Flavonoids: A treasure house of prospective pharmacological potentials.

Flavonoids are organic compounds characterized by a range of phenolic structures, which are abundantly present in various natural sources such as fruits, vegetables, cereals, bark, roots, stems, flowers, tea, and wine. The health advantages of these natural substances are renowned, and initiatives are being taken to extract the flavonoids. Apigenin, galangin, hesperetin, kaempferol, myricetin, naringenin, and quercetin are the seven most common compounds belonging to this class. A thorough analysis of bibliographic records from reliable sources including Google Scholar, Web of Science, PubMed, ScienceDirect, MEDLINE, and others was done to learn more about the biological activities of these flavonoids. These flavonoids appear to have promising anti-diabetic, anti-inflammatory, antibacterial, antioxidant, antiviral, cytotoxic, and lipid-lowering activities, according to evidence from in vitro, in vivo, and clinical research. The review contains recent trends, therapeutical interventions, and futuristic aspects of flavonoids to treat several diseases like diabetes, inflammation, bacterial and viral infections, cancers, and cardiovascular diseases. However, this manuscript should be handy in future drug discovery. Despite these encouraging findings, a notable gap exists in clinical research, hindering a comprehensive understanding of the effects of flavonoids at both high and low concentrations on human health. Future investigations should prioritize exploring bioavailability, given the potential for high inter-individual variation. As a starting point for further study on these flavonoids, this review paper may promote identifying and creating innovative therapeutic uses.

Isolation of bioactive phytochemicals from Crinum asiaticum L. along with their cytotoxic and TRAIL-resistance abrogating prospect assessment.

Crinum asiaticum L. (Amaryllidaceae) is a perennial bulbous herb, locally utilized for possessing multifaceted pharmacological properties including anticancer, immune-stimulating, analgesic, antiviral, antimalarial, antibacterial and antifungal, in addition to its popularity as an aesthetic plant. Separation of MeOH extract of C. asiaticum leaves yielded three known compounds as cycloneolitsol (1), hippeastrine (2) and ß-sitosterol (3). Among these, compounds 1 and 2 were subjected to the cytotoxic assay and found that they induced mild effect against HCT116, Huh7 and DU145 cell lines with the IC50 values from 73.76 to 132.53 µM. When tested for TRAIL-resistance abrogating activity, 1 (100 µM) along with TRAIL (100 ng/mL) showed moderate activity in AGS cells producing 25 % more inhibition than the agent alone. Whereas 2 (20 and 30 µM) in combination with TRAIL (100 ng/mL) exhibited strong activity in abrogating TRAIL-resistance and caused 34 % and 36 % more inhibition in AGS cells, respectively. The in-silico studies of compound 2 revealed high docking hits with the TRAIL-associated anti-apoptotic proteins which give a justification for the regulatory interactions to induce such abrogating activity. It is still recommended to conduct further investigations to understand their exact molecular mechanism.

Anti-diabetic and anti-urease inhibition potential of Amomum dealbatum Roxb. seeds through a bioassay-guided approach.

Using HPLC-PDA and HRMS analysis, five compounds p-coumaric acid, sinapic acid, quercetin, trans-ferulic and gallic acid were identified in seeds of Amomum dealbatum Roxb. The GC-MS analysis identified 1-dodecanol, phenol, 3,5-bis(1,1-dimethylethyl), Oleic Acid and 1-Heptacosanol which possess anti-diabetic properpties. A bioassay-guided technique was used to determine the degree of inhibition that A. dealbatum seeds crude methanol extract and its most active sub-fraction had against the α-glucosidase and Helicobacter pylori urease enzymes. In the Rat L6 myoblast cell line, glucose absorption through the GLUT4 transporter of most active subfraction (EASF80) was examined. According to a molecular docking investigation, these compounds strongly interacted with the GLUT4 transporter, H pylori and α-glucosidase enzyme. Sinapic acid interacted most strongly with the H. pylori urease enzyme while gallic acid interacted with both the α-glucosidase enzyme and the GLUT4 transporter. Additionally, a molecular docking simulation study was carried out to recognise the stability of the complexes.

Therapeutic potentials of Adenostemma lavenia (L.) O.Kuntze evidenced into an array of pharmacological effects and ligand-receptor interactions.

This study constructed the phytochemical profiles of Adenostemma lavenia (L) methanol extract (MEAL) and investigated its anti-nociceptive, anti-diarrheal, antipyretic, thrombolytic and anthelmintic effects. The GC-MS characterized MEAL had undergone an in vivo antipyretic effect assayed on Swiss albino mice adopting the yeast-induced pyrexia model, antinociceptive activity tested following acetic acid-induced writhing and formalin-induced licking paw models, anti-diarrheal effect in castor oil-induced diarrhea, castor oil-induced enteropooling, and charcoal-induced intestinal transit tests, in vitro thrombolytic effect using clot-lysis model and anthelmintic effects assayed on Tubifex tubifex nematode. The MEAL biometabolites and associated proteins of target diseases were interacted with computational analysis. The MEAL showed a significant dose-dependent percentage of inhibition in acetic acid-induced writhing and formalin-induced paw licking displaying inhibition of 80.40% in acetic acid-induced writhing and 36.23% and 58.21% in the second phase of the formalin-induced model. The MEAL inhibition of 34.37%, 35.29%, and 42.95% in castor oil-induced diarrhea, castor oil-induced enteropooling, and charcoal-induced gastrointestinal motility, respectively. The MEAL significantly reduced yeast-induced pyrexia. Its biometabolites showed remarkable (-4.1 kcal/mol to 7.4 kcal/mol) binding affinity with the protein receptors. Caryophyllene and Cyclobarbital yielded the best binding scores in this research. Results suggest that pure compounds-based pharmacological investigations are necessary to affirm the therapeutic effects.

Papaverine: A Miraculous Alkaloid from Opium and Its Multimedicinal Application.

The pharmacological actions of benzylisoquinoline alkaloids are quite substantial, and have recently attracted much attention. One of the principle benzylisoquinoline alkaloids has been found in the unripe seed capsules of Papaver somniferum L. Although it lacks analgesic effects and is unrelated to the compounds in the morphine class, it is a peripheral vasodilator and has a direct effect on vessels. It is reported to inhibit the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) phosphodiesterase in smooth muscles, and it has been observed to increase intracellular levels of cAMP and cGMP. It induces coronary, cerebral, and pulmonary artery dilatation and helps to lower cerebral vascular resistance and enhance cerebral blood flow. Current pharmacological research has revealed that papaverine demonstrates a variety of biological activities, including activity against erectile dysfunction, postoperative vasospasms, and pulmonary vasoconstriction, as well as antiviral, cardioprotective, anti-inflammatory, anticancer, neuroprotective, and gestational actions. It was recently demonstrated that papaverine has the potential to control SARS-CoV-2 by preventing its cytopathic effect. These experiments were carried out both in vitro and in vivo and require an extensive understanding of the mechanisms of action. With its multiple mechanisms, papaverine can be considered as a natural compound that is used to develop therapeutic drugs. To validate its applications, additional research is required into its precise therapeutic mechanisms as well as its acute and chronic toxicities. Therefore, the goal of this review is to discuss the major studies and reported clinical studies looking into the pharmacological effects of papaverine and the mechanisms of action underneath these effects. Additionally, it is recommended to conduct further research via significant pharmacodynamic and pharmacokinetic studies.

Analysis of bioactive compounds present in different crude extracts of Benincasa hispida and Cucurbita moschata seeds by gas chromatography-mass spectrometry.

Plant seeds are the resources of many different bioactive components. The chemical composition of the different crude extracts from Benincasa hispida (White pumpkin) and Cucurbita moschata (Pumpkin) seeds with three different polarity-based solvents (n-hexane, n-hexane-chloroform (2:1), and methanol) was analyzed to identify the biologically active compounds. Each of the extracts was analyzed by gas chromatography-mass spectrometry. Different extracts of targeted seeds showed different biologically active compounds that have different pharmacological potentialities. 9, 12-Octadecadienoic acid (ZZ) was the most potent bioactive compound present in three different extracts of both B. hispida and C. moschata. Another bioactive compound comparatively low percentage present in both plants was n-hexadecanoic acid. Other major pharmacologically active compounds present in both plants were 9- Octadecenoic acid (Z)-, methyl ester, and 9, 12-Octadecadienoic acid methyl ester (E, E). Besides these compounds, a few more biologically active compounds were present in the two plants separately. The findings of this study support the use of these seeds in modern functional foods, nutraceuticals, and medicinal purposes, and the whole seeds would give better health benefits rather than use any extract. Although further pharmacological examinations should be carried out to conclude the medicinal application of the seeds of these two plants as well as to understand the mechanism of the potential health benefits.

A ~24 kDa protein isolated from protein isolates of Hawaijar, popular fermented soy food of North-East India exhibited promising antidiabetic potential via stimulating PI3K/AKT/GLUT4 signaling pathway of muscle glucose metabolism.

The present study investigated the antidiabetic potential of protein isolates from Hawaijar (HPI), a popular fermented soybean food of North-East India. Treatment with HPI significantly upregulated glucose uptake, glucose utilization, glucose-6-phosphate, and stimulated PI3K/AKT/GLUT4 pathway in high-glucose (HG)-treated myotubes. Signal silencing studies demonstrated that knockdown of insulin-dependent signaling molecule (IR) but not insulin-independent signaling molecule (AMPK) significantly inhibited HPI-induced activation of PI3K/AKT/GLUT4 pathway and glucose uptake in HG-treated myotubes. SDS-PAGE and immunoblotting analyses of HPI showed the reduction and/or absence of various subunits of 7S and 11S globulin protein and appearance of new proteins compared to respective non-fermented soy protein isolates. Using various chromatographic techniques, the present study further isolated a single protein (ISP, ~24 kDa) from HPI as one of the bioactive principles with promising glucose utilization potential via stimulating PI3K/AKT/GLUT4 pathway in HG-treated cells. ISP treatment along with insulin significantly stimulated PI3K/AKT/GLUT4 pathway and glucose uptake compared to either insulin or ISP alone treated cells against HG exposure suggesting the insulin sensitizing effect of ISP. Furthermore, ISP supplementation significantly reduced metabolic markers linked with diabetes in high-fructose high-fat diet-fed animal model of type 2 diabetes. This study demonstrated a novel molecular mechanism underlying the promising antidiabetic potential of HPI.

Antidiabetic Potential of Commonly Available Fruit Plants in Bangladesh: Updates on Prospective Phytochemicals and Their Reported MoAs.

Diabetes mellitus is a life-threatening disorder affecting people of all ages and adversely disrupts their daily functions. Despite the availability of numerous synthetic-antidiabetic medications and insulin, the demand for the development of novel antidiabetic medications is increasing due to the adverse effects and growth of resistance to commercial drugs in the long-term usage. Hence, antidiabetic phytochemicals isolated from fruit plants can be a very nifty option to develop life-saving novel antidiabetic therapeutics, employing several pathways and MoAs (mechanism of actions). This review focuses on the antidiabetic potential of commonly available Bangladeshi fruits and other plant parts, such as seeds, fruit peals, leaves, and roots, along with isolated phytochemicals from these phytosources based on lab findings and mechanism of actions. Several fruits, such as orange, lemon, amla, tamarind, and others, can produce remarkable antidiabetic actions and can be dietary alternatives to antidiabetic therapies. Besides, isolated phytochemicals from these plants, such as swertisin, quercetin, rutin, naringenin, and other prospective phytochemicals, also demonstrated their candidacy for further exploration to be established as antidiabetic leads. Thus, it can be considered that fruits are one of the most valuable gifts of plants packed with a wide spectrum of bioactive phytochemicals and are widely consumed as dietary items and medicinal therapies in different civilizations and cultures. This review will provide a better understanding of diabetes management by consuming fruits and other plant parts as well as deliver innovative hints for the researchers to develop novel drugs from these plant parts and/or their phytochemicals.

Anxiolytic, antidepressant and antioxidant activity of the methanol extract of Canarium resiniferum leaves.

Background and aim: This study evaluated the anxiolytic, antidepressant, and antioxidant activity of the methanol extract of Canarium resiniferum (MECR) leaves, and determined the total phenolic and flavonoid contents in this extract. Experimental procedure: The anxiolytic effect of MECR (100, 200, 400 mg/kg, p. o.) was tested in mice using the elevated plus-maze (EPM) test, the hole-board test (HBT), and the light-dark box (LDB) test. Its antidepressant effect was evaluated in the tail suspension (TST) and the forced swim (FST) tests. The total phenolic (TPC) and flavonoid (TFC) content was measured using standard colorimetric assays. Antioxidant activity was determined using the DPPH radical scavenging and ferric reducing antioxidant power (FRAP) assays. Results and conclusion: MECR, at all doses, showed dose-dependent anxiolytic activity. At 400 mg/kg, it significantly increased the time spent and number of entries in the open arms (EPM test), the number of head-dips (HBT), and the time spent into the light compartment (LDB) test compared to the control. In the TST and FST, MECR dose-dependently reduced the duration of immobility compared to untreated animals. This was significant for all doses except for 100 mg/kg in the FST model. MECR showed high TPC and TFC (90.94 ± 0.75 mg GAE/g and 51.54 ± 0.78 mg QE/g of dried extract, respectively) and displayed potent activity in the DPPH radical scavenging (IC50 = 177.82 µg/mL) and FRAP assays. These findings indicate that C. resiniferum has the potential to alleviate anxiety and depression disorders, which merits further exploration.

Biochemical and Pharmacological aspects of Ganoderma lucidum: Exponent from the in vivo and computational investigations.

Ganoderma lucidum is known as lingzhi mushroom, which is said to have medicinal properties by the local residents. This research was focused to assess the antidepressant, anxiolytic, and sedative activities of the mentioned mushroom extracts by means of in vivo and in silico approaches. The antidepressant, anxiolytic, and sedative properties of the methanol extracts of G. lucidum (MEGL) were assessed using the forced swim test hole board, open field test, elevated plus maze, hole cross test, and thiopental sodium-induced sleeping time. The extracts revealed significant antidepressant, anxiolytic, and sedative activities in a dose-dependent manner. Rutin and quercetin were found to be the most effective enzyme inhibitors in the molecular docking study. According to the findings of in vivo and molecular docking study, it could be forecast that, the extract could have substantial antidepressant, anxiolytic, and sedative characteristics and deep molecular strategies on this extracts might create a target for the development of novel therapeutics. Further investigations are needed to appraise the molecular mechanisms implicated and isolate the bioactive components.

Opportunities and challenges in stem cell therapy in cardiovascular diseases: Position standing in 2022.

This study intends to evaluate the development, importance, pre-clinical and clinical study evaluation of stem cell therapy for the treatment of cardiovascular disease. Cardiovascular disease is one of the main causes of fatality in the whole world. Though there are great progressions in the pharmacological and other interventional treatment options, heart diseases remain a common disorder that causes long-term warnings. Recent accession promotes the symptoms and slows down the adverse effects regarding cardiac remodelling. But they cannot locate the problems of immutable loss of cardiac tissues. In this case, stem cell treatment holds a promising challenge. Stem cells are the cells that are capable of differentiating into many cells according to their needs. So, it is assumed that these cells can distinguish into many cells and if these cells can be individualized into cardiac cells then they can be used to replace the damaged tissues of the heart. There is some abridgment in this therapy, none the less stem cell therapy remains a hopeful destination in the treatment of heart disease.

A popular fermented soybean food of Northeast India exerted promising antihyperglycemic potential via stimulating PI3K/AKT/AMPK/GLUT4 signaling pathways and regulating muscle glucose metabolism in type 2 diabetes.

This study examined the antidiabetic efficacy of popular fermented soybean foods (FSF) of Northeast (NE) India. Results showed that among different FSF, aqueous extract of Hawaijar (AEH), a traditional FSF of Manipur, NE India, significantly augmented glucose utilization in cultured myotubes treated with high glucose (HG, 25 mM). Furthermore, AEH also upregulated glucose uptake, glucose-6-phosphate level, and phopho-PI3K/phospho-AKT/phospho-AMPK/GLUT4 protein expression in HG-treated myotubes. In vivo studies demonstrated that AEH supplementation (50, 100, or 200 mg/kg body weight/day, oral gavaging, 16 weeks) reduced body weight, fasting blood glucose, glycated hemoglobin, insulin resistance, and glucose intolerance in rats fed with high-fat diet (HFD). AEH supplementation stimulated phopho-PI3K/phospho-AKT/phospho-AMPK/GLUT4 signaling cascades involved in glucose metabolism of muscle tissues in diabetic rats. Chemical profiling of AEH (SDS-PAGE, immunoblotting, and HRMS) suggests the possible role of bioactive proteins/peptides and isoflavones underlying the antihyperglycemic potential AEH. Results from this study will be helpful for developing food-based prophylactics/therapeutics in managing hyperglycemia. PRACTICAL APPLICATIONS: Fermented soybean foods are gaining acceptance due to multiple health benefits. This study for the first time reports the antidiabetic potential of Hawaijar, an indigenous fermented soybean food of North-East India. Higher abundance of bioactive compounds (isoflavones and proteins/peptides) in Hawaijar may be responsible for the alleviation of impaired glucose metabolism associated with diabetes. The findings may be helpful for the development of a novel therapeutic to achieve better control of hyperglycemia and improve the lives of the patient population with diabetes.

Isolation, Characterization and Pharmacological Investigations of a New Phenolic Compound along with Four Others Firstly Reported Phytochemicals from Glycosmis cyanocarpa (Blume) Spreng.

Plants are serving the mankind with important bioactive phytochemicals from the very ancient ages to develop novel therapeutics against different disease states. Glycosmis cyanocarpa (Blume) Spreng is a plant from the Rutaceae family and a very less explored species from the Glycosmis genus. Thus, this present study was intended to present the chemical and biological investigation of Glycosmis cyanocarpa (Blume) Spreng. The chemical investigation resulted in the isolation of one new phenolic compound to the best of our knowledge which is (4-(3-hydroxy-2-methylpropyl)-2-methoxyphenol) (1) along with four known compounds that are isolated for the first time from this species- 3-methyl-1H-indole (2), Tri-transpoly-cis prenol-12 (3), Stigmasterol (4) and ß-sitosterol (5). Their chemical structures were elucidated based on extensive spectroscopic methods, including 1D and 2D NMR, and comparison with the available literature data. Isolated phytochemicals were further investigated to unveil their antioxidant properties with IC50 values (ranged from 9.97-75.48 µg/mL), cytotoxicity with LC50 values (ranged from 1.02-1.92 µg/mL), and antibacterial properties against some selected Gram (+) ve and Gram (-) ve bacteria. Among the compounds, 3-methyl-1H-indole (2) was found to be the most active against Staphylococcus aureus. Moreover, the phenolic compound (1) and the alkaloid (2) revealed the highest antioxidant (9.97 µg/mL) and cytotoxic activities (1.02 µg/mL), respectively. Thus, the isolation of these bioactive phytochemicals from the plant revealed a new perception in the study arena of drug discovery and the findings may ease the development and discovery of novel therapeutics. Further investigations are still recommended to understand their exact molecular mechanism and toxicological impact.

Role of Gut Microbiome in Autism Spectrum Disorder and Its Therapeutic Regulation.

Autism spectrum disorder (ASD) is a neurological disorder that affects normal brain development. The recent finding of the microbiota-gut-brain axis indicates the bidirectional connection between our gut and brain, demonstrating that gut microbiota can influence many neurological disorders such as autism. Most autistic patients suffer from gastrointestinal (GI) symptoms. Many studies have shown that early colonization, mode of delivery, and antibiotic usage significantly affect the gut microbiome and the onset of autism. Microbial fermentation of plant-based fiber can produce different types of short-chain fatty acid (SCFA) that may have a beneficial or detrimental effect on the gut and neurological development of autistic patients. Several comprehensive studies of the gut microbiome and microbiota-gut-brain axis help to understand the mechanism that leads to the onset of neurological disorders and find possible treatments for autism. This review integrates the findings of recent years on the gut microbiota and ASD association, mainly focusing on the characterization of specific microbiota that leads to ASD and addressing potential therapeutic interventions to restore a healthy balance of gut microbiome composition that can treat autism-associated symptoms.

Chemico-Biological Profiling of Blumea lacera (Burm.f.) DC. (Family: Asteraceae) Provides New Insights as a Potential Source of Antioxidant, Cytotoxic, Antimicrobial, and Antidiarrheal Agents.

Blumea lacera (Burm.f.) DC., popular for its traditional use in different diseases, was employed in phytochemical and biological investigations. The chemical studies led to the isolation of acyclic diterpene-phytol (1) along with two fatty acids-linolenic acid (2) and oleic acid (3). All the structures were determined by 1H NMR spectroscopic analysis and first time reported from this plant. Different fractions of crude methanol extract were subjected to antioxidant, cytotoxicity, antimicrobial, and antidiarrheal assays. The molecular docking studies have been implemented using PyRx, UCSF Chimera, Discovery Studio, and online tools. In addition, The ADME/T analysis and PASS prediction were implemented by using PASS online tools. In the molecular docking study of antioxidant, cytotoxicity, antimicrobial, and antidiarrheal activity, the compounds showed strong binding affinity ranging from -4.5 to -6.2 kcal/mol. Again, all three isolated compounds met the preconditions of Lipinski's five rules for drug discovery. In DPPH free radical scavenging assay, the pet-ether and chloroform soluble fraction showed noteworthy antioxidant activity sowing promising IC50 values (10.76 µg/ml and 11.77 µg/ml, respectively), compared to the standard (6.05 µg/ml) with a total phenolic content range of 7.33-40.33 mg of GAE/gm. The pet-ether soluble fraction revealed substantial cytotoxicity showing an LC50 value of 1.03 µg/ml, compared to the standard (0.93 µg/ml). Besides, ethyl acetate soluble fraction showed moderate activity against both Gram-positive and Gram-negative bacteria, while both ethyl acetate and pet-ether soluble fraction showed excellent dose-dependent antidiarrheal activity.

Biological Functions of Dillenia pentagyna Roxb. Against Pain, Inflammation, Fever, Diarrhea, and Thrombosis: Evidenced From in vitro, in vivo, and Molecular Docking Study.

Dillenia pentagyna Roxb. is traditionally used to treat cancer, wound healing, diabetes, and diarrhea in local tribes. This study was designed to evaluate the pharmacological potentiality of this plant. In vivo analgesic, anti-inflammatory, and antipyretic studies of the methanol extracts of D. pentagyna (MEDP) leaves were performed by using acetic acid-induced nociception, formalin-induced paw licking, and yeast-induced pyrexia assay methods, respectively. In vivo antidiarrheal activity was carried out in mice by following castor oil-induced diarrhea and gastrointestinal transit manner. In vitro thrombolytic experiment was performed employing the clot lysis activity. Besides, a molecular docking study was performed by executing the software (PyRx, Discovery Studio, and UCSF Chimera). In the acetic acid-induced writhing study, MEDP possesses significant writhing inhibition in a dose-dependent manner. It showed 50.86% of maximum inhibition of pain in the case of MEDP at a dose of 400 mg/kg body weight. In the anti-inflammatory study, maximum inhibition rate was observed at a value of 59.98 and 41.29% in early and late phases, respectively, at the dose of 400 mg/kg body weight. In the case of yeast-induced hyperpyrexia, MEDP reduced hyperpyrexia in a dose-dependent manner. In the antidiarrheal assay, MEDP moderately inhibited the occurrence of diarrhea in all the experiments. In the thrombolytic study, a moderate (17.76%) clot lysis potency has been yielded by MEDP. Again, the molecular docking simulation revealed strong binding affinities with almost all the targeted proteins. The present study suggests that the MEDP possesses remarkable pharmacological activity and this finding validated the ethnobotanical significance of D. pentagyna as the source of pain, fever, and diarrhea management agent.

Chemico-Pharmacological Screening of the Methanol Extract of Gynura nepalensis D.C. Deciphered Promising Antioxidant and Hepatoprotective Potentials: Evidenced from in vitro, in vivo, and Computer-Aided Studies.

Gynura nepalensis D.C. (family: Asteraceae) has abundant uses in the alternative medicinal practice, and this species is commonly used in the treatment of diabetes, rheumatism, cuts or wounds, asthma, kidney stones, cough, urinary tract bleeding, gall bladder stones, hepatitis, diarrhea, hemorrhoids, constipation, vomiting, fertility problems, blood poisoning, septicemia, skin allergy, indigestion, high cholesterol levels, and so on. This study aims to investigate the hepatoprotective and antioxidant potential of the methanol extract of the Gynura nepalensis D.C. (GNME) along with chemical profiling with phytochemical screening. Moreover, prospective phytocompounds have been screened virtually to present the binding affinity of the bioactive components to the hepatic and oxidative receptors. In the hepatoprotective study, alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total protein (TP), and lipid peroxidation (LP) and total bilirubin (TB) have been assessed, and in the antioxidant study, the DPPH free radical scavenging, total antioxidant flavonