

Current Trends in Antiviral Ethnopharmacology

Studies have shown the antiviral efficacy of several ethnomedicinal plants affecting various stages of viral growth.⁹² Herbal preparations are widely used as antiviral drugs,^92–94 and ethnopharmacological preparations are currently being classified for their activity against viral infections.^92,95

Table 2 below shows the compiled list of some African ethnomedicinal plants that have been used and are still in use for the treatment and management of HSV-1 infection for several centuries. Plants with efficacy against HSV-1 infection were identified across several plant families (from family Anacardiaceae to Zygophyllaceae). The total number of plant families from which specific plants were identified is 15 in all, and these families are as follows: Anacardiaceae, Apocynaceae, Asteraceae, Capparaceae, Combretaceae, Ephedraceae, Ericaceae, Frankeniaceae, Geraniaceae, Leguminosae, Mimosaceae, Moringaceae, Sterculiaceae, Tamaricaceae, and Zygophyllaceae. The same family size dominance was observed for Capparaceae, Combretaceae, and Leguminosae (Table 2).

Table 2.

List of African Medicinal Plants That Have Demonstrated Inhibitory Activity Against HSV-1 Infection.

Scientific Name (Family)	Part used	Extract	in vivo/in vitro	Assay/reference
Capparis sinaica Veill. in Duh. (Capparaceae) Compounds/Phytochemicals : Quercetin, Quercetin-7-o-rutinoside, Luteolin, Kaempferol-3-galactose, and Quercetin-7-O-glucoside	Aerial	Aqueous ethanol	Vero cells	Plaque reduction/inhibition assay^96,97
Cyperus rotundus L. (Capparaceae) Compounds/Phytochemicals : Luteolin-7-O-glucoside, Tricin, (+)-catechin, quercetin, (−)-cypera-2,4-diene, 4α,5β-oxidoeudesm-11-en-3α-ol, and Rotundine A	Tuber	Aqueous ethanol	Vero cells	Plaque reduction/inhibition assay^96,98
Ephedra alata Decne. (Ephedraceae) Compounds/Phytochemicals : Phedrine, Pseudoephedrine, Trans-cinnamic acid, Catechin, Syringin, Epicatechin, Symplocoside, Kaempferol 3-O-rhamnoside 7-O-glucoside, Isovitexin 2-O-rhamnosid, and Luteolin-7-O-glucuronide flavonoid	Aerial	Aqueous ethanol	Vero cells	Plaque reduction/inhibition assay^96,99
Moringa peregrina (Forssk.) Fiori. (Moringaceae) Compounds/Phytochemicals : Lupeol acetate, β-amyrin, α-amyrin, β-sitosterol, and β-sitosterol-3-O-β-D-glucoside	Seed	Aqueous ethanol	Vero cells	Plaque reduction/inhibition assay^96,100
Tamarix nilotica (Ehrenb.) Bunge. (Tamaricaceae) Compounds/Phytochemicals : Gallic acid, Quercetin, Kaempferol, di-Galloylglucose, Kaempferol glucuronide, and Methyl-quercetin	Aerial	Aqueous ethanol	Vero cells	Plaque reduction/inhibition assay^96,101
Erica multiflora L. (Ericaceae) Compounds/Phytochemicals : Quercetin, Kaempferol, Myricetin, Uinic acid, Caffeic acid hexoside, 3-O-caffeoylquinic acid, P-coumaric acid hexoside, and Syringic acid hexoside	Aerial	Methanolic	Vero cells	Plaque reduction/inhibition assay^93,102
Frankenia pulverulenta L. (Frankeniaceae) Compounds/Phytochemicals : Dihydrotecomanine, 5,7-Dodecadiyn-1,12-diol, 6-Acetyl-β-d-mannose, Gamolenic acid, And Gibberellic acid	Whole plant	Methanolic/acetonic	Vero cells	Plaque reduction/inhibition assay^93,103
Zygophyllum album L. (Zygophyllaceae) Compounds/Phytochemicals : Hyacinthine, 1-Nonen-4-ol, Nonanal, 1,2-Dihydro-14,6-trimethyl naphthalene, Bis(2-ethyl hexyl) phthalate, Quercetin 3-sulfate, Isorhamnetin-3-O-rutinoside, and Quinovicacid 3-0-rhamnoside	Whole plant	Acetonic	Vero cells	Plaque reduction/inhibition assay^93,104,105
Pelargonium sidoides DC. (Geraniaceae) Compounds/Phytochemicals : 7-hydroxy-5,6-di-methoxycoumarin, 6,8-dihydroxy-5,7-dimethoxycoumarin, 6-Methoxy-7-(sulfooxy)-2H-1-benzopyran-2-one, and 6,8-Bis(sulfooxy)-7-methoxy-2H-1-benzopyran-2-one	Roots	Aqueous-ethanolic	RC-37 cells	Plaque reduction/inhibition assay^94,106,107
Helichrysum aureonitens Sch. Bip. (Asteraceae) Compounds/Phytochemicals: 35,7-trihydroxyflavone, 3-Caffeoylquinic acid, 5-Caffeoylquinic acid, 4,5-Dicaffeoylquinic acid, Ferulic acid, and 13S-Hydroxy-9Z,11E,15Z-octadecatrienoic acid	Shoots	Aqueous	Human lung fibroblast	Plaque reduction/inhibition assay^95,108,109
Combretum micranthum (Combretaceae) Compounds/Phytochemicals : C-glycosylflavones, vitexin, isovitexin, orientin, and homoorientin, m-inositol and sorbitol, myricetin-3-O-glucoside, and myricetin-3-O-rutinoside	Leaves	Methanolic	Vero cells	Plaque reduction/inhibition assay^96,110
Bauhinia thonningii (Schum.) (Leguminosae) Compounds/Phytochemicals : C-methylflavonols, quercetin, 6,8-di-C-methylquercetin 3-methyl ether, 6-C-methylquercetin 3,7-dimethyl ether, 6,8-di-C-methylquercetin 3,7-dimethyl ether, 6-C-methylquercetin 3-methyl ether, 6-C-methylquercetin 37,3′-trimethyl ether, 6,8-di-C-methyl- kaempferol 3-methyl ether, 6,8-di-C-methylkaempferol 3,7-dimethyl ether, and quercitrin	Leaves	Methanolic	Human colonic cancer cells (HT-29)	Plaque reduction/inhibition assay^111,112
Anacardium occidentale L. (Anacardiaceae) Compounds/Phytochemicals : 2-(10″Z, 13″Z-nonadecadienoyl)-6-(8′Z, 11′Z-pentadecadienyl) salicylic acid, (+)-catechin, (-)-epicatechin, epigallocatechin, protocatechuic, cinnamic acids, syringic, p-coumaric acids,5-hydroxymethylfurfural, catechin, epicatechin, epigallocatechin and gallic acid, and 2-(8″Z-eicosenoyl)-6-(8′Z-pentadecenyl) salicylic acid	Bark	Methanolic	Human colonic cancer cells (HT-29)	Plaque reduction/inhibition assay^111,113
Dichrostachys glomerate (Chiev.) (Mimosaceae) Compounds/Phytochemicals : flavonoids, phenolic compounds, alkaloids, tannins, saponins, quinones, glycosides, and terpenoids	Leaves	Methanolic	Human colonic cancer cells (HT-29)	Plaque reduction/inhibition assay¹¹¹
Sterculia setigera (Del.) (Sterculiaceae) Compounds/Phytochemicals : Procyanidin dimer B, Procyanidin trimer C1, Procyandin tetramer, (+)- Catechin, and 3,4-Dimethoxyphenol b-D-apiofuranosyl(1″ ➞ 6″)-b-D-glucopyranoside	Bark	Methanolic	Human colonic cancer cells (HT-29)	Plaque reduction/inhibition assay^111,114
Detarium senegalensis (Leguminosae) Compounds/Phytochemicals : 34,5-tri-O-galloylquinic acid, caffeoylquinic acids, caffeic acid, synapoic acid, and 34,5-tri-O-caffeoylquinic acid	Leaves	Methanolic	Human colonic cancer cells (HT-29)	Plaque reduction/inhibition assay^111,115
Guiera senegalensis (J.F. Gmelin) (Combretaceae) Compounds/Phytochemicals : 3˗O˗Galloylquinic acid, 4˗O˗Galloylquinic acid, 1,3˗Di˗O˗galloylquinic acid, 3,4˗ Di˗O˗galloylquinic acid, and 4,5˗ Di˗O˗galloylquinic acid	Leaves	Methanolic	Human colonic cancer cells (HT-29)	Plaque reduction/inhibition assay^111,116
Carissa edulis (Forssk.) Vahl (Apocynaceae) Compounds/Phytochemicals : Ursolic acid, carissone, caredulis, -{1-[2-(2 hydroxypropoxy) propoxy] propan-2-yloxy}, carissanol, β-sitosterol, scopoletin, butyl-O-α-l-rhamnoside, kaempferol, rutin, and quercetin-3-O-glucoside-7,3′,4′-trimethyl ether	Roots	Aqueous	Vero Cells and Balb/C mice	Plaque reduction/inhibition assay^117–119

