Atrazine Toxicity: The Possible Role of Natural Products for Effective Treatment.

There are various herbicides which were used in the agriculture industry. Atrazine (ATZ) is a chlorinated triazine herbicide that consists of a ring structure, known as the triazine ring, along with a chlorine atom and five nitrogen atoms. ATZ is a water-soluble herbicide, which makes it capable of easily infiltrating into majority of the aquatic ecosystems. There are reports of toxic effects of ATZ on different systems of the body but, unfortunately, majority of these scientific reports were documented in animals. The herbicide was reported to enter the body through various routes. The toxicity of the herbicide can cause deleterious effects on the respiratory, reproductive, endocrine, central nervous system, gastrointestinal, and urinary systems of the human body. Alarmingly, few studies in industrial workers showed ATZ exposure leading to cancer. We embarked on the present review to discuss the mechanism of action of ATZ toxicity for which there is no specific antidote or drug. Evidence-based published literature on the effective use of natural products such as lycopene, curcumin, Panax ginseng, Spirulina platensis, Fucoidans, vitamin C, soyabeans, quercetin, L-carnitine, Telfairia occidentalis, vitamin E, Garcinia kola, melatonin, selenium, Isatis indigotica, polyphenols, Acacia nilotica, and Zingiber officinale were discussed in detail. In the absence of any particular allopathic drug, the present review may open the doors for future drug design involving the natural products and their active compounds.

Immunosuppressive Effects of Annona muricata L. Leaf Extract on Cellular and Humoral Immune Responses in Male Wistar Rats.

BACKGROUND: Annona muricata L. (Annonaceae) (AM)'s remarkable anti-inflammatory and anti-cancer activities make it a targeted plant to be explored for its immunomodulatory properties. Traditional practitioners have employed various components of AM to cure a variety of ailments, including cancer, diabetes, and inflammation. OBJECTIVE: The present study evaluated the immunosuppressive effects of 80% ethanol extract of of AM leaves in male Wistar rats on different parameters of humoral and cellular immune responses. METHODS: AM leaf extract (AMLE) was analyzed using UHPLC-MS/MS to profile its secondary metabolites. AMLE was rich in polyphenols which include (epi)catechin-(epi)catechin-(epi) catechin, caffeic acid, coumaroylquinic acid, hyperin, kaempferol, quinic acid and rutin. The rats were administered 100, 200 and 400 mg/kg bw of the extract daily for 14 days. The effects of AMLE on innate immune responses were determined by evaluating phagocytosis, neutrophils migration, reactive oxygen species (ROS) release, CD11b/CD18 integrin expression, and ceruloplasmin, lysozyme and myeloperoxidase (MPO) levels. The adaptive immune parameters were evaluated by immunizing the rats with sheep red blood cells (sRBC) on day 0 and administered orally with AMLE for 14 days. RESULTS: AMLE established significant immunosuppressive effects on the innate immune parameters by inhibiting the neutrophil migration, ROS production, phagocytic activity and expression of CD11b/CD18 integrin in a dose-dependent pattern. AMLE also suppressed ceruloplasmin, MPO and lysozyme expressions in the rat plasma dose-dependently. AMLE dose-dependently inhibited T and B lymphocytes proliferation, Th1 and Th2 cytokine production, CD4+ and CD8+ co-expression in splenocytes, immunoglobulins (IgM and IgG) expression and the sRBC-induced swelling rate of rat paw in delayed-type hypersensitivity (DTH). CONCLUSION: The strong inhibitory effects on the different parameters of humoral and cellular responses indicate that AMLE has potential to be an important source of effective immunosuppressive agents.

Treatment of Glaucoma with Natural Products and Their Mechanism of Action: An Update.

Glaucoma is one of the leading causes of irreversible blindness. It is generally caused by increased intraocular pressure, which results in damage of the optic nerve and retinal ganglion cells, ultimately leading to visual field dysfunction. However, even with the use of intraocular pressure-lowering eye drops, the disease still progresses in some patients. In addition to mechanical and vascular dysfunctions of the eye, oxidative stress, neuroinflammation and excitotoxicity have also been implicated in the pathogenesis of glaucoma. Hence, the use of natural products with antioxidant and anti-inflammatory properties may represent an alternative approach for glaucoma treatment. The present review highlights recent preclinical and clinical studies on various natural products shown to possess neuroprotective properties for retinal ganglion cells, which thereby may be effective in the treatment of glaucoma. Intraocular pressure can be reduced by baicalein, forskolin, marijuana, ginsenoside, resveratrol and hesperidin. Alternatively, Ginkgo biloba, Lycium barbarum, Diospyros kaki, Tripterygium wilfordii, saffron, curcumin, caffeine, anthocyanin, coenzyme Q10 and vitamins B3 and D have shown neuroprotective effects on retinal ganglion cells via various mechanisms, especially antioxidant, anti-inflammatory and anti-apoptosis mechanisms. Extensive studies are still required in the future to ensure natural products' efficacy and safety to serve as an alternative therapy for glaucoma.

Natural Product-based Nanomedicine: Recent Advances and Issues for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) affects the elderly and is characterized by progressive neurodegeneration caused by different pathologies. The most significant challenges in treating AD include the inability of medications to reach the brain because of its poor solubility, low bioavailability, and the presence of the blood-brain barrier (BBB). Additionally, current evidence suggests the disruption of BBB plays an important role in the pathogenesis of AD. One of the critical challenges in treating AD is the ineffective treatments and their severe adverse effects. Nanotechnology offers an alternative approach to facilitate the treatment of AD by overcoming the challenges in drug transport across the BBB. Various nanoparticles (NP) loaded with natural products were reported to aid in drug delivery for the treatment of AD. The nano-sized entities of NP are great platforms for incorporating active materials from natural products into formulations that can be delivered effectively to the intended action site without compromising the material's bioactivity. The review highlights the applications of medicinal plants, their derived components, and various nanomedicinebased approaches for the treatment of AD. The combination of medicinal plants and nanotechnology may lead to new theragnostic solutions for the treatment of AD in the future.

Beneficial effects of natural products on female sexual dysfunction: A systematic review and meta-analysis.

BACKGROUND: Female sexual dysfunction (FSD) includes female orgasmic disorder, female sexual interest or arousal disorder, and genito-pelvic pain or penetration disorder. FSD affects 40% of women worldwide, but it is understudied and likely undertreated. Natural products are frequently used by women to treat FSD, but scientific evidence of their efficacy is lacking. OBJECTIVE: This systematic review and meta-analysis focused on the study of the efficacy of natural products on FSD. STUDY DESIGN: Systematic review and meta-analysis of existing studies on natural products in the treatment of FSD. METHODS: The literature search included MEDLINE, EMBASE, PsycINFO, and the Cochrane Central Register of Controlled Trial databases for studies published from January 2000 to February 2020. The quality and the level of evidence of the studies were assessed. The association between natural products and FSD was summarized using standardized mean differences (SMD) with a 95% confidence interval (CI). RESULTS: A total of 536 studies were identified, with 20 of them meeting the criteria. According to this meta-analysis, Tribulus terrestris showed a significant positive effect in improving overall female sexual function (SMD = 1.12, 95% CI = 0.46 - 1.79, p = 0.001) and individual sexual arousal (SMD = 1.03, 95% CI = 0.22 - 1.84, p = 0.013), sexual desire (SMD = 1.08, 95% CI = 0.52 - 1.63, p ≤ 0.001) and sexual orgasm (SMD = 0.51, 95% CI = 0.02 - 1.00, p = 0.040) domains compared to placebo. Panax ginseng was found to be effective in treating sexual arousal (SMD = 0.54, 95% CI = 0.11 - 0.97, p = 0.014) and sexual desire (SMD = 0.59, 95% CI = 0.27 - 0.90, p < 0.001) compared to placebo. Meanwhile, other natural products reviewed in this study, such as Trifolium pretense, did not differ significantly from placebo in terms of improving FSD. CONCLUSION: Preliminary evidence suggests that Tribulus terrestris and Panax ginseng may be effective as alternative treatments for FSD in a clinical setting.

Co-Morbid Erectile Dysfunction (ED) and Antidepressant Treatment in a Patient - A Management Challenge?

Throughout the world, antidepressants (AD) and phosphodiesterase-5 inhibitors (PDE-5i) are the commonly prescribed psychopharmacological agents for treating patients with co-morbid mental health problem and sexual dysfunction (SD). The serotonergic and noradrenergic ADs, although effective, are not without any SD adverse-effects, especially erectile dysfunction (ED). ED is a failure to obtain a satisfactory erection for rewarding sexual coitus during the phases of male's sexual arousal. It is recognized as an important reason why non-adherence to treatment was observed in patients who were on AD. AD intervention caused remission to some of the pre- treatment psychopathology of ED. However, in many patients, AD potentially magnified the unwanted sexual sideeffects. This made the situation challenging for the mental health professional. These challenges are based on the complexity of ED, its etiology and the associated risk factors, which further add to its AD side-effect. The neuro-psychopharmacological basis for AD treatment selection was deliberated. Bio-psycho-social interventions are recommended at two pivotal stages. Firstly, a step should be taken for proper assessment (e.g. detailed history, psychosocial and laboratory investigations); and identify few modifiable risk factors for ED and associated mental health issues. Secondly, with guidance of an algorithm pathway, a practical intervention should include strategies such as dose reduction, augmentation or changing to an AD with lesser or no sexual adverse-effects. It is recommended that bupropion and mirtazepine to be prescribed when patients develop adverse sexual effects with serotonin selective reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI) and tricyclic antidepressant (TCA). Few suggestions which may be borne in mind are revising sexual scripts and improving sexual techniques, life-style modifications, psychotherapy and other nonpharmacological approaches which may be beneficial to both patients and their partners.

Kratom and Future Treatment for the Opioid Addiction and Chronic Pain: Periculo Beneficium?

Kratom (Mitragyna speciosa), a naturally existing plant found in South-East Asia, is traditionally used as a herb to help elevate a person's energy and also to treat numerous medical ailments. Other than the analgesic property, kratom has been used as an agent to overcome opioid withdrawal as it contains natural alkaloids, i.e. mitragynine, 7-hydroxymitragynine, and MGM-9, which has agonist affinity on the opioid receptors, including mu (µ) and kappa (κ). The role of neural reward pathways linked to µ-opioid receptors and both dopaminergic and gamma-Aminobutyric acid (GABA)-ergic interneurons that express µ-opioid receptors were deliberated. However, kratom has been reported to be abused together with other illicit substances with high risk of potential addiction. There are also anecdotes of adverse effects and toxicity of kratom, i.e. tremor, fatigue, seizure, and death. Different countries have distinctive regulation and policy on the plantation and use of this plant when most of the countries banned the use of it because of its addiction problems and side effects. The aim of this review is to highlight on the potential use of kratom, unique 'herbs" as a substitution therapy for chronic pain and opioid addiction, based on the neurobiological perspective of pain and the underlying mechanism of actions of drug addiction.

Molecular Concept of Diabetic Wound Healing: Effective Role of Herbal Remedies.

The incidence of diabetes mellitus (DM) is on the rise, worldwide. One of the main complications in DM is delayed wound healing and it often requires amputation. Various drugs were used to treat DM but they presented with adverse effects. Often, patients failed to comply with such treatment. This opened the door for complementary and alternative medicine. In the present review, we explored the molecular concept of wound healing occurring in different stages with special emphasis to DM. We also highlighted the potential herbal products such as NF3 (Chinese 2-Herb Formula), Zicao, Jing Wan Hong ointment, Aleo vera, mixture of Adiantum capillus-veneris, Commiphora molmol, Aloe vera, and henna, Phenol-rich compound sweet gel, Jinchuang ointment, San-huang-sheng-fu (S) oil, Yi Bu A Jie extract, Astragali Radix (AR) and Rehmanniae Radix (RR), Yiqi Huayu, Tangzu yuyang ointment, Shengji Huayu recipe, Angelica sinensis, Lithospermun erythrorhison, Hippophae rhamnoides L., Curcuma longa and Momordica charantia that could be used effectively to treat DM wounds. Future clinical trials are needed for designing potential drugs which may be effective in treating DM wounds.

Virgin coconut oil and diabetic wound healing: histopathological and biochemical analysis

Delayed wound healing (the diabetic ulcer) is one of the major complications of diabetes mellitus (DM), which has shown an increasing trend over previous decades to affect almost 15% of diabetic patients. Virgin coconut oil (VCO) is a natural oil rich in vitamins and antioxidants and possesses antimicrobial and antiviral activities. In the current study, we evaluated the effects of topical application of VCO on wound healing in diabetes-induced Sprague-Dawley rats. A total of 72 animals were divided into 4 groups: i.e. (I) non-diabetic nontreated (NN), (II) diabetic non-treated (DN), (III) diabetic treated with VCO (VCO), and (IV) diabetic treated with silver sulfadiazine cream (SS). Wounds were inflicted on all groups using punch biopsy needles, and the animals were treated for 14 days. Wound closure rate (WCR) was measured on day 5, 10, and 14. Histological analysis was performed on day 7 and 14. Total protein content and superoxide dismutase (SOD) activity were measured on day 1, 7, and 14. WCR in VCO group was higher on all days compared to DN. Histological analysis revealed that VCO promoted re-epithelialization and increased collagen content of wound tissue. Total protein content in VCO group was higher on day 7 and 14 compared to both DN and SS groups. VCO showed insignificant effects on SOD levels. In summary, VCO was found to be better than silver sulfadiazine cream in the healing of diabetic wounds via promoting reepithelialization and collagen synthesize as well as increasing WCR and total protein content

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Herbs for Effective Treatment of Diabetes Mellitus Wounds: Medicinal Chemistry and Future Therapeutic Options.

The incidence of diabetes mellitus (DM) has increased globally. Various complications such as blindness, nephropathy leading to renal failure, neuropathy, foot ulceration, amputation, and disturbance in autonomic nervous system were reported. Although, allopathy treatment still remains the treatment of choice, there is a need to look at the easy availability, patient compliance and cheaper cost of the drugs used in day-day practice. In this regard, complementary and alternative medicine has a greater role to play. Numerous plant extracts were shown to exhibit antihyperglycemic properties. In the present review, we surfed published literature in Pubmed and google databases with regard to the herbs used for DM wound treatment. We also discuss the possible mechanism of wound healing in DM with regard to advanced glycation end products, inflammation, macrophages, non-leukocytic cells such as keratinocytes, fibroblasts and endothelial cells, matrix metalloproteinase and miRNA. The review opens the door for effective treatment of DM wounds with plant extracts and plan future treatment options.

Emerging Trends On Drug Delivery Strategy of Momordica charantia against Diabetes and its Complications.

BACKGROUND: The incidence of diabetes mellitus has increased drastically over the past few decades. This oxidant-antioxidant imbalance resulting in complication of diabetes mellitus includes macro- and microvascular complications. Resistance to conventional treatment and patient compliance has paved the way to the usage of effective natural products and supplements. Momordica charantia (bitter gourd) is widely consumed in many parts of Malaysia as a vegetable. Momordica charantia (MC) is mainly used in the management of diabetes mellitus. OBJECTIVE: The present review discusses the literature concerning the antidiabetic and antioxidant properties of MC focusing on the complication of diabetes mellitus along with its mode of delivery. We found that among the whole part of MC, its fruit extract has been widely studied, therapeutically. The evidence based analysis of the beneficiary effects of MC on the different organs involved in diabetes complication is also highlighted. This review elucidated an essential understanding of MC based drug delivery system in both clinical and experimental studies and appraised the great potential of the protein based MC extract against diabetes mellitus. CONCLUSION: The review paper is believed to assist the researchers and medical personnel in treating diabetic associated complications.

Changes in blood pressure, vascular reactivity and inflammatory biomarkers following consumption of heated corn oil.

Consumption of corn oil for cooking purpose is gaining popularity. The present study examined the effect of heated corn oil on blood pressure and its possible mechanism in experimental rats. Thirty male Sprague-Dawley rats were randomly divided into 5 groups and were fed with the following diets, Group I was fed with basal diet only; whereas group II,III,IV and V were fed with basal diet fortified with 15% (w/w) either fresh, once-heated, five-times-heated or ten-times-heated corn oil, respectively for 16 weeks. Body weight, blood pressure were measured at baseline and weekly interval for 16 weeks. Inflammatory biomarkers which included soluble intracellular adhesion molecules (sICAM), soluble vascular adhesion molecules (sVCAM) and C reactive protein (CRP), were measured at baseline and the end of 16 weeks. The rats were sacrificed and thoracic aorta was taken for measurement of vascular reactivity. There was significant increase in the blood pressure in the groups fed with heated once, five-times (5HCO) and ten-times-heated corn oil (10-HCO) compared to the control. The increase in the blood pressure was associated with an increase in CRP, sICAM and sVCAM, reduction in vasodilatation response to acetylcholine and greater vasoconstriction response to phenylephrine. The results suggest that repeatedly heated corn oil causes elevation in blood pressure, vascular inflammation which impairs vascular reactivity thereby predisposing to hypertension. There is a need to educate people not to consume corn oil in a heated state.

Piper betel leaves induces wound healing activity via proliferation of fibroblasts and reducing 11ß hydroxysteriod dehydrogenase-1 expression in diabetic rat.

BACKGROUND: Increased oxidative stress and stress enzyme 11ß hydroxysteriod dehydrogenase-1 (11ß HSD-1) served as the major contributing factors for delayed wound healing in diabetes mellitus (DM). Piper betel (PB) leaves are reported to possess anti-diabetic, anti-oxidant and anti-microbial properties. OBJECTIVE: The objective was to investigate the effectiveness of topical application of PB leaves extract on oxidative stress and 11ß hydroxysteriod dehydrogenase-1 (11ß HSD-1) expression in diabetic wounds. MATERIALS AND METHODS: A total 64 male Sprague-Dawley rats were randomly chosen. The experimental rats received a single intramuscular injection of streptozotocin (45 mg/kg). Four full thickness (6 mm) wounds were created on the dorsum of each rat. The animals were equally divided (n = 8) into four groups based on the days of treatment (i.e. days 3 and 7): Control (Ctrl), diabetic untreated (DM-Ctrl), diabetic treated with 1% silver nitrate cream (DM-SN) and diabetic treated with 50 mg/kg of P. betel leaves extract (DM-PB). The rats were sacrificed on day 3 and 7 of post wound creations. RESULTS: Following day 7 wound creation, topical application of PB extract showed significant increase in hydroxyproline content, superoxide dismutase (SOD) level and decreased malondialdehyde (MDA) level, 11ß-HSD-1 enzyme expression in the diabetic wounds compared to untreated diabetic wounds. The results were supported by the observations based on histological and ultrastructural features of the wound tissue applied with PB extract. CONCLUSION: PB leaves extract improved the delayed wound healing in diabetes mellitus by decreasing the oxidative stress markers and 11ß HSD-1 expression.

Herbal Supplements and Hepatotoxicity: A Short Review.

Herbal products have gained popularity over the past few decades. The reasons attributed to the rise in popularity are cheaper costs, easy availability, patient compliance and fewer side effects. However, liver toxicity following consumption of herbal remedies is on the increase. Thus, there is an urgent need to understand the mechanism of action of the herbal supplements on the liver. Occasionally, herbal supplements may also interact with conventional drugs. The present review focusses on a few herbs such as Aloe barbadensis, Atractylis gummifera, Centella asiatica, Mitragyna speciosa, Morinda citrifolia, Larea tridentata, Symphytum officinale, Teucrium chamaedrys and Xanthium strumarium, which are reported to cause hepatotoxicity in humans and animals. Prior knowledge on hepatotoxicity caused by herbs may be beneficial for clinicians and medical practitioners.

Effects of the phytoestrogen genistein on the development of the reproductive system of Sprague Dawley rats.

OBJECTIVES: Genistein is known to influence reproductive system development through its binding affinity for estrogen receptors. The present study aimed to further explore the effect of Genistein on the development of the reproductive system of experimental rats. METHODS: Eighteen post-weaning female Sprague Dawley rats were divided into the following groups: (i) a control group that received vehicle (distilled water and Tween 80); (ii) a group treated with 10 mg/kg body weight (BW) of Genistein (Gen 10); and (iii) a group treated with a higher dose of Genistein (Gen 100). The rats were treated daily for three weeks from postnatal day 22 (P22) to P42. After the animals were sacrificed, blood samples were collected, and the uteri and ovaries were harvested and subjected to light microscopy and immunohistochemical study. RESULTS: A reduction of the mean weekly BW gain and organ weights (uteri and ovaries) were observed in the Gen 10 group compared to the control group; these findings were reversed in the Gen 100 group. Follicle stimulating hormone and estrogen levels were increased in the Gen 10 group and reduced in the Gen 100 group. Luteinizing hormone was reduced in both groups of Genistein-treated animals, and there was a significant difference between the Gen 10 and control groups (p<0.05). These findings were consistent with increased atretic follicular count, a decreased number of corpus luteum and down-regulation of estrogen receptors-a in the uterine tissues of the Genistein-treated animals compared to the control animals. CONCLUSION: Post-weaning exposure to Genistein could affect the development of the reproductive system of ovarian-intact experimental rats because of its action on the hypothalamic-pituitary-gonadal axis by regulating hormones and estrogen receptors.

Effects of the phytoestrogen genistein on the development of the reproductive system of Sprague Dawley rats

OBJECTIVES: Genistein is known to influence reproductive system development through its binding affinity for estrogen receptors. The present study aimed to further explore the effect of Genistein on the development of the reproductive system of experimental rats. METHODS: Eighteen post-weaning female Sprague Dawley rats were divided into the following groups: (i) a control group that received vehicle (distilled water and Tween 80); (ii) a group treated with 10 mg/kg body weight (BW) of Genistein (Gen 10); and (iii) a group treated with a higher dose of Genistein (Gen 100). The rats were treated daily for three weeks from postnatal day 22 (P22) to P42. After the animals were sacrificed, blood samples were collected, and the uteri and ovaries were harvested and subjected to light microscopy and immunohistochemical study. RESULTS: A reduction of the mean weekly BW gain and organ weights (uteri and ovaries) were observed in the Gen 10 group compared to the control group; these findings were reversed in the Gen 100 group. Follicle stimulating hormone and estrogen levels were increased in the Gen 10 group and reduced in the Gen 100 group. Luteinizing hormone was reduced in both groups of Genistein-treated animals, and there was a significant difference between the Gen 10 and control groups (p<0.05). These findings were consistent with increased atretic follicular count, a decreased number of corpus luteum and down-regulation of estrogen receptors-a in the uterine tissues of the Genistein-treated animals compared to the control animals. CONCLUSION: Post-weaning exposure to Genistein could affect the development of the reproductive system of ovarian-intact experimental rats because of its action on the hypothalamic-pituitary-gonadal axis by regulating hormones and estrogen receptors.