Animal Venoms as Potential Source of Anticonvulsants.

Epilepsy affects millions of people worldwide, and there is an urgent need to develop safe and effective therapeutic agents. Animal venoms contain diverse bioactive compounds like proteins, peptides, and small molecules, which may possess medicinal properties against epilepsy. In recent years, research has shown that venoms from various organisms such as spiders, ants, bees, wasps, and conus snails have anticonvulsant and antiepileptic effects by targeting specific receptors and ion channels. This review underscores the significance of purified proteins and toxins from these sources as potential therapeutic agents for epilepsy. In conclusion, this review emphasizes the valuable role of animal venoms as a natural resource for further exploration in epilepsy treatment research.

Anti-Cancer Mechanisms of Diarylpentanoid MS17 (1,5-Bis(2-hydroxyphenyl)-1,4-pentadiene-3-one) in Human Colon Cancer Cells: A Proteomics Approach.

Diarylpentanoids are synthesized to overcome curcumin's poor bioavailability and low stability to show enhanced anti-cancer effects. Little is known about the anti-cancer effects of diarylpentanoid MS17 (1,5-bis(2-hydroxyphenyl)-1,4-pentadiene-3-one) in colon cancer cells. This study aimed to elucidate molecular mechanisms and pathways modulated by MS17 in colon cancer based on proteomic profiling of primary SW480 and metastatic SW620 colon cancer cells. Cytotoxicity and apoptotic effects of MS17 were investigated using MTT assay, morphological studies, and Simple Western analysis. Proteomic profiling using LC/MS analysis identified differentially expressed proteins (DEPs) in MS17-treated cells, with further analysis in protein classification, gene ontology enrichment, protein-protein interaction network and Reactome pathway analysis. MS17 had lower EC50 values (SW480: 4.10 µM; SW620: 2.50 µM) than curcumin (SW480: 17.50 µM; SW620: 13.10 µM) with a greater anti-proliferative effect. MS17 treatment of 1× EC50 induced apoptotic changes in the morphology of SW480 and SW620 cells upon 24 h treatment. A total of 24 and 92 DEPs (fold change ≥ 1.50) were identified in SW480 and SW620 cells, respectively, upon MS17 treatment of 2× EC50 for 24 h. Pathway analysis showed that MS17 may induce its anti-cancer effects in both cells via selected DEPs associated with the top enriched molecular pathways. RPL and RPS ribosomal proteins, heat shock proteins (HSPs) and ubiquitin-protein ligases (UBB and UBC) were significantly associated with cellular responses to stress in SW480 and SW620 cells. Our findings suggest that MS17 may facilitate the anti-proliferative and apoptotic activities in primary (SW480) and metastatic (SW620) human colon cancer cells via the cellular responses to stress pathway. Further investigation is essential to determine the alternative apoptotic mechanisms of MS17 that are independent of caspase-3 activity and Bcl-2 protein expression in these cells. MS17 could be a potential anti-cancer agent in primary and metastatic colon cancer cells.

Comparative Proteomic Analysis of the Venoms from the Most Dangerous Scorpions in Morocco: Androctonus mauritanicus and Buthus occitanus.

Morocco is known to harbor two of the world's most dangerous scorpion species: the black Androctonus mauritanicus (Am) and the yellow Buthus occitanus (Bo), responsible for 83% and 14% of severe envenomation cases, respectively. Scorpion venom is a mixture of biological molecules of variable structures and activities, most of which are proteins of low molecular weights referred to as toxins. In addition to toxins, scorpion venoms also contain biogenic amines, polyamines, and enzymes. With the aim of investigating the composition of the Am and Bo venoms, we conducted an analysis of the venoms by mass spectrometry (ESI-MS) after separation by reversed-phase HPLC chromatography. Results from a total of 19 fractions obtained for the Am venom versus 22 fractions for the Bo venom allowed the identification of approximately 410 and 252 molecular masses, respectively. In both venoms, the most abundant toxins were found to range between 2-5 kDa and 6-8 kDa. This proteomic analysis not only allowed the drawing of an extensive mass fingerprint of the Androctonus mauritanicus and Buthus occitanus venoms but also provided a better insight into the nature of their toxins.

Behavioural, genomics and proteomic approach to examine Alzheimer's disease in zebrafish.

Globally around 24 million elderly population are dealing with dementia, and this pathological characteristic is commonly seen in people suffering from Alzheimer's disease (AD). Despite having multiple treatment options that can mitigate AD symptoms, there is an imperative call to advance our understanding of the disease pathogenesis to unfold disease-modifying treatments/therapies. To explore the driving mechanisms of AD development, we stretch out further to study time-dependant changes after Okadaic acid (OKA)-induced AD-like conditions in zebrafish. We evaluated the pharmacodynamics of OKA at two-time points, i.e., after 4-days and 10-days exposure to zebrafish. T-Maze was utilized to observe the learning and cognitive behaviour, and inflammatory gene expressions such as 5-Lox, Gfap, Actin, APP, and Mapt were performed in zebrafish brains. To scoop everything out from the brain tissue, protein profiling was performed using LCMS/MS. Both time course OKA-induced AD models have shown significant memory impairment, as evident from T-Maze. Gene expression studies of both groups have reported an overexpression of 5-Lox, GFAP, Actin, APP, and OKA 10D group has shown remarkable upregulation of Mapt in zebrafish brains. In the case of protein expression, the heatmap suggested an important role of some common proteins identified in both groups, which can be explored further to investigate their mechanism in OKA-induced AD pathology. Presently, the preclinical models available to understand AD-like conditions are not completely understood. Hence, utilizing OKA in the zebrafish model can be of great importance in understanding the pathology of AD progression and as a screening tool for drug discovery.

Embelin prevents amyloid-beta accumulation via modulation of SOD1 in a Streptozotocin-induced AD-like condition: An evidence from in vitro investigation.

Embelin is a neuroprotective compound with therapeutic benefit against experimental Alzheimer's disease (AD)-like condition. In the quest of untangling the underlying mechanism behind the neuroprotective effect of Embelin in AD, an in-vitro study of Embelin against neuronal damage induced by Streptozotocin (STZ) in rat hippocampal neuronal culture was performed. Current findings demonstrated that Embelin (2.5-10 µM) has efficiently protected hippocampal neurons against STZ (8 mM)-induced neurotoxicity. An increase in amyloid precursor protein (APP), microtubule-associated protein tau (MAPT), glycogen synthase kinase 3 alpha (GSK-3α) and glycogen synthase kinase 3 beta (GSK-3ß) expression levels was observed when STZ (8 mM) stimulation was done for 24 h in the hippocampal neurons. A significant downregulation in the mRNA expression levels of APP, MAPT, GSK-3α, and GSK-3ß upon pre-treatment with different doses of Embelin (2.5 µM, 5 µM and 10 µM) reflects that Embelin attenuated STZ-induced dysfunction of insulin signaling (IR). Embelin significantly modulated the mRNA expression of scavenger enzyme Superoxide dismutase (SOD1). Furthermore, STZ had significantly upregulates an expression of Aß. On the contrary, pre-treatment with three doses of Embelin reversed an Aß-induced neuronal death. Our findings suggest that, Embelin prevents Aß accumulation via SOD1 pathway to protect against AD-like condition.

Potential economic and clinical implications of improving access to snake antivenom in five ASEAN countries: A cost-effectiveness analysis.

BACKGROUND: Despite domestic production of antivenoms in the Association of Southeast Asian Nations (ASEAN) countries, not all victims with snakebite envenomings indicated for antivenom received the appropriate or adequate effective dose of antivenom due to insufficient supply and inadequate access to antivenoms. We aimed to conduct a cost-effectiveness analysis to project the potential economic and clinical impact of improving access to antivenoms when all snakebite envenomings in ASEAN countries were hypothetically treated with geographically appropriate antivenoms. METHODOLOGY: Using a decision analytic model with input parameters from published literature, local data, and expert opinion, we projected the impact of "full access" (100%) to antivenom, compared to "current access" in five most impacted ASEAN countries, including Indonesia (10%), Philippines (26%), Vietnam (37%), Lao PDR (4%), and Myanmar (64%), from a societal perspective with a lifetime time horizon. Sensitivity analyses were performed. PRINCIPAL FINDINGS: In base-case analyses, full access compared to current access to snake antivenom in the five countries resulted in a total of 9,362 deaths averted (-59%), 230,075 disability-adjusted life years (DALYs) averted (-59%), and cost savings of 1.3 billion USD (-53%). Incremental cost-effectiveness ratios (ICERs) of improving access to antivenom found higher outcomes but lower costs in all countries. Probabilistic sensitivity analyses of 1,000 iterations found that 98.1-100% of ICERs were cost-saving. CONCLUSION/SIGNIFICANCE: Improving access to snake antivenom will result in cost-saving for ASEAN countries. Our findings emphasized the importance of further strengthening regional cooperation, investment, and funding to improve the situation of snakebite victims in ASEAN countries.

Neuroprotective effect of phospholipase A2 from Malaysian Naja sumatrana venom against H2O2-induced cell damage and apoptosis.

Oxidative stress is one of the factors involved in the pathogenesis of several neurodegenerative diseases. It has been reported that a secretory phospholipase A2 known as A2-EPTX-NSm1a has lower cytotoxicity in neuronal cells compared to its crude Naja sumatrana venom. In this study, A2-EPTX-NSm1a was tested for its neuroprotective activity on human neuroblastoma cells (SH-SY5Y) differentiated into cholinergic neurons against oxidative stress induced by hydrogen peroxide (H2O2). H2O2 treatment alone increased the caspase-3 and caspase-8 activities, whereas pre-treatment with A2-EPTX-NSm1a reduced the activity of these apoptosis-associated proteins. Moreover, A2-EPTX-NSm1a protects the morphology and ultrastructure of differentiated SH-SY5Y cells in the presence of H2O2. Oxidative stress increased the number of small mitochondria. Further evaluation showed the size of mitochondria with a length below 0.25 µm in oxidative stress conditions is higher than the control group, suggesting mitochondria fragmentation. Pre-treatment with A2-EPTX-NSm1a attenuated the number of mitochondria in cells with H2O2 Furthermore, A2-EPTX-NSm1a altered the expression of several neuroprotein biomarkers of GDNF, IL-8, MCP-1, TIMP-1, and TNF-R1 in cells under oxidative stress induced by H2O2. These findings indicate that anti-apoptosis with mitochondria-related protection, anti-inflammatory effect, and promote expression of important markers for cell survival may underlie the neuroprotective effect of A2-EPTX-NSm1a in cholinergic rich human cells under oxidative stress, a vital role in the neuronal disorder.

Typical response of CD14++CD16- monocyte to knee synovial derived mediators as a key target to overcome the onset and progression of osteoarthritis.

Objective: Synovitis with increased infiltration of immune cells is observed in osteoarthritis (OA). Given the inflammatory condition of synovitis, we explored the protein profile of OA synovium (OAS) and its effect on circulating monocytes activation, migration, and functional commitments. Methods: Knee-synovium was acquired from end-stage OA (N = 8) and trauma patients (Trauma baseline control: TBC; N = 8) for characterization using H&E histology, IHC (iNOS), LCMS-QTOF, and MALDI-imaging. Response of peripheral blood monocytes to OAS conditioned-media (OACM) was observed using transwell (n = 6). The migrated cells were captured in SEM, quantified using phase-contrast microphotographs, and their activation receptors (CCR2, CXCR2, CX3CR1, and CD11b), pro-inflammatory genes, and phagocytic potential were studied using flow cytometry, gene expression array/qPCR, and latex beads (LB) phagocytosis assay, respectively. Results: The Venn diagram displayed 119 typical proteins in OAS, while 55 proteins in TBCS. The STRING protein network analysis indicated distinctive links between proteins and gene ontology (GO) and revealed proteins associated with leukocyte-mediated immunity in OAS as compared to TBC. The MALDI-imaging showed typical localized proteins at 2234.97, 2522.61, 2627.21, 3329.50, and 3539.69 m/z and IHC confirmed pro-inflammatory iNOS expression in OA synovium. CD14++CD16- classical monocytes significantly migrated in OACM and expressed CCR2, CXCR2, and CD11b receptors, TNFRSF11A, MAPK1, S100A8, HSPB1, ITGAL, NFATC1, IL13RA1, CD93, IL-1ß, TNF-α, and MYD88 genes and increased LB uptake as compared to SFM. Conclusion: Our findings suggest that the differential protein profile of OA synovium and the classical monocytes migrated, activated, and functionally committed in response to these mediators could be of therapeutic advantage.

In Vitro neurotoxicity and myotoxicity of Malaysian Naja sumatrana and Naja kaouthia venoms: Neutralization by monovalent and Neuro Polyvalent Antivenoms from Thailand.

Naja sumatrana and Naja kaouthia are medically important elapids species found in Southeast Asia. Snake bite envenoming caused by these species may lead to morbidity or mortality if not treated with the appropriate antivenom. In this study, the in vitro neurotoxic and myotoxic effects N. sumatrana and N. kaouthia venoms from Malaysian specimens were assessed and compared. In addition, the neutralizing capability of Cobra Antivenom (CAV), King Cobra Antivenom (KCAV) and Neuro Polyvalent Antivenom (NPAV) from Thailand were compared. Both venoms produced concentration-dependent neurotoxic and myotoxic effects in the chick biventer cervicis nerve-muscle preparation. Based on the time to cause 90% inhibition of twitches (i.e. t90) N. kaouthia venom displayed more potent neurotoxic and myotoxic effects than N. sumatrana venom. All three of the antivenoms significantly attenuated venom-induced twitch reduction of indirectly stimulated tissues when added prior to venom. When added after N. sumatrana venom, at the t90 time point, CAV and NPAV partially restored the twitch height but has no significant effect on the reduction in twitch height caused by N. kaouthia venom. The addition of KCAV, at the t90 time point, did not reverse the attenuation of indirectly stimulated twitches caused by either venom. In addition, none of the antivenoms, when added prior to venom, prevented attenuation of directly stimulated twitches. Differences in the capability of antivenoms, especially NPAV and CAV, to reverse neurotoxicity and myotoxicity indicate that there is a need to isolate and characterize neurotoxins and myotoxins from Malaysian N. kaouthia and N. sumatrana venoms to improve neutralization capability of the antivenoms.

Estimating economic and disease burden of snakebite in ASEAN countries using a decision analytic model.

BACKGROUND: Understanding the burden of snakebite is crucial for developing evidence-informed strategies to pursue the goal set by the World Health Organization to halve morbidity and mortality of snakebite by 2030. However, there was no such information in the Association of Southeast Asian Nations (ASEAN) countries. METHODOLOGY: A decision analytic model was developed to estimate annual burden of snakebite in seven countries, including Malaysia, Thailand, Indonesia, Philippines, Vietnam, Lao PDR, and Myanmar. Country-specific input parameters were sought from published literature, country's Ministry of Health, local data, and expert opinion. Economic burden was estimated from the societal perspective. Costs were expressed in 2019 US Dollars (USD). Disease burden was estimated as disability-adjusted life years (DALYs). Probabilistic sensitivity analysis was performed to estimate a 95% credible interval (CrI). PRINCIPAL FINDINGS: We estimated that annually there were 242,648 snakebite victims (95%CrI 209,810-291,023) of which 15,909 (95%CrI 7,592-33,949) were dead and 954 (95%CrI 383-1,797) were amputated. We estimated that 161,835 snakebite victims (69% of victims who were indicated for antivenom treatment) were not treated with antivenom. Annual disease burden of snakebite was estimated at 391,979 DALYs (95%CrI 187,261-836,559 DALYs) with total costs of 2.5 billion USD (95%CrI 1.2-5.4 billion USD) that were equivalent to 0.09% (95%CrI 0.04-0.20%) of the region's gross domestic product. >95% of the estimated burdens were attributed to premature deaths. CONCLUSION/SIGNIFICANCE: The estimated high burden of snakebite in ASEAN was demonstrated despite the availability of domestically produced antivenoms. Most burdens were attributed to premature deaths from snakebite envenoming which suggested that the remarkably high burden of snakebite could be averted. We emphasized the importance of funding research to perform a comprehensive data collection on epidemiological and economic burden of snakebite to eventually reveal the true burden of snakebite in ASEAN and inform development of strategies to tackle the problem of snakebite.

Situation of snakebite, antivenom market and access to antivenoms in ASEAN countries.

INTRODUCTION: Snakebite envenoming is a neglected tropical disease posing public health challenges globally. The Association of Southeast Asian Nations (ASEAN) countries are among the tropical regions with disproportionately high incidence of snakebite. Hence, this study aimed to review the situation of snakebite, antivenom market and access to antivenoms in ASEAN. METHODS: This mixed-methods study included comprehensive literature review and in-depth interviews with key informants to assess the situation of management system of snakebite, antivenom market and access to antivenoms in seven ASEAN countries, including Malaysia, Thailand, Indonesia, Philippines, Vietnam, Lao PDR and Myanmar. Data were analysed by a framework method. RESULTS: ASEAN have developed various strategies to improve outcomes of snakebite victims. Five domestic antivenom manufacturers in the region produce up to 288 375 vials of antivenoms annually with the value of US$13 058 053 million which could treat 42 213 snakebite victims. However, there remain challenges to be addressed especially the lack of snakebite-related informatics system, inadequate antivenoms at the healthcare facilities and when the majority of snakebite victims seek traditional healers instead of conventional treatment. CONCLUSION: Improving the situation of snakebite and antivenom is not only about the availability of antivenom, but the whole landscape of surrounding management and supporting system. The assessment of the situation of snakebite and antivenom is crucial for countries or regions where snakebites are prevalent to recognise their current standpoint to inform the development of strategies to achieve the goal set by the WHO of halving the global burden of snakebite by 2030.

Poloxamer 188 (P188), A Potential Polymeric Protective Agent for Central Nervous System Disorders: A Systematic Review.

Poloxamer 188 (P188) is an FDA-approved biocompatible block copolymer composed of repeating units of Poly(Ethylene Oxide) (PEO) and poly(propylene oxide) (PPO). Due to its amphiphilic nature and high Hydrophile-Lipophile Balance (HLB) value of 29, P188 is used as a stabilizer/emulsifier in many cosmetics and pharmaceutical preparations. While the applications of P188 as an excipient are widely explored, the data on the pharmacological activity of P188 are scarce. Notably, the neuroprotective potential of P188 has gained a lot of interest. Therefore, this systematic review is aimed at summarizing evidence of neuroprotective potential of P188 in CNS disorders. The PRISMA model was used, and five databases (Google Scholar, Scopus, Wiley Online Library, ScienceDirect, and PubMed) were searched with relevant keywords. The search resulted in 11 articles, which met the inclusion criteria. These articles described the protective effects of P188 on traumatic brain injury or mechanical injury in cells, neurotoxicity, Parkinson's disease, Amyotrophic lateral sclerosis (ALS), and ischemia/ reperfusion injury from stroke. All the articles were original research in experimental or pre-clinical stages using animal models or in vitro systems. The reported activities demonstrated the potential of P188 as a neuroprotective agent in improving CNS conditions such as neurodegeneration.

Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer.

Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhance treatment efficacy. Curcumin is an attractive therapeutic agent mainly due to its potent anti-cancer effects, extensive range of targets and minimal toxicity. Out of the numerous documented targets of curcumin, RTKs appear to be one of the main nodes of curcumin-mediated inhibition. Many studies have found that curcumin influences RTK activation and their downstream signaling pathways resulting in increased apoptosis, decreased proliferation and decreased migration in cancer both in vitro and in vivo. This review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways. Combination studies of curcumin and RTK inhibitors were also analysed with emphasis on their common molecular targets.

The Crosstalk Between Signaling Pathways and Cancer Metabolism in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Metabolic reprogramming represents an important cancer hallmark in CRC. Reprogramming core metabolic pathways in cancer cells, such as glycolysis, glutaminolysis, oxidative phosphorylation, and lipid metabolism, is essential to increase energy production and biosynthesis of precursors required to support tumor initiation and progression. Accumulating evidence demonstrates that activation of oncogenes and loss of tumor suppressor genes regulate metabolic reprogramming through the downstream signaling pathways. Protein kinases, such as AKT and c-MYC, are the integral components that facilitate the crosstalk between signaling pathways and metabolic pathways in CRC. This review provides an insight into the crosstalk between signaling pathways and metabolic reprogramming in CRC. Targeting CRC metabolism could open a new avenue for developing CRC therapy by discovering metabolic inhibitors and repurposing protein kinase inhibitors/monoclonal antibodies.

Isolation and Characterization of A2-EPTX-Nsm1a, a Secretory Phospholipase A2 from Malaysian Spitting Cobra (Naja sumatrana) Venom.

Phospholipase A2 (PLA2) toxins are one of the main toxin families found in snake venom. PLA2 toxins are associated with various detrimental effects, including neurotoxicity, myotoxicity, hemostatic disturbances, nephrotoxicity, edema, and inflammation. Although Naja sumatrana venom contains substantial quantities of PLA2 components, there is limited information on the function and activities of PLA2 toxins from the venom. In this study, a secretory PLA2 from the venom of Malaysian N. sumatrana, subsequently named A2-EPTX-Nsm1a, was isolated, purified, and characterized. A2-EPTX-Nsm1a was purified using a mass spectrometry-guided approach and multiple chromatography steps. Based on LC-MSMS, A2-EPTX-Nsm1a was found to show high sequence similarity with PLA2 from venoms of other Naja species. The PLA2 activity of A2-EPTX-Nsm1 was inhibited by 4-BPB and EDTA. A2-EPTX-Nsm1a was significantly less cytotoxic in a neuroblastoma cell line (SH-SY5Y) compared to crude venom and did not show a concentration-dependent cytotoxic activity. To our knowledge, this is the first study that characterizes and investigates the cytotoxicity of an Asp49 PLA2 isolated from Malaysian N. sumatrana venom in a human neuroblastoma cell line.

In vitro inhibitory effects of glucosamine, chondroitin and diacerein on human hepatic CYP2D6.

OBJECTIVES: Glucosamine, chondroitin and diacerein are natural compounds commonly used in treating osteoarthritis. Their concomitant intake may trigger drug-natural product interactions. Cytochrome P450 (CYP) has been implicated in such interactions. Cytochrome P450 2D6 (CYP2D6) is a major hepatic CYP involved in metabolism of 25% of the clinical drugs. This study aimed to investigate the inhibitory effect of these antiarthritic compounds on CYP2D6. METHODS: CYP2D6 was heterologously expressed in Escherichia coli. CYP2D6-antiarthritic compound interactions were studied using in vitro enzyme kinetics assay and molecular docking. RESULTS: The high-performance liquid chromatography (HPLC)-based dextromethorphan O-demethylase assay was established as CYP2D6 marker. All glucosamines and chondroitins weakly inhibited CYP2D6 (IC50 values >300 µM). Diacerein exhibited moderate inhibition with IC50 and Ki values of 34.99 and 38.27 µM, respectively. Its major metabolite, rhein displayed stronger inhibition potencies (IC50=26.22 µM and Ki =32.27 µM). Both compounds exhibited mixed-mode of inhibition. In silico molecular dockings further supported data from the in vitro study. From in vitro-in vivo extrapolation, rhein presented an area under the plasma concentration-time curve (AUC) ratio of 1.5, indicating low potential to cause in vivo inhibition. CONCLUSIONS: Glucosamine, chondroitin and diacerein unlikely cause clinical interaction with the drug substrates of CYP2D6. Rhein, exhibits only low potential to cause in vivo inhibition.

Mechanistic role of boswellic acids in Alzheimer's disease: Emphasis on anti-inflammatory properties.

The resin/gum of Boswellia species belonging to the family of Burseraceae is a naturally occurring mixture of bioactive compounds, which was traditionally used as a folk medicine to treat conditions like chronic inflammation. Several research studies have also explored its' therapeutic potential against multiple neurodegenerative diseases such as Alzheimer's disease (AD). The main chemical constituents of this gum include boswellic acids (BAs) like 3-O-acetyl-11-keto-ß boswellic acid (AKBA) that possess potent anti-inflammatory and neuroprotective properties in AD. It is also involved in inhibiting the acetylcholinesterase (AChE) activity in the cholinergic pathway and improve choline levels as well as its binding with nicotinic receptors to produce anti-inflammatory effects. Multiple shreds of evidence have demonstrated that BAs modulate key molecular targets and signalling pathways like 5-lipoxygenase/cyclooxygenase, Nrf2, NF-kB, cholinergic, amyloid-beta (Aß), and neurofibrillary tangles formation (NFTs) that are involved in AD progression. The present review focuses on the possible mechanistic therapeutic role of BAs in modulating the 5-LOX/COX pathway in arachidonic acid metabolism, activating Nrf2 through binding of ARE, inhibiting NF-kB and AChE activity. In addition, an inhibition of amyloid plaques (Aß) and neurofibrillary tangles (NFTs) induced neurotoxicity and neuroinflammation in AD by BAs is also discussed in this review. We have also highlighted that BAs possess beneficial effects in AD by targeting multiple molecular pathways and makes it an emerging drug candidate for treating neurodegenerative diseases.

Antimicrobial Resistance Patterns and Risk Factors Associated with Salmonella spp. Isolates from Poultry Farms in the East Coast of Peninsular Malaysia: A Cross-Sectional Study.

The burden of antimicrobial use in agricultural settings is one of the greatest challenges facing global health and food security in the modern era. Malaysian poultry operations are a relevant but understudied component of epidemiology of antimicrobial resistance. We aimed to identify the prevalence, resistance patterns, and risk factors associated with Salmonella isolates from poultry farms in three states of East Coast Peninsular Malaysia. Between 8 February 2019 and 23 February 2020, a total of 371 samples (cloacal swabs = 259; faecal = 84; Sewage = 14, Tap water = 14) was collected from poultry operations. Characteristics of the sampled farms and associated risk factors were obtained using semi-structured questionnaires. Presumptive Salmonella spp. isolates were identified based on colony morphology with subsequent biochemical and PCR confirmation. Susceptibility of isolates was tested against a panel of 12 antimicrobials using disk diffusion method. Our findings revealed that the proportion of Salmonella spp.-positive isolates across sample source were as following: cloacal swab (46.3%, 120/259); faecal (59.5%, 50/84); in tap water (14.3%, 2/14); and in sewage sample (35.7%, 5/14). Isolates from faecal (15.5%, 13/84), cloacal (1.2%, 3/259), and sewage (7.1%, 1/14) samples were significantly resistant to at least five classes of antimicrobials. Resistance to Sulfonamides class (52%, 92/177) was predominantly observed followed by tetracycline (39.5%, 70/177) and aminoglycosides (35.6%, 63/177). Multivariate regression analysis identified intensive management system (OR = 1.55, 95% CI = 1.00-2.40) as a leading driver of antimicrobial resistance (AMR) acquisition. A prevalence of resistance to common antimicrobials was recorded for sulfamethoxazole (33.9%), tetracycline (39.5%), and trimethoprim-sulphamethoxazole (37.9%). A close association between different risk factors and the prevalence of AMR of Salmonella strains suggests a concern over rising misuse of veterinary antimicrobials that may contribute to the emergence and evolution of multidrug-resistant pathogen isolates. One Health approach is recommended to achieve a positive health outcome for all species.

Diarylpentanoid (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one) (MS13) Exhibits Anti-proliferative, Apoptosis Induction and Anti-migration Properties on Androgen-independent Human Prostate Cancer by Targeting Cell Cycle-Apoptosis and PI3K Signalling Pathways.

Diarylpentanoids exhibit a high degree of anti-cancer activity and stability in vitro over curcumin in prostate cancer cells. Hence, this study aims to investigate the effects of a diarylpentanoid, 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one (MS13) on cytotoxicity, anti-proliferative, apoptosis-inducing, anti-migration properties, and the underlying molecular mechanisms on treated androgen-independent prostate cancer cells, DU 145 and PC-3. A cell viability assay has shown greater cytotoxicity effects of MS13-treated DU 145 cells (EC50 7.57 ± 0.2 µM) and PC-3 cells (EC50 7.80 ± 0.7 µM) compared to curcumin (EC50: DU 145; 34.25 ± 2.7 µM and PC-3; 27.77 ± 6.4 µM). In addition, MS13 exhibited significant anti-proliferative activity against AIPC cells compared to curcumin in a dose- and time-dependent manner. Morphological observation, increased caspase-3 activity, and reduced Bcl-2 protein levels in these cells indicated that MS13 induces apoptosis in a time- and dose-dependent. Moreover, MS13 effectively inhibited the migration of DU 145 and PC-3 cells. Our results suggest that cell cycle-apoptosis and PI3K pathways were the topmost significant pathways impacted by MS13 activity. Our findings suggest that MS13 may demonstrate the anti-cancer activity by modulating DEGs associated with the cell cycle-apoptosis and PI3K pathways, thus inhibiting cell proliferation and cell migration as well as inducing apoptosis in AIPC cells.

Naturally Occurring HMGB1 Inhibitor, Glycyrrhizin, Modulates Chronic Seizures-Induced Memory Dysfunction in Zebrafish Model.

Glycyrrhizin (GL) is a well-known pharmacological inhibitor of high mobility group box 1 (HMGB1) and is abundantly present in the licorice root (Glycyrrhiza radix). HMGB1 protein, a key mediator of neuroinflammation, has been implicated in several neurological disorders, including epilepsy. Epilepsy is a devastating neurological disorder with no effective disease-modifying treatment strategies yet, suggesting a pressing need for exploring novel therapeutic options. In the current investigation, using a second hit pentylenetetrazol (PTZ) induced chronic seizure model in adult zebrafish, regulated mRNA expression of HMGB1 was inhibited by pretreatment with GL (25, 50, and 100 mg/kg, ip). A molecular docking study suggests that GL establishes different binding interactions with the various amino acid chains of HMGB1 and Toll-like receptor-4 (TLR4). Our finding suggests that GL pretreatment reduces/suppresses second hit PTZ induced seizure, as shown by the reduction in the seizure score. GL also regulates the second hit PTZ induced behavioral impairment and rescued second hit PTZ related memory impairment as demonstrated by an increase in the inflection ratio (IR) at the 3 h and 24 h T-maze trial. GL inhibited seizure-induced neuronal activity as demonstrated by reduced C-fos mRNA expression. GL also modulated mRNA expression of BDNF, CREB-1, and NPY. The possible mechanism underlying the anticonvulsive effect of GL could be attributed to its anti-inflammatory activity, as demonstrated by the downregulated mRNA expression level of HMGB1, TLR4, NF-kB, and TNF-α. Overall, our finding suggests that GL exerts an anticonvulsive effect and ameliorates seizure-related memory disruption plausibly through regulating of the HMGB1-TLR4-NF-kB axis.