The aqueous ethanol extracts of Capparis sinaica (plant part: Aerial) (Figure 2A), Cyperus rotundus (plant part: Tuber) (Figure 2B), Ephedra alata (plant part: Aerial) (Figure 2C), Moringa peregrina (plant part: Seed) (Figure 2D), and Tamarix nilotica (plant part: Aerial) (Figure 2E) were found to possess anti-viral capacity against HSV-1 invasion of Vero cells in plaque reduction assay.⁹⁶ The aqueous ethanol root extract of Pelargonium sidoides (Figure 2F), when investigated using RC-37 cells, demonstrated its capacity as an inhibitor of HSV-1 invasion.⁹⁴

Figure 2.

Photographs of some of the plants listed in Table 2.

Methanolic extracts of Erica multiflora (plant part: Aerial) (Figure 2G),⁹³ Combretum micranthum (plant part: Leaves) (Figure 2H),⁹⁶ and Bauhinia thonningii (plant part: Leaves) (Figure 2I)¹¹¹ have been identified as potent anti-HSV-1 agents using plaque reduction assay. However, both methanolic and acetonic extracts of the whole Frankenia pulverulenta (Figure 2J) plant demonstrated their ability to inhibit and reduce HSV-1 infection, when tested on Vero cells using a plaque reduction assay.⁹³ Also, the whole plant acetonic extract of Zygophyllum album (Figure 2K) reduced and inhibited HSV-1 invasion when investigated in Vero cells using plaque reduction assay.⁹³

Anti-HSV-1 inhibition and reduction potential were observed for the aqueous shoots and roots extract of Helichrysum aureonitens (Figure 2L) and Carissa edulis respectively. The extract from Helichrysum aureonitens inhibited and reduced HSV-1 invasion of Human lung fibroblast cells,⁹⁵ whiles the extract of Carissa edulis (Figure 2M) demonstrated its anti-HSV-1 capacity in both in Vero cells and Balb/C mice.⁷⁴

Many other plants have also demonstrated their capacity to inhibit and reduce HSV-1 infection when their methanolic extracts were investigated in human colonic cancer cells (HT-29).¹¹¹ The bark extracts of Anacardium occidentale (Figure 2N) and Sterculia setigera (Figure 2O) were identified as potential HSV-1 inhibitors. Furthermore, the methanolic leaves extracts of Dichrostachys glomerate, Detarium senegalensis (Figure 2P), and Guiera senegalensis (Figure 2Q) have been observed to reduce and inhibit HSV-1 infection in vivo.¹¹¹

Some African Plants and Traditional Foodstuff Used as Functional Foods

Functional Food

The gut microecology is the physiologic base for the consequence of prebiotics and probiotics on the host.^108,120,121 Generally, probiotics and prebiotics are used in the production of functional foodstuff; containing healthy food microbes that are important for the biological processes of the human gut when ingested. And this is achieved by adding healthy microorganisms (probiotics) or indigestible polysaccharides (prebiotics) that artificially impact the host by selectively stimulating the growth of intestinal flora.^118,122,123

In 1989, Fuller (1989) gave the first generally accepted definition of probiotics, which states that probiotics are “A live microbial feed supplement that beneficially affects the host animal by improving its intestinal microbial balance”.^124,125 However, in 2001, probiotics were further defined by the Food and Agriculture Organization (FAO)/World Health Organization (WHO) (2001).¹²⁶ This definition described probiotics as “live microorganisms that when administered in adequate amounts confer health benefit effects on the host”.¹²⁷ It should be noted that some of these beneficial microorganisms for the health of the human gut originate from fermented foodstuffs or the environment.¹²⁸ The sole purpose of consuming foodstuff produced with probiotics is to prevent the thriving of pathogenic bacteria and their metabolites and to enhance the immune system in its response to infection and maintain proper intestinal function. Whiles, on the other hand, prebiotics are food items that promote the propagation and persistence of probiotic bacteria and beneficial pro-health microbes in the human gut.^122,126

Some African Functional Foodstuffs

In recent times, several traditional African foods have been given functional food roles. These include traditional meals prepared either by way of fermentation, roots and tubers as well as some edible seaweeds, based on their ability to alter the colonic microbiome; either by contributing to its composition directly or by serving as a growth medium for the flora thereby directly contributing to human health.^129–132

Probiotic Foodstuff

Several indigenous African traditional fermented foodstuff qualify as probiotic, however, not all fermented foodstuff can be classified as probiotic until some basic conditions are met.¹³³ Only fermented foodstuffs that meet the following conditions can be considered as probiotic foodstuffs.¹³⁴

A probiotic foodstuff must meet the following conditions:

- Have live organisms (10⁶ cfu / ml).

- The organisms must be members of the lactic acid bacteria (LAB) family.

- Organisms must be resistant to gastric acidity and bile salts.

- Must have no negative nutritional effects on the human body.

Probiotic Microorganisms

Probiotic organisms are largely functionally beneficial microbes that are able to convert the chemical components of raw plant and/or animal materials through fermentation. Which basically, augments the sensory quality of food and nutrients bio-availability, thus enhancing human health by contributing to the gut microflora equilibrium. These microbes also degrade mycotoxins and phytic acid among others, whiles producing compounds with antimicrobial and antioxidant properties.^133,135

Microorganisms that qualify as probiotics:

Lactobacillus species: Lactobacillus casei, L. acidophilus, L. brevis, L. lactis, L. plantarum, L. fermentum, L. delbrueckii var. Bulgaricus.

