Repurposing cancer drugs, batimastat and marimastat, to inhibit the activity of a group I metalloprotease from the venom of the Western Diamondback rattlesnake, Crotalus atrox

Snakebite envenomation causes over 140,000 deaths every year predominantly in developing countries. As a result, it is one of the most lethal neglected tropical diseases. It is associated with an incredibly complex pathophysiology due to the vast number of unique toxins/proteins found in the venoms of diverse snake species found worldwide. Here, we report the purification and functional characteristics of a group I metalloprotease (CAMP-2) from the venom of the western diamondback rattlesnake, Crotalus atrox. Its sensitivity to matrix metalloprotease inhibitors (batimastat and marimastat) was established using specific in vitro experiments and in silico molecular docking analysis. CAMP-2 shows high sequence homology to atroxase from the venom of Crotalus atrox and exhibits collagenolytic, fibrinogenolytic and mild haemolytic activities. It exerts a mild inhibitory effect on agonist-induced platelet aggregation in the absence of plasma proteins. Its collagenolytic activity was completely inhibited by batimastat and marimastat. Zinc chloride also inhibits the collagenolytic activity of CAMP-2 by around 75% at 50 M, while it is partially potentiated by calcium chloride. Molecular docking studies demonstrate that batimastat and marimastat are able to bind strongly to the active site residues of CAMP-2. This study demonstrates the impact of matrix metalloprotease inhibitors in the modulation of a purified, group I metalloprotease activities in comparison to the whole venom. By improving our understanding of snake venom metalloproteases and their sensitivity to small molecule inhibitors, we can begin to develop novel and improved treatment strategies for snakebites

Synthetic flavonoids as novel modulators of platelet function and thrombosis

Cardiovascular diseases represent a major cause of mortality and morbidity in the world and thrombotic conditions such as heart attacks and strokes are caused by unwarranted activation of platelets and subsequent formation of blood clots (thrombi) within the blood vessels during pathological circumstances. Therefore, platelets act as a primary therapeutic target to treat and prevent thrombotic conditions. Current treatments are limited due to intolerance and they are associated with severe side effects such as bleeding complications. Hence, the development of novel therapeutic strategies for thrombotic diseases is an urgent priority. Flavonoids are naturally occurring plant-derived molecules that exert numerous beneficial effects in humans through modulating the functions of distinct cell types. However, naturally occurring flavonoids suffer from several issues such as poor solubility, lipophilicity, and bioavailability, which hinder their efficacy and potency. Despite this, flavonoids act as versatile templates for the design and synthesis of novel molecules for various therapeutic targets. Indeed, several synthetic flavonoids have recently been developed to improve their stability, bioavailability and efficacy including for the modulation of platelet function. Here, we provide insight into the actions of certain natural flavonoids along with the advantages of synthetic flavonoids in the modulation of platelet function, haemostasis and thrombosis

Exploring quercetin and luteolin derivatives as antiangiogenic agents

The formation of new blood vessels from the pre-existing vasculature (angiogenesis) is a crucial stage in cancer progression and, indeed, angiogenesis inhibitors are now used as anticancer agents, clinically. Here we have explored the potential of flavonoid derivatives as antiangiogenic agents. Specifically, we have synthesised methoxy and 4-thio derivatives of the natural flavones quercetin and luteolin, two of which (4-thio quercetin and 4-thio luteolin) had never been previously reported. Seven of these compounds showed significant (P<0.05) antiangiogenic activity in an in vitro scratch assay. Their activity ranged from an 86% inhibition of the vascular endothelium growth factor (VEGF)-stimulated migration (observed for methoxyquercetin at 10 µM and for luteolin at 1 µM) to a 36% inhibition (for thiomethoxy quercetin at 10 µM). Western blotting studies showed that most (4 out of 7) compounds inhibited phosphorylation of the VEGF receptor-2 (VEGFR2), suggesting that the antiangiogenic activity was due to an interference with the VEGF/VEGFR2 pathway. Molecular modelling studies looking at the affinity of our compounds towards VEGFR and/or VEGF confirmed this hypothesis, and indeed the compound with the highest antiangiogenic activity (methoxyquercetin) showed the highest affinity towards VEGFR and VEGF. As reports from others have suggested that structurally similar compounds can elicit biological responses via a non-specific, promiscuous membrane perturbation, potential interactions of the active compounds with a model lipid bilayer were assessed via DSC. Luteolin and its derivatives did not perturb the model membrane even at concentrations 10 times higher than the biologically active concentration and only subtle interactions were observed for quercetin and its derivatives. Finally, cytotoxicity assessment of these flavonoid derivatives against MCF-7 breast cancer cells demonstrated also a direct anticancer activity albeit at generally higher concentrations than those required for an antiangiogenic effect (10 fold higher for the methoxy analogues). Taken together these results show promise for flavonoid derivatives as antiangiogenic agents

A cross-sectional study on referred obstretric patients to a tertiary care centre

Background: Most of the obstetric patients can be managed at primary health center. Identifying high risk obstetric cases, severe maternal complications and timely referring them to a centre equipped with basic emergency obstetric and newborn care helps to reduce feto-maternal mortality and morbidity. This study was aimed to study the clinical profile of referred obstetric patients to SSIMS &amp; RC and made to assess the feto- maternal outcome. Methods: A prospective observational study was conducted from June 2023 to May 2024 in the department of Obstetrics and Gynecology at SS institute of medical sciences and Research Centre, Davanagere. The study included all women referred while pregnant (irrespective of gestational age) during labor and within immediate postpartum (1 week following delivery). Sociodemographic profile, cause for referral and maternal and perinatal outcome was studied. Results: In the present study 276 obstetrics patients were included. The main causes for referral were previous LSCS 76 (27.5%), pre-eclampsia 20 (7.24%), Rh negative pregnancy 20 (7.24%), preterm labor 16 (5.79%) and postpartum referral 4 (1.44%). Among them 228 (91.9%) underwent emergency LSCS and 20 (8.06%) delivered vaginally. Main maternal complications observed were acute renal failure 8 (40%), wound sepsis 4 (20%), peripartum cardiomyopathy 2 (10%), postpartum psychosis 2(10%). Out of 248 deliveries;158 babies were healthy (63.7%) and 90 (36.2%) babies had NICU admission. Conclusions: Ours being a tertiary care hospital, wide spectrum of complicated obstetric cases is referred to us. Referral system is an important part of health care system. Identification of high-risk women and timely referral to an equipped center will help in reducing feta-maternal morbidity and mortality.

Anaesthetic Challenges in A Decompensated Liver Diasease Patient Posted for Bipolar Hemiarthroplasty with A Subarachanoid Blockade

Owing to the Increased Incidence of chronic liver disease, the risk of Mortality &amp; Morbidity in Surgery and anesthesia are manifold. Chronic liver disease patients manifest either in compensated state or Decompensated state (Ascites, variceal bleed; Hepatic Encephalopathy, Spontaneous Bacterial Peritonitis, Hepatorenal &amp; Hepatopulmonary Syndrome). Perioperative risk &amp; post-operative outcome can be validated with child Pugh Turcotte scoring and Model for End stage Liver Disease score. (MELD) In this study we would like to share the perioperative Management which was involved in a case of chronic liver disease with elevated LFT; deranged coagulation profile. However with proper pre-operative Evaluation &amp; Optimization, perioperative care the complications and mortality can be minimized

An Ayurvedic pragmatic approach to Non-alcoholic Steatohepatitis vis-à-vis Yakritodara

Liver is considered to be the key organ of the body as it is concerned with filtration, metabolism, detoxification and other vital functions. Non Alcoholic Steatohepatitis (NASH) represents a part of a wide spectrum of Non Alcoholic Fatty Liver Disease (NAFLD). NASH is typically associated with Obesity, Type II Diabetes, Dyslipidemia and the Metabolic Syndrome. Epidemiological studies suggest the prevalence of NAFLD is around 9% to 32% of general population in India with a higher prevalence in those with Obesity and Diabetes. It can be understood that the Nidana and Samprapti of Yakritodara is similar to the etiopathogenesis of Non-alcoholic Steatohepatitis (NASH). Ayurveda known for its safe and cost effective medication has a great potential in treating NASH. Virechana being the most suitable Shodhana Karma is indicated in liver disorders in Bahu Doshavastha and Srotorodha. Hence, it is the need of the hour to search an effective and safe Hepatoprotective ideal remedy from the Ayurvedic treasure of therapeutics for the welfare of mankind

Comparison of natural farming with organic and conventional farming practices in green gram-paddy cropping system

Natural farming system (NFS) is one of the traditional cultivation methods to cut down production costs as well as dependence on external inputs. Being considered as an agro-ecologically diverse farming practice, it brings a host of ecological and social benefits. In order to know the sustainance of natural farming practice, field experiments were conducted at Zonal Agriculture Research Station (ZARS), V.C. Farm, Mandya, Karnataka, India for consecutive years (2019 to 2022). The experiments were laid out in a randomized complete block design comprised of five replication and four different farming practices as treatments namely, absolute control (AC), organic production system (OPS), Natural farming system (NFS) and recommended package of practice (RPP) of UAS, GKVK, Bengaluru. The pooled data of farming practices indicated significant variation in growth, yield and nutrient uptake, among farming practices significantly higher growth, yield and nutrient uptake were recorded with RPP both in green gram and paddy. The results of four years pooled data indicated that compared to conventional farming practice, natural farming recorded decreased yield of 134 (23.53%) and 3350 kg ha-1 (74.49%) in green gram and paddy, respectively. Also recorded 33.38% and 30.23% weed control efficiency by mulching in green gram and paddy, respectively. Based on this study we found that low nutrient demanding crops such as green gram (Pulses) are more suitable under natural farming compared high nutrient demanding crops viz., Paddy. Yields under natural farming can be enhanced by application of Farm yard manure and other natural sources for plant nutrition

The endogenous antimicrobial cathelicidin LL37 induces platelet activation and augments thrombus formation

Platelet-associated complications including thrombosis, thrombocytopenia and haemorrhage are commonly observed during various inflammatory diseases such as psoriasis, sepsis and inflammatory bowel disease. Despite the reported evidence on numerous mechanisms/molecules that may contribute to the dysfunction of platelets, the primary mechanisms that underpin platelet-associated complications during inflammatory diseases are not fully established. Here, we report the discovery of formyl peptide receptor 2, FPR2/ALX in platelets, and its primary role in the development of platelet-associated complications via ligation with its ligand, LL37. LL37 acts as a powerful endogenous antimicrobial peptide but it also regulates innate immune responses. We demonstrate the impact of LL37 in the modulation of platelet reactivity, haemostasis, and thrombosis. LL37 activates a range of platelet functions, enhances thrombus formation, and shortens the tail bleeding time in mice. By utilising a pharmacological inhibitor and Fpr2/3 (an orthologue of human FPR2/ALX)-deficient mice, the functional dependence of LL37 on FPR2/ALX was determined. Since the level of LL37 is increased in numerous inflammatory diseases, these results point towards a critical role for LL37 and FPR2/ALX in the development of platelet-related complications in such diseases. Hence, a better understanding of the clinical relevance of LL37 and FPR2/ALX in diverse pathophysiological settings will pave the way for the development of improved therapeutic strategies for a range of thromboinflammatory diseases

Isorhapontigenin, a resveratrol analogue selectively inhibits ADP-stimulated platelet activation

Isorhapontigenin is a polyphenolic compound found in Chinese herbs and grapes. It is a methoxylated analogue of a stilbenoid, resveratrol, which is well-known for its various beneficial effects including anti-platelet activity. Isorhapontigenin possesses greater oral bioavailability than resveratrol and has also been identified to possess anti-cancer and anti-inflammatory properties. However, its effects on platelet function have not been reported previously. In this study, we report the effects of isorhapontigenin on the modulation of platelet function. Isorhapontigenin was found to selectively inhibit ADP-induced platelet aggregation with an IC50 of 1.85µM although it displayed marginal inhibition on platelet aggregation induced by other platelet agonists at 100µM. However, resveratrol exhibited weaker inhibition on ADP-induced platelet aggregation (IC50>100µM) but inhibited collagen induced platelet aggregation at 50µM and 100µM. Isorhapontigenin also inhibited integrin αIIbβ3 mediated inside-out and outside-in signalling and dense granule secretion in ADP-induced platelet activation but interestingly, no effect was observed on α-granule secretion. Isorhapontigenin did not exert any cytotoxicity on platelets at the concentrations of up to 100µM. Furthermore, it did not affect haemostasis in mice at the IC50 concentration (1.85µM). In addition, the mechanistic studies demonstrated that isorhapontigenin increased cAMP levels and VASP phosphorylation at Ser157 and decreased Akt phosphorylation. This suggests that isorhapontigenin may interfere with cAMP and PI3K signalling pathways that are associated with the P2Y12 receptor. Molecular docking studies emphasised that isorhapontigenin has greater binding affinity to P2Y12 receptor than resveratrol. Our results demonstrate that isorhapontigenin has selective inhibitory effects on ADP-stimulated platelet activation possibly via P2Y12 receptor

Superior Supercapacitive Performance in Porous Nanocarbons

Porous nanocarbons with average particle size 20–40 nm were developed using biowaste oil palm leaves as a precursor. Simple pyrolysis was carried out at 700 °C under nitrogen atmosphere. Obtained porous nanocarbons showed excellent porous nature along with spherical shape. Symmetric supercapacitor fabricated from porous nanocarbons showed superior supercapacitance performance where high specific capacitance of 368 F/g at 0.06 A/g in 5 M KOH were reported. It also exhibited high stability (96% over 1700 cycles) and energy density of 13 Wh/kg. Low resistance values were obtained by fitting the impedance spectra, thus indicating the availability of these materials as supercapacitors electrode. The presented method is cost effective and also in line with waste to wealth approach