Insights into New Therapeutic Approaches for the Treatment and Management of Polycystic Ovary Syndrome: An Updated Review.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a long-term, highly prevalent, complex heterogeneous, polygenic endocrine disorder characterized by both metabolic and reproductive disorders. It affects 6-23% of reproductive-age women globally. OBJECTIVE: This review aims to facilitate an understanding of novel PCOS management approaches and highlight the results from relevant interventional animal and human studies. METHODS: Manual search on PubMed, Cochrane, and Scopus databases was performed for relevant articles, preclinical and clinical trials based on related keywords. RESULTS: According to a multitude of studies, PCOS has evolved over time, but a substantial lag remains in management approaches. New insights into the cross-talk between muscle, brain, fat, and ovaries pointed out new therapeutic targets. This review has highlighted the efficacy of a wide spectrum of novel therapeutic agents [Phosphodiesterase-4 Inhibitors, Glucagon-like peptide-1 receptor agonists, nutritional supplements (Vitamins D and K, omega-3, prebiotics, probiotics and synbiotics), fecal microbiota transplantation (FMT) and intestinal cytokine IL-22] as PCOS therapeutic options. These novel therapies combine anti-inflammatory, insulinsensitizing, and anti-obesity activities, along with the restoration of the gut microbiota and thus hold the potential to address the basic pathogenic mechanisms of PCOS. CONCLUSION: Exhaustive, multicentric and multiethnic studies are vital to generating a network of normative data to better figure out the PCOS trajectory and change prognostic outcomes. Preclinical and clinical data are warranted to corroborate the new therapeutics and direct health care resources accordingly.

Ethnobotanical and conservation studies of tree flora of Shiwalik mountainous range of District Bhimber Azad Jammu and Kashmir, Pakistan.

The present study was carried out to explore and document traditional ethnobotanical knowledge of indigenous rural communities of Shiwalik mountainous range regarding tree flora of the area, District Bhimber of Azad Jammu and Kashmir, Pakistan. The local people of the area primarily depend on wild flora for life sustenance and cure of different infirmities. In this research, data was collected through visual appraisal and participatory rural approach using questionnaire method by applying semi-structured and structured-interview protocols (S4 Table). To validate and explore novelty of research work, various quantitative ethnobotanical indices like informant consensus factor, use value index, fidelity level, relative frequency of citation, relative importance of plants, rank order of priority, Jaccard index and priority ranking were used. The highest ICF was found for jaundice with 0.91 value followed by ICF values of 0.89, 0.86 and 0.85 for wounds, skin diseases and stomach pains, respectively. Fidelity level predicted that Azadirachta indica (Indian lilac tree) ranked first (100%) for its prevalent use in ethnomedicines. Highest use value index (0.61) was found for Azadirachta indica while the highest relative frequency of citation (55) was measured for Melia azedarach. The relative order of priority index was the highest for Azadirachta indica and Acacia arabica L. (ROP = 100) depicting their prevalent use in ethnomedicines. For EB study, the highest relative importance (50.8) was found for Azadirachta indica with good number of agro-uses and its seeds and bark are sold or marketed in local markets to prepare herbal therapeutics by indigenous practioners. The Jaccard index depicted that many traditional ethnomedicinal uses of prescribed trees were novel in recipe form or first time reported such as Senegalia modesta (Phulai) resin was used to prepare 'Panjoori' a local tonic prepared from cow or buffalo butter mixing with seeds of Papaver somnifera (Kashkhash) and Prunus amygdalus (Badaam). The wood of many trees like Pinus roxburghii (pine), Dalbergia sissoo (rosewood), Senegalia modesta (Phulai), Acacia. Arabica (kikar), Bombax cieba (cotton tree) is commercially sold as timber in markets (S3 Table). The research proved that population explosion and climate changes have triggered severe biotic and abiotic pressure on tree flora of the study area of Bhimber, AJK. The research describes that plants like Terminalia belerica (belerica), Terminalia arjuna (arjun tree), Cassia fistula (Indian laburnum), Butea monosperma (bastard teak), Phyllanthus emblica (Indian gooseberry), Morus laevigata (Shah toot), Bauhinia variegata (orchid tree) and Flacourtia indica (Indian plum/ kakoo) are threatened species and their population is highly reduced and if reclamation measures for their conservation are not taken, it may lead towards their complete loss from the area. This research recommends sustainable ethnobotanical use of tree flora, their growth and conservation for green and ecofriendly environment for safe and secure future of human generation.

The modulation of PI3K/Akt pathway by 3ß hydroxylup-12-en-28-oic acid isolated from Thymus linearis induces cell death in HCT-116 cells.

The presence of intricate carbon skeletons in natural compounds enhances their bioactivity spectrum with unique modes of action at several targets in various dreadful diseases like cancer. The present study was designed to purify the molecules from Thymus linearis and elucidate their antiproliferative activity. The compounds were isolated from the active methanolic extract of Thymus linearis through column chromatography and characterized by various spectroscopic techniques. Antiproliferative activity of isolated compounds was evaluated using MTT assay on cancer and normal cell lines. Mechanism of cell death was elucidated using flow cytometric, microscopic, and Western blot analysis. Four compounds, Sitosterol, Chrysin, 3ß-hydroxylup-12-en-28-oic acid (3BH), and ß-Sitosterol glycoside, were isolated. Among these, 3BH was most potent antiproliferative agent across all cell lines under study, HCT-116 being the most affected one. 3BH was demonstrated to downregulate PI3Ksubunits (p110α and p85α), downstream pAktSer473 and prompted G1 phase cell cycle arrest. The cell cycle CDK inhibitor p27 and p21 were upregulated with simultaneous downregulation of cyclin D1 and cyclin E in HCT-116 cells. This was accompanied by apoptosis, as depicted by decrease in Bcl-2/Bax ratio, with increase in active caspases-3 and caspase-9, cleavage of PARP-1, the generation of reactive oxygen species (ROS), and the loss of mitochondrial membrane potential. The findings established that 3BH induced cell death in HCT-116 cells by modulating PI3K/Akt signaling axis, impeding cell cycle, and instigating apoptosis.

Inventorization of traditional ethnobotanical uses of wild plants of Dawarian and Ratti Gali areas of District Neelum, Azad Jammu and Kashmir Pakistan.

BACKGROUND: An ethnobotanical expedition was conducted to document the traditional ethnobotanical (TEB) uses of wild flora of Dawarian and Ratti Gali villages of District Neelam, Azad Jammu and Kashmir (AJK) Pakistan. District Neelam has rich plant diversity and is hub of many endemic plant species while the study areas are not yet explored. The research area: Dawarian and Rati Gali (DRG) area is mountaineous terrain and villages are located on far and farther distances. DRG area has rich biocultural and plant diversity comprising of different ethnic groups of Kashmir state. The current research was aimed to explore and document traditional medicines (TEMs) and other domestic and commercial uses of wild plants. This study will assist to evaluate conservation and commercial worth of wild flora which can be potential candidate for drug discovery through ethnopharmacological analysis. METHODS: The current quantitative ethnobotanical research was carried out in 2018 by interviewing 150 indigenous informants (90 male and 60 female) of DRG area using questionnaire applying structured and semi structured interview methodology. Data analysis was analyzed by using quantitative ethnobotanical statistical tools such as fidelity level (FL), informant consensus factor (ICF), Spearman's rank correlation (SRC) and data matrix ranking (DMR). RESULTS: The indigenous people of DRG area use wild plants in their daily life to cope life necessities i.e. food, vegetables, fodder, fuel, shelter, timber and herbal medicines. TEMs are primarily used to cure different infirmities like diabetics, asthma, dysentery, constipation, cold, fever, joint pain, wound healing, cancer, cardiovascular disorders, epilepsy, kidney infections and many types of skin diseases. Current study revealed the data of 103 wild plants species belonging to 46 plant families from selected areas of District Neelum, AJK. Results depicted that Asteraceae ranked 1st (12 plants spp). Among plant parts used leaf ranked 1st (18%), followed by seed (17%) and root (13%). While prevalent form recipe mode was decoction (20%), followed by powder (17%) and extract (14%) and fodder was highest (37%) EB use-form fodder, followed by food (32%) and fuel (17%). Quantitative ethnobotanical analysis (QEA) was carried to find the reliability and novelty of the study. Five plant species including Berberis lyceum (FL = 97.78%), Isodon rugosus (FL = 95.71%), Saussurea lappa (FL = 94.74%), Aconitum heterophyllum (FL = 92.71%) and Taxus baccata (91.58%) had shown high fidelity level which confirmed that these plants have high medicinal worth in study area. The highest value (0.94) of ICF was for diseases group "tuberculosis and leucorrhea", followed by stomachache and flatulence (0.93), diabetics and blood pressure (0.92) and asthma and chest infections (0.88). For other uses fuel with ICF (0.83) ranked first and second was hedging and thatching (ICF = 0.82) where people use plants or their parts for construction. Spearman's rank correlation (SRC) test indicated that number of TEB uses increases if number of species is increased. Jaccard index (JI) analysis depicted that 56.31% plants are being used as TEMs which are first time explored from the study area. While 26.21% plants are being used in different TEB uses which are different from past cited literature. These novel findings of research indicate that wild flora of the study area has great potential for novel drug discovery and provision of materialist services for the indigenous communities. CONCLUSION: The present research revealed that TEMs uses of 58 plants are novel being first time reported from the study area (DRG) of District Neelam of AJK. The results showed that plants like Acer cappadocicum, Ajuga bracteosa and Swertia paniculata are used to cure diabetes, Viscum album, Viola canescens, Taxus baccata are used for cure of cancer, Isodon rugosus, Polygala chinensis are used in TEMs for treating cardiovascular disorders and Anaphalis triplinervis is used for epilepsy. Berberis lyceum, Ajuga bracteosa, Aconitum heterophyllum, Bistorta amplexicaule, Saussurea lapa and Jurinea dolomiaea are severely threatened and there is urgent need to do conservation measures for available of valuable MPs to the indigenous communities for life necessities and for future research. The current study will also be useful addition in ethnobotanical database, preservation of traditional culture and drug discovery and drug development through future ethnopharmacological research.

Hepatoprotective Potential of Elsholtzia densa Against Acute and Chronic Models of Liver Damage in Wistar Rats.

The aim of the present study was to evaluate the hepatoprotective activity of methanolic extract of Elsholtzia densa against experimentally induced acute (CCl4) and chronic (paracetamol) liver injury in albino wistar rats. Activity was measured by monitoring the serum levels of ALT, ALP AST and LDH, total protein levels, bilirubin and albumin. The results of the CCl4 and paracetamol-induced liver toxicity experiments showed that the rats treated with the methanolic extract of Elsholtzia densa exhibited a significant decrease in biochemical parameters as well as the proteins, which were all elevated in the CCl4 and paracetamol group. The extract at a concentration of 300 mg/kg body wt. showed a significant decline (P≤0.05) in the levels of AST, ALT, ALP and LDH to 69.50±2.23IU/L, 60.01±2.25IU/L,46.20±2.24 IU/L and 150.21±5.68IU/L in CCl4 injected animals and 51.12±2.20 IU/L,49.15±3.25 IU/L, 44.12±2.56 IU/L and 125.15±4.45 IU/L in paracetamol-treated animals when compared to the control group. The activities of tissue antioxidants GSH, GPx, GR, GST and CAT was significantly (P≤0.05) restored in dose dependent manner in animals treated with extracts as with acute and chronic hepatotoxic models. The current study confirmed the hepatoprotective effect of methanolic extract of Elsholtzia densa against the model hepatotoxicant CCl4 and paracetamol.