Bifidobacterium species: Bifidobacterium breve, Bf. animalis, Bf. Lactis, Bf. bifidum, Bf. longum, Bf. Adolescentis.

Other organisms: Lactococcus lactis, Enterococcus faecium, Enterococcuc faecalis, Pediococcus acidolactici, Streptococcus salivarus var. thermophilus, Saccharomyces boulardi).¹³⁴

Prebiotics Foodstuff

Generally, prebiotics are indigestible foodstuff that beneficially affect the host health. Prebiotics are able to selectively stimulating the activity and/or growth of a particular or a group of gut-microorganisms which subsequently enhance host health.¹³⁶ For a foodstuff to qualify as prebiotic, the following under listed criteria must be met.

Prebiotic Classification Criteria

A prebiotic foodstuff must meet the following criteria:

Be resistant to the upper gut tract.

Undergo fermentation by the intestinal microbiota.

It should be beneficial to the host's health.

Selectively stimulate probiotics.

Have stability to food processing treatment.¹³²

Listed in Table 3 below are several traditional probiotic foodstuffs produced by random fermentation in some African countries. These African functional foods are produced from different kinds of raw materials. The raw materials may include, among others, cereals, legumes, milk, and fish.

Table 3.

Some Traditional African Probiotic non-Alcoholic Foodstuffs Produced by Spontaneous Fermentation.

Traditional Food (Raw material)	Country and reference
Fura (millet), Nunu (milk), Koko (maize), Pito (millet / sorghum), Kenkey (maize), Agbelima (cassava) and Bonome (fish)	Ghana^137,138
Ogi (maize) and Kunuzaki (millet)	Nigeria¹³⁸
Mawe (maize)	Benin¹³⁸
Mbege (millet)	Tanzania¹³⁸
Ben-saalga (millet)	Burkina Faso¹³⁸
Bogobe (soghum)	Botswana¹³⁸
Humulur and Hussuwa (soghum)	Sudan¹³⁸
Bouza and kishk (wheat)	Egypt¹³⁸
Uji (maize) and Kule naoto (milk)	Kenya¹³⁹
Amasi (milk), Mahewu (maize) and Munkoyo (maize)	SA/ Zimbabwe^134,139
Ergo (milk) and Ititu (milk)	Ethiopia¹³⁹

***SA = South Africa.

Several African seaweeds that are traditionally used as food have also been credited with the attributes of functional foods (Table 4). Most of these prebiotic seaweeds can be found in South Africa and Morocco (based on available publications). Not many such plants have been described from other countries on the continent. However, some of these gut-friendly and healthy seaweeds can also be found in East and West Africa.

Table 4.

Some African Seaweeds/Macroalgae with Prebiotic Capacity.

Scientific name(s) of Algae/Seaweed	Country and reference
Meristotheca senegalensis (Solieriaceae)	Senegal¹⁴⁰
Hypnea musciformis (Cystocloniaceae)
Kappaphycus alvarezii (Solieriaceae)	Tanzania¹⁴⁰
Gelidium abbotiorum (Gelidiaceae)	Morocco¹⁴⁰
Gelidium canariense (Gelidiaceae)
Gelidium corneum (Gelidiaceae)
Gelidium crinale (Gelidiaceae)
Gelidium latifolium (Gelidiaceae)
Gelidium microdon (Gelidiaceae)
Gelidium pulchellum (Gelidiaceae)
Gelidium pusillum (Gelidiaceae)
Gelidium spinosum (Gelidiaceae)
Pterocladiella Caerulescens (Pterocladiaceae)
Pterocladiella capillacea (Pterocladiaceae)
Gigartina acicularis (Gigartinaceae)
Gigartina pistillata (Gigartinaceae)
Gigartina teedii (Gigartinaceae)
Spirulina platensis (Spirulinaceae)	South Africa^140,141
Chlorococcum littorale (Chlorococcaceae)
Dunaliella salina (Dunaliellaceae)
Scenedesmus magnus (Scenedesmaceae)
Chlorella pyrenoidosa (Chlorellaceae)
Chlorella ellipsoidea (Chlorellaceae)
Gelidium abbotiorum (Gelidiaceae)
Gelidium pristoides (Gelidiaceae)
Gelidium pteridifolium (Gelidiaceae)

Note: Plant family names were retrieved form World Register of Marine Species (WoRMS); https://www.marinespecies.org/index.php.¹⁴²

Some leafy vegetables and wild African fruits (such as baobab, wild berries, and rosehip) have also been credited with prebiotic properties (Table 5). The membership of prebiotic plants doesn't go without the inclusion of roots and tubers. A good number of roots and tubers found throughout the continent have also been categorized as prebiotic plants. These include yam, cassava, potato and ginger among many others.

Table 5.

Some Prebiotic African Wild Fruits, Leafy Vegetables, and Roots and Tubers.

Common name	Scientific name	Part used	Country and Reference
Baobab	Adansonia digitata L.	Ripe Fruit	Africa^128,143
Wild berries	Rubus cuneifolius	Ripe Fruit	Lesotho, Swazilandand South Africa¹²⁸
Rosehip	Rosa rubiginosa	Ripe Fruit
Thistle	Sonchus dregeanus	Leaves
Red pigweed	Amaranthus retroflexus	Leaves
Wild spinach	Chenopodium album	Leaves
Sting nettle plant	Urtica dioica	Leaves
Hare-bell	Wahlengergia androsacea	Leaves
Cape pepper cress	Lepidium capense	Leaves
Wild nemesia	Nemesia fruticans	Leaves
Purples	Berkheya purpurea	Leaves	Africa^128,143
Wild mustard	Sisymbrium thelungii	Leaves	Lesotho, Swaziland and South Africa¹²⁸
Sedge	Cyperus esculentus	Leaves
Thistle	Sonchas integrifolius	Leaves
Wonderberry	Solanum retroflexum	Leaves
Wild jute plant	Corchorus tridens	Leaves
Pigweed	Amaranthus hybridus	Leaves
Sweet potato	Ipomoea batatas	Roots	Africa¹⁴⁰
Yam	Dioscorea alata	Roots
Carrot	Daucus carota L.	Roots
Ginger	Zingiber officinale	Roots
Cassava	Manihot esculenta	Roots
Cocoyam	Xanthosoma sagittifolium	Roots
Taro	Colocasia esculenta	Roots

Conclusion

Irrespective of the large use of ethnomedicinal plants in Africa, not much scientific studies have been done on the use of ethnomedicine for the treatment and management of age-related dementia, viz-a-viz AD. However, both in vivo use and in vitro assessment of African ethnomedicinal plants have demonstrated the potential of these plants in the treatment of dementia and AD-related phenotypes, suggesting that they contain biocompounds that are effective in the prevention and stalling of the progression of AD. Thus, we might be able to find potential plant sources for a novel class of anti-age-related dementia drugs. The ethnomedicinal use of plants as antiviral agents has existed on the African continent for many years. The use of these ethnomedicinal plants by traditional healers, coupled with current research findings, has demonstrated the potential of ethnomedicine as a source for the development of new anti-HSV-1 drugs and possibly a cure. There is therefore the need to conduct further studies on plants that are traditionally used in the treatment of HSV-1 or in the botanical classes of those already identified in order to possibly carry them along the drug development pipeline. Finally, considering the general benefit of prebiotics and probiotics on overall human health, it is certainly of utmost importance to include prebiotics and probiotics in daily food intake. When a good balance is struck between prebiotics and probiotics, optimal synergy is likely to be achieved between prebiotics and probiotics, which will be beneficial to overall host health. This can be achieved by regulating the gut flora using functional food as therapy.

Footnotes

Acknowledgments

Not applicable.

Authors’ Contributions

E.J.T. did the literature search prepared initial draft. M.Y.O.A reviewed the initial draft and included , D.L.S. conducted literature search and made inputs into Tables 1–3, M.M. conducted literature search and made inputs into tables Table 3 and A.O. generated the idea and reviewed the final draft.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethics Approval and Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Materials

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

ORCID iDs

Edward Jenner Tettevi

Augustine Ocloo

References

Alzheimer

Stelzmann

Schnitzlein

Murtagh

. An English translation of Alzheimer’s 1907 paper, ‘Uber eine eigenartige Erkankung der Hirnrinde’. Clin Anat N Y N. 1995;8(6):429‐431. doi:10.1002/ca.980080612.

Deture

Dickson

. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener. 2019;14(1):1‐18. doi:10.1186/s13024-019-0333-5.

Hebert

Beckett

Evans

, et al. Age-specific incidence of Alzheimer’s disease in a community population. JAMA J Am Med Assoc. 1995;273(17):1354‐1359. doi:10/bqdw58.

Schultz

Del Tredici

Braak

. Neuropathology of Alzheimer’s disease. In: Richter

Richter

eds., Alzheimer’s Disease Current Clinical Neurology. Humana Press; 2003:21‐32. doi:10.1385/1-59259-661-4:21

Teixeira

Silva

Andrade

Borges

. Alzheimer’s disease and antioxidant therapy: how long how far? Curr Med Chem. 2013;20(24):2939‐2952. doi:10/f434q3.

Van Duijn

Hofman

. Risk factors for Alzheimer’s disease: the EURODEM collaborative re-analysis of case-control studies. Neuroepidemiology. 1992;11(SUPPL.):106‐113. doi:10/c7xmwz

Luthra

Roy

. Role of medicinal plants against neurodegenerative diseases. Curr Pharm Biotechnol. 2022;23(1):123‐139. doi:10/gn8hrz.

Goedert

Spillantini

. A century of Alzheimer’s disease. Science. 2006;314(5800):777‐781. doi:10/dvczfj.

Hoshi

Sato

Matsumoto

, et al. Spherical aggregates of β-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3β. Proc Natl Acad Sci U S A. 2003;100(11):6370‐6375. doi:10.1073/pnas.1237107100.

10.

Walsh

Selkoe

. Aβ oligomers—A decade of discovery. J Neurochem. 2007;101(5):1172‐1184. doi:10.1111/j.1471-4159.2006.04426.x.

11.

Takahashi

Almeida

Kearney

, et al. Oligomerization of Alzheimer’s β-amyloid within processes and synapses of cultured neurons and brain. J Neurosci. 2004;24(14):3592‐3599. doi:10.1523/JNEUROSCI.5167-03.2004.

12.

Wisniewski

Ghiso

Frangione

. Peptides homologous to the amyloid protein of Alzheimer’s disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. Biochem Biophys Res Commun. 1991;179(3):1247‐1254. doi:10.1016/0006-291X(91)91706-I.

13.

Viola

Velasco

Klein

. Why Alzheimer’s is a disease of memory: the attack on synapses by Aβ oligomers (ADDLs). J Nutr Health Aging. 2008;12(1). doi:10.1007/bf02982587.

14.

Herring

Ambrée

Tomm

, et al. Environmental enrichment enhances cellular plasticity in transgenic mice with Alzheimer-like pathology. Exp Neurol. 2009;216(1):184‐192. doi:10.1016/j.expneurol.2008.11.027.

15.

Dobson

Itzhaki

. Herpes simplex virus type 1 and Alzheimer’s disease. Neurobiol Aging. 1999;20(4):457‐465. doi:10.1016/S0197-4580(99)00055-X.

16.

Marcocci

Napoletani

Protto

, et al. Herpes simplex virus-1 in the brain: the dark side of a sneaky infection. Trends Microbiol. 2020;28(10):808‐820. doi:10.1016/j.tim.2020.03.003.

17.

Protto

Marcocci

Miteva

, et al. Role of HSV-1 in Alzheimer’s disease pathogenesis: a challenge for novel preventive/therapeutic strategies. Curr Opin Pharmacol. 2022;63:102200. doi:10.1016/j.coph.2022.102200.

18.

Wang

Geng

. Alzheimer’s disease hypothesis and related therapies. Transl Neurodegener. 2018;7(1):1‐7. doi:10.1186/s40035-018-0107-y.

19.

Liu

Xie

Meng

Kang

. History and progress of hypotheses and clinical trials for Alzheimer’s disease. Signal Transduct Target Ther. 2019;4(1):29. doi:10.1038/s41392-019-0063-8.

20.

Vogt

Kerby

Dill-McFarland

, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep. 2017;7(1):13537. doi:10/gcgx4f.

21.

Jamieson

Maitland

Wilcock

Craske

Itzhaki

. Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol. 1991;33(4):224‐227. doi:10.1002/jmv.1890330403.

22.

Jamieson

Wilcock

Yates

Itzhaki

. Herpes simplex virus type 1 DNA is present in specific regions of brain from aged people with and without senile dementia of the Alzheimer type. J Pathol. 1992;167(4):365‐368.

23.

Wozniak

Shipley

Combrinck

Wilcock

Itzhaki

. Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer’s disease patients. J Med Virol. 2005;75(2):300‐306. doi:10.1002/jmv.20271.

24.

Baringer

Pisani

. Herpes simplex virus genomes in human nervous system tissue analyzed by polymerase chain reaction. Ann Neurol. 1994;36(6):823‐829. doi:10.1002/ana.410360605.

25.

Gordon

McQuaid

Cosby

. Detection of herpes simplex virus (types 1 and 2) and human herpesvirus 6 DNA in human brain tissue by polymerase chain reaction. Clin Diagn Virol. 1996;6(1):33‐40. doi:10.1016/0928-0197(95)00203-0.

26.

Bertrand

Guillaume

Hellauer

, et al. Distribution of herpes simplex virus type 1 DNA in selected areas of normal and Alzheimer’s disease brains: a PCR study. Neurodegener J Neurodegener Disord Neuroprotection Neuroregeneration. 1993;2:201‐208.

27.

Itzhaki

Maitland

Wilcock

Yates

Jamieson

. Detection by polymerase chain reaction of herpes Simplex virus type 1 (HSV1) DNA in brain of aged normals and Alzheimer’s disease patients. In: Corain

Iqbal

Nicolini

Winblad

Wisniewski

Zatta

eds., Alzheimer’s Disease: Advances in Clin. 1993:97–102.

28.

Pawelec

Barnett

Forsey

, et al. T cells and aging, January 2002 update. Front Biosci. 2002;7:d1056‐d1183. doi:10.1134/S207905701701009X.

29.

Itzhaki

. Herpes simplex virus type 1 and Alzheimer’s disease: increasing evidence for a major role of the virus. Front Aging Neurosci. 2014;6:1‐9. doi:10.3389/fnagi.2014.00202.

30.

Jiang

Huang

Liu

Zhao

. The gut microbiota and Alzheimer’s disease. J Alzheimers Dis. 2017;58(1):1‐15. doi:10/f9xmc2.

31.

Belkaid

Harrison

. Homeostatic immunity and the microbiota—ScienceDirect. Immunity. 2017;46(4):562‐576. doi:10.1016/j.immuni.2017.04.008.Homeostatic.

32.

Jandhyala

Talukdar

Subramanyam

Vuyyuru

Sasikala

Reddy

. Role of the normal gut microbiota. World J Gastroenterol WJG. 2015;21(29):8787‐8803. doi:10/f7pk72.

33.

D’Argenio

Sarnataro

. Microbiome influence in the pathogenesis of prion and Alzheimer’s diseases. Int J Mol Sci. 2019;20(19):4704. doi:10.3390/ijms20194704.

34.

Klingelhoefer

Reichmann

. Pathogenesis of Parkinson disease—the gut–brain axis and environmental factors. Nat Rev Neurol. 2015;11(11):625‐636. doi:10.1038/nrneurol.2015.197.

35.

Bostanciklioğlu

. The role of gut microbiota in pathogenesis of Alzheimer’s disease. J Appl Microbiol. 2019;127(4):954‐967. doi:10.1111/jam.14264.

36.

Lane

Hardy

Schott

. Alzheimer’s disease. Eur J Neurol. 2018;25(1):59‐70.

37.

Roy

. Role of medicinal plants against Alzheimer’s disease. Published online 2018. doi:10/gmpqsn

38.

Desai

Grossberg

. Diagnosis and treatment of Alzheimer’s disease. Neurology. Published online 2005. doi:10/gmmqht

39.

Mintah

Asafo-Agyei

Acher

, et al. We Are IntechOpen, the World ‘ s Leading Publisher of Open Access Books Built by Scientists, for Scientists TOP 1% . Vol 32; 1989.

40.

Ayeni

Gong

Yuan

Bai

Liao

. Medicinal plants for anti-neurodegenerative diseases in West Africa. J Ethnopharmacol. Published online 2021:114468. doi:10.1016/j.jep.2021.114468

41.

Fabricant

Farnsworth

. The value of plants used in traditional medicine for drug discovery. Environ Health Perspect. 2001;109(SUPPL. 1):69‐75. doi:10/dgw3xj

42.

Mahapatra

Bhowmik

Banerjee

Das

Ojha

Chattopadhyay

. Ethnomedicinal wisdom: an approach for antiviral drug development. In: Ahmad Khan

Ahmad

Chattopadhyay

, eds. New Look to Phytomedicine. Academic Press; 2019:35‐61. doi:10.1016/B978-0-12-814619-4.00003-3.

43.

Ahmad

Khalid

. Chapter 3—therapeutic aspects of probiotics and prebiotics. In: Holban

Grumezescu

, eds. Diet, Microbiome and Health. Handbook of Food Bioengineering. Academic Press; 2018:53‐91. doi:10.1016/B978-0-12-811440-7.00003-X.

44.

Adams

Gmünder

Hamburger

. Plants traditionally used in age related brain disorders—A survey of ethnobotanical literature. J Ethnopharmacol. 2007;113(3):363‐381.

45.

Andrieu

Gillette

Amouyal

, et al. Association of Alzheimer’s disease onset with Ginkgo Biloba and other symptomatic cognitive treatments in a population of women aged 75 years and older from the EPIDOS study. J Gerontol Ser A. 2003;58(4):M372‐M377. doi:10/bjpm5h.

46.

Gertz

Kiefer

. Review about Ginkgo Biloba special extract EGb 761 (Ginkgo). Curr Pharm Des. 2003;10(3):261‐264. doi:10/b36ggn.

47.

Hostettmann

Borloz

Urbain

Marston

. Natural product inhibitors of acetylcholinesterase. Curr Org Chem. 2006;10(8):825‐847. doi:10/cm9fhh.

48.

Verger

. Ewé: The Use of Plants in Yoruba Society. Odebrecht; Editora Schwarcz; 1995.

49.

Anyanwu-Ndulewe

Adepoju-Bello

Fageyinbo

Coker

. Extract of the leaves of Hydrolea glabra Schum. & Thonn. (Hydrophyllaceae), exerts anxiolytic effect on Swiss Albino mice. Trop J Nat Prod Res. 2018;2:413‐417. doi:10/gmndms.

50.

Kokwaro

. Medicinal Plants of East Africa. East African Literature Bureau; 1976. Accessed August 28, 2021. http://erepository.uonbi.ac.ke/handle/11295/34820

51.

Tulika

Mala

. Pharmaceutical potential of aquatic plant Pistia stratiotes (L.) and Eichhornia crassipes. J Plant Sci. Special Issue. Medicinal Plants. 2015;3:10–18.

52.

Stafford

. Southern African plants used to treat central nervous system related disorders. Published online 2009:270.

53.

Adewusi

Fouche

Steenkamp

. Cytotoxicity and acetylcholinesterase inhibitory activity of an isolated crinine alkaloid from Boophane disticha (Amaryllidaceae). J Ethnopharmacol. 2012;143(2):572‐578. doi:10.1016/j.jep.2012.07.011.

54.

Aderogba

Ndhlala

Van Staden

. Acetylcholinesterase inhibitors from Croton sylvaticus ethyl acetate leaf extract and their mutagenic effects. Nat Prod Commun. 2013;8(6):1934578X1300800628.

55.

Adewusia

Foucheb

Steenkamp

. Effect of four medicinal plants on amyloid-β induced neurotoxicity in SHSY5Y cells. Afr J Tradit Complement Altern Med. 2013;10(4):6‐11.

56.

Adewusi

Steenkamp

. In vitro screening for acetylcholinesterase inhibition and antioxidant activity of medicinal plants from Southern Africa. Asian Pac J Trop Med. 2011;4(10):829‐835. doi:10.1016/S1995-7645(11)60203-4.

57.

Awuni

Arhin

Frempong

Essegbey

. Ghana Herbal Pharmacopoeia. Science and Technology Policy Research Institute; 2015.

58.

Oboh

Ademosun

Ogunsuyi

Oyedola

Olasehinde

Oyeleye

. In vitro anticholinesterase, antimonoamine oxidase and antioxidant properties of alkaloid extracts from kola nuts (Cola acuminata and Cola nitida). J Complement Integr Med. 2019;16(1):20160155. doi:10.1515/jcim-2016-0155.

59.

Dorothy

. Phytochemistry and Bioactive Natural Products from Lannea Alata, Lannea Rivae, Lannea Schimperi and Lannea Schweinfurthii. University of Kwazulu-Natal; 2014. Accessed May 26, 2022. https://ukzn-dspace.ukzn.ac.za/bitstream/handle/10413/12422/Okoth_Akinyi_Dorothy_2014.pdf?sequence=1&isAllowed=y

60.

Anokwuru

Tankeu

Van vuuren

, et al. Unravelling the antibacterial activity of Terminalia sericea root bark through a metabolomic approach. Molecules. 2020;25:3683. doi:10.3390/molecules25163683.

61.

Hritcu

Noumedem

Cioanca

Hancianu

Kuete

Mihasan

. Methanolic extract of Piper nigrum fruits improves memory impairment by decreasing brain oxidative stress in amyloid Beta(1–42) rat model of Alzheimer’s disease. Cell Mol Neurobiol. 2014;34(3):437‐449. doi:10/f5vjx7.

62.

Ahmed

Salem

Sabry

Husein

Kotob

. Possible therapeutic uses of Salvia triloba and Piper nigrum in Alzheimer’s disease–induced rats. J Med Food. 2013;16(5):437‐446. doi:10.1089/jmf.2012.0165.

63.

Eldeen

IMS

. Pharmacological Investigation of Some Trees Used In South African Traditional Medicine. University of KwaZulu-Natal; 2005. Accessed May 29, 2022. https://ukzn-dspace.ukzn.ac.za/bitstream/handle/10413/5526/Elden_Ibrahim_2005.pdf?sequence=1&isAllowed=y

64.

Bombardelli

Bonati

Gabetta

Mustich

. Triterpenoids of Terminalia sericea. Phytochemistry. 1974;13(11):2559‐2562. doi:10.1016/S0031-9422(00)86936-8.

65.

Foyet

Wado

Hervé

Assongalem

Eyong

. Anticholinesterase and antioxidant potential of hydromethanolic extract of Ziziphus mucronata (Rhamnaceae) leaves on scopolamine-induced memory and cognitive dysfunctions in mice. Evid Based Complement Alternat Med. 2019;2019:1‐14. doi:10.1155/2019/4568401.

66.

Amoateng

Quansah

Karikari

, et al. Medicinal plants used in the treatment of mental and neurological disorders in Ghana. Evid Based Complement Alternat Med. 2018;2018:1‐14. doi:10/gmmqt5.

67.

Sonibare

Ayoola

. Medicinal plants used in the treatment of neurodegenerative disorders in some parts of Southwest Nigeria. Afr J Pharm Pharmacol. 2015;9(38):956‐965. doi:10/gmmq9x.

68.

Kamal

Manmohan

Birendra

. A Review on Chemical and Medicobiological Applications of. Published online 2011:6.

69.

Bizimenyera

Aderogba

Eloff

Swan

. Potential of neuroprotective antioxidant-based therapeutics from Peltophorum africanum Sond.(Fabaceae). Afr J Tradit Complement Altern Med. 2007;4(1):99‐106.

70.

Elisha

Elgorashi

Hussein

Duncan

Eloff

. Acetylcholinesterase inhibitory effects of the bulb of Ammocharis coranica (Amaryllidaceae) and its active constituent lycorine. South Afr J Bot. 2013;85:44‐47. doi:10.1016/j.sajb.2012.11.008.

71.

Ajiwhen

Bisong

. Effect of ethanolic extract of Carpolobia lutea G. Don (polygalaceae) root on learning and memory in CD1 mice. Published online 2013. Accessed August 29, 2021. https://www.researchgate.net/publication/263165628_Effect_of_ethanolic_extract_of_Carpolobia_lutea_G_Don_polygalaceae_root_on_learning_and_memory_in_CD1_mice

72.

Folashade

Adewolu

. Medicinal Plants Used in Management and Treatment of Alzheimer’s Disease in Africa: An Insight into Therapeutic Avenues and Possible Development as Future Phytopharmaceuticals. Published online May 31, 2020. doi:10/gmndqv.

73.

Jilani

Tagwireyi

Gadaga

Maponga

Mutsimhu

. Cognitive-enhancing effect of a hydroethanolic extract of Crinum macowanii against memory impairment induced by aluminum chloride in BALB/c mice. Behav Neurol. 2018;2018:2057219. doi:10.1155/2018/2057219.

74.

Stafford

Pedersen

van Staden

Jäger

. Review on plants with CNS-effects used in traditional South African medicine against mental diseases. J Ethnopharmacol. 2008;119(3):513‐537. doi:10/brcmf6.

75.

Molahloe

. Phytochemical and Bioactivity Investigations on Aptosimum Elongatum Engl. Extracts. 2019. https://scholar.ufs.ac.za/bitstream/handle/11660/10666/MolahloeTS.pdf?sequence=1&isAllowed=y

76.

Ojo

Ajiboye

, et al. HPLC-DAD fingerprinting analysis, antioxidant activities of Tithonia diversifolia (Hemsl.) A. Gray leaves and its inhibition of key enzymes linked to Alzheimer’s disease. Toxicol Rep. 2018;5:585‐592. doi:10.1016/j.toxrep.2018.05.003.

77.

Ekwutosi

Ganiyu

Benneth

Olugbenga

. Evaluation of the memory enhancing activity of dichloromethane fraction of the methanolic extract of Pycnanthus angolensis stem bark on experimental models of memory impairment. Drug Res. 2019;69(10):551‐558.

78.

Elufioye

Obuotor

Agbedahunsi

Adesanya

. Cholinesterase inhibitory activity and structure elucidation of a new phytol derivative and a new cinnamic acid ester from Pycnanthus angolensis | Elsevier Enhanced Reader. https://reader.elsevier.com/reader/sd/pii/S0102695X16300102?token=3A224314D73AA5E10149C8BD3FA9C5743ED1AD2AEA888A94C54EFDB988250C3912F9C84E834D184CC78767BC12229D86&originRegion=eu-west-1&originCreation=20220531153849. doi:10.1016/j.bjp.2016.01.010

79.

Rocha

Rodrigues

Pereira

, et al. Biochemical profile and in vitro neuroprotective properties of Carpobrotus edulis L., a medicinal and edible halophyte native to the coast of South Africa. South Afr J Bot. 2017;111:222‐231. doi:10.1016/j.sajb.2017.03.036.

80.

Elufioye

Oladele

Cyril-Olutayo

Agbedahunsi

Adesanya

. Ethnomedicinal study and screening of plants used for memory enhancement and antiaging in Sagamu, Nigeria. Ethnomedicinal study and screening of plants used for memory enhancement and antiaging in Sagamu, Nigeria. Published 2012. Accessed August 28, 2021. http://catalog.ihsn.org/citations/48500

81.

Ishola

Awoyemi

Afolayan

. Involvement of antioxidant system in the amelioration of scopolamine-induced memory impairment by grains of paradise (Aframomum melegueta K. Schum.) extract. Drug Res. 2016;66(9):455‐463. doi:10.1055/s-0042-109391.

82.

Igado

Olopade

. A review on the possible neuroprotective effects of Moringa oleifera leaf extract. Niger J Physiol Sci. 2016;31(2):183‐187. doi:10.4314/njps.v31i2.

83.

Olasehinde

Olaniran

Okoh

. Aqueous–ethanol extracts of some South African seaweeds inhibit beta-amyloid aggregation, cholinesterases, and beta-secretase activities in vitro. J Food Biochem. 2019;43(7). doi:10/gf3685.

84.

Wang

Zheng

Huang

, et al. Eckmaxol, a phlorotannin extracted from Ecklonia maxima, produces anti-β-amyloid oligomer neuroprotective effects possibly via directly acting on glycogen synthase kinase 3β. ACS Chem Neurosci. 2018;9(6):1349‐1356. doi:10.1021/acschemneuro.7b00527.

85.

Klose

Griehl

Roßner

Schilling

. Natural products from plants and algae for treatment of Alzheimer’s disease: a review. Biomolecules. 2022;12(5):694. doi:10.3390/biom12050694.

86.

Oboh

Ademiluyi

Akinyemi

. Inhibition of acetylcholinesterase activities and some pro-oxidant induced lipid peroxidation in rat brain by two varieties of ginger (Zingiber officinale). Exp Toxicol Pathol. 2012;64(4):315‐319. doi:10/fc7dhv.

87.

Arcusa

Villaño

Marhuenda

Cano

Cerdà

Zafrilla

. Potential role of ginger (Zingiber officinale Roscoe) in the prevention of neurodegenerative diseases. Front Nutr. 2022;9. doi:10.3389/fnut.2022.809621.

88.

Chaitanya

. Structure and organization of virus genomes. Genome Genomics. Published online November 18, 2019:1‐30. doi:10/gm5z5m

89.

Ferreira

Paiva

SSM

Carmo

, et al. Identification of herpesviruses types 1 to 8 and human papillomavirus in acute apical abscesses. J Endod. 2011;37(1):10‐16. doi:10.1016/j.joen.2010.09.009.

90.

Chattopadhyay

Khan

MTH

. Ethnomedicines and ethnomedicinal phytophores against herpesviruses. Biotechnol Annu Rev. 2008;14:297‐348. doi:10.1016/S1387-2656(08)00012-4.

91.

Álvarez

Aldudo

Alonso

Santana

Valdivieso

. Herpes simplex virus type 1 induces nuclear accumulation of hyperphosphorylated tau in neuronal cells. J Neurosci Res. 2012;90(5):1020‐1029. doi:10.1002/jnr.23003.

92.

Akram

Tahir

Shah

SMA

, et al. Antiviral potential of medicinal plants against HIV, HSV, influenza, hepatitis, and coxsackievirus: a systematic review. Phytother Res. 2018;32(5):811‐822. doi:10.1002/ptr.6024.

93.

Rivera

González-Stuart

Ortiz

Rodríguez

Anaya

Meza

. Herbal product use in non-HIV and HIV-positive hispanic patients. J Natl Med Assoc. 2005;97(12):1686‐1691.

94.

Seeff

Curto

Szabo

, et al. Herbal product use by persons enrolled in the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial. Hepatology. 2008;47(2):605‐612. doi:10/cgkz8h.

95.

Newman

Cragg

. Natural Products as Sources of New Drugs over the Last 25 Years. Published 2007. Accessed September 5, 2021. https://click.endnote.com/viewer?doi=10.1021%2Fnp068054v&token=WzQ5MjQ0MCwiMTAuMTAyMS9ucDA2ODA1NHYiXQ.EMSb-Dgre2v3P7NxsQJxZu9_cck

96.

Soltan

Zaki

. Antiviral screening of forty-two Egyptian medicinal plants. J Ethnopharmacol. 2009;126(1):102‐107. doi:10.1016/j.jep.2009.08.001.

97.

Ghazal

ESA

Khamis

IMA

Elhaw

MHM

. Chemical Constituents of Capparis sinaica Veill. Plant and its Antimicrobial Effects. Published online 2015:12.

98.

Babiaka

Moumbock AF

Günther

Ntie-Kang

. Natural products in Cyperus rotundus L. (Cyperaceae): an update of the chemistry and pharmacological activities. RSC Adv. 2021;11(25):15060‐15077. doi:10.1039/D1RA00478F.

99.

Al-Rimawi

Abu-Lafi

Abbadi

Alamarneh

AAA

Sawahreh

Odeh

. Analysis of phenolic and flavonoids of wild ephedra alata plant extracts by LC/PDA and LC/MS and their antioxidant activity. Afr J Tradit Complement Altern Med. 2017;14(2):130‐141. doi:201703290659.

100.

Abd Rani

Husain

Kumolosasi

. Moringa genus: a review of phytochemistry and pharmacology. Front Pharmacol. 2018;9. doi:10.3389/fphar.2018.00108.

101.

Sekkien

Swilam

Ebada

, et al. Polyphenols from Tamarix nilotica: LC–ESI-MSn profiling and in vivo antifibrotic activity. Molecules. 2018;23(6):1411. doi:10.3390/molecules23061411.

102.

Khlifi

Dhaouefi

Toumia

, et al. Erica multiflora extract rich in quercetin-3-O-glucoside and kaempferol-3-O-glucoside alleviates high fat and fructose diet-induced fatty liver disease by modulating metabolic and inflammatory pathways in Wistar rats. J Nutr Biochem. 2020;86:108490. doi:10.1016/j.jnutbio.2020.108490.

103.

Altameme

. A chemical composition of halophyte plant Frankenia pulverulenta L. (Frankeniaceae) in Iraq depending on GC-MS and FT-IR techniques. J Chem Pharm Sci. 2017;10(1):26–33.

104.

Kchaou

Ben

Salah H

Mnafgui

, et al. Chemical composition and biological activities of Zygophyllum album (L.) essential oil from Tunisia. J Agric Sci Technol. 2018.

105.

Belmimoun

Meddah

Larbi

Sonnet

. Phytochemical study of zygophyllum album extract. Int J Eng Technol Manag Res. 2017;4(5):1‐10. doi:10.29121/ijetmr.v4.i5.2017.73.

106.

Moyo

Van Staden

. Medicinal properties and conservation of Pelargonium sidoides DC. J Ethnopharmacol. 2014;152(2):243‐255. doi:10.1016/j.jep.2014.01.009.

107.

Iacovelli

Costanza

Romeo

, et al. Interaction of Pelargonium sidoides compounds with lactoferrin and SARS-CoV-2: insights from molecular simulations. Int J Environ Res Public Health. 2022;19(9):5254. doi:10.3390/ijerph19095254.

108.

Meyer

JJM

Afolayan

Taylor

Engelbrecht

. Inhibition of herpes simplex virus type 1 by aqueous extracts from shoots of Helichrysum aureonitens (Asteraceae). J Ethnopharmacol. 1996;52(1):41‐43. doi:10.1016/0378-8741(96)01387-6.

109.

Vervoort

Steenkamp

Prinsloo

. Metabolomic profile of medicinal plants with anti-RVFV activity. Heliyon. 2022;8(2):e08936. doi:10.1016/j.heliyon.2022.e08936.

110.

Welch

. Chemistry and Pharmacology of Kinkéliba (Combretum Micranthum), a West African Medicinal Plant. Rutgers University—Graduate School—New Brunswick; 2010. doi:10.7282/T3TM7B7P.

111.

Sassi

Bourgougnon

Aouni

. Natural product research : Formerly natural product letters antiviral activity of some tunisian medicinal plants against herpes simplex virus type 1. 2008;(July 2015):37–41.

112.

Ibewuike

Ogungbamila

Ogundaini

Okeke

Bohlin

. Antiinflammatory and antibacterial activities of C-methylflavonols from Piliostigma thonningii. Phytother Res. 1997;11(4):281‐284. doi:10.1002/(SICI)1099-1573(199706)11:4<281::AID-PTR281>3.0.CO;2-9.

113.

Salehi

Gültekin-Özgüven

Kırkın

, et al. Anacardium plants: chemical,nutritional composition and biotechnological applications. Biomolecules. 2019;9(9):465. doi:10.3390/biom9090465.

114.

Alshambaty

Yagi

Elbashir

, et al. Chemical constituents and biological activities of African medicinal tree Sterculia setigera Delile stem bark. South Afr J Bot. 2021;143:274‐281. doi:10.1016/j.sajb.2020.10.008.

115.

Aquino

De Simone

De Tommasi

Pizza

. Structure and biological activity of triterpenoids and aromatic compounds from medicinal plants. Studies in Natural Products Chemistry. 1995;17:113–152. 10.1016/S1572-5995(05)80083-3

116.

Dirar

Devkota

. Ethnopharmacological uses, phytochemistry and pharmacological activities of Guiera senegalensis J.F. Gmel. (Combretaceae). J Ethnopharmacol. 2021;267:113433. doi:10.1016/j.jep.2020.113433.

117.

Schnitzler

Schneider

Stintzing

Carle

Reichling

. Efficacy of an aqueous Pelargonium sidoides extract against herpesvirus. Phytomedicine Int J Phytother Phytopharm. 2008;15(12):1108‐1116. doi:10/bwwtv8.

118.

Tolo

Rukunga

Muli

, et al. Anti-viral activity of the extracts of a Kenyan medicinal plant Carissa edulis against herpes simplex virus. J Ethnopharmacol. 2006;104(1–2):92‐99. doi:10.1016/j.jep.2005.08.053.

119.

Dhatwalia

Kumari

Verma

, et al. Phytochemistry, pharmacology, and nutraceutical profile of Carissa species: an updated review. Molecules. 2021;26(22):7010. doi:10.3390/molecules26227010.

120.

Ferrea

Canessa

Sampietro

Cruciani

Romussi

Bassetti

. In vitro activity of a Combretum micranthum extract against herpes simplex virus types 1 and 2. Antiviral Res. 1993;21(4):317‐325. doi:10.1016/0166-3542(93)90010-G.

121.

Kudi

Myint

. Antiviral activity of some Nigerian medicinal plant extracts. J Ethnopharmacol. 1999;68(1-3):289‐294. doi:10/b3j3v9.

122.

Mintah

Asafo-Agyei

Acher

, et al.. Medicinal Plants for treatment of prevalent diseases. Pharmacognosy-Medicinal Plants 2019.

123.

Luckey

. Introduction to intestinal microecology. Am J Clin Nutr. 1972;25(12):1292‐1294. doi:10/gmkw4x.

124.

Park

Floch

. Prebiotics, probiotics, and dietary fiber in gastrointestinal disease. Gastroenterol Clin North Am. 2007;36(1):47‐63. doi:10.1016/j.gtc.2007.03.001

125.

Vonk

. Manipulation of colonic flora as ecosystem and metabolic organ: consequences for the organism—preface. Scand J Gastroenterol. 1997;32:1‐1.

126.

Sanders

. Probiotics: definition, sources, selection, and uses. Clin Infect Dis. 2008;46(s2):S58‐S61. doi:10/bs58kw.

127.

Bottazzi

. Food and feed production with microorganisms. Biotechnology. 1983;5:315‐363.

128.

Gibson

Roberfroid

. Dietary Modulation of the Human Colonie Microbiota: Introducing the Concept of Prebiotics. Published online 1995:12.

129.

Food and Agriculture Organization of the United Nations, World Health Organization (eds). Probiotics in Food: Health and Nutritional Properties and Guidelines for Evaluation. Food and Agriculture Organization of the United Nations: World Health Organization; 2006.

130.

Kheoane

Tarirai

Gadaga

Leonard

Nyanzi

. Antioxidant and prebiotic activity of selected edible wild plant extracts. J Food Res. 2016;6(1):7. doi:10.5539/jfr.v6n1p7.

131.

Ahmed

Wang

Anjum

Ahmad

Raza

. Characterization of new exopolysaccharides produced by coculturing of L. kefiranofaciens with yoghurt strains. Int J Biol Macromol. 2013;59:377‐383. doi:10/f43686.

132.

Wang

. Prebiotics: present and future in food science and technology. Food Res Int. 2009;42(1):8‐12. doi:10/cr2vjd.

133.

Kechagia

Basoulis

Konstantopoulou

, et al. Health benefits of probiotics: a review. ISRN Nutr. 2013;2013:481651. doi:10/gb668q.

134.

Ukeyima

Enujiugha

. Current applications of probiotic foods in Africa. Afr J Biotechnol. 2010;9(4):394‐401.

135.

Kouhounde

Coulibaly

Kifouli

, et al. Trends in Probiotic Applications 6 Probiotics: A Sustainable Option for Food Safety and Preservation in Africa Probiotics: A Sustainable Option for Food Safety and Preservation. 2018.

136.

Stanton

Gardiner

Meehan

, et al. Market potential for probiotics. Am J Clin Nutr. 2001;73(2 Suppl):476S‐483S. doi:10/gn8svm

137.

Ansong

. Probiotic potential of traditional fermented foods in Ghana. Published online 2020:3.

138.

Franz

CMAP

Huch

Mathara

, et al. African fermented foods and probiotics. Int J Food Microbiol. 2014;190:84‐96. doi:10/f6mjx7.

139.

Rousseau

Lepargneur

Roques

Remaud-Simeon

Paul

. Prebiotic effects of oligosaccharides on selected vaginal lactobacilli and pathogenic microorganisms. Anaerobe. 2005;11(3):145‐153. doi:10/fq88qm.

140.

Charoensiddhi

Abraham

Zhang

. Chapter four—seaweed and seaweed-derived metabolites as prebiotics. In: Toldrá

, ed. Advances in Food and Nutrition Research, Vol. 91. Academic Press; 2020:97‐156. doi:10.1016/bs.afnr.2019.10.001

141.

Hadebe

. Isolation and Characterization of Prebiotic Oligosaccharides from Algal Extracts and Their Effect on Gut Microflora . 2016.

142.

WoRMS Editorial Board. WoRMS—World Register of Marine Species. Published 2022. Accessed June 1, 2022. https://www.marinespecies.org/index.php

143.

Mokoena

Mutanda

Olaniran

. Perspectives on the probiotic potential of lactic acid bacteria from African traditional fermented foods and beverages. Food Nutr Res. 2016;60(1):29630. doi:10.3402/fnr.v60.29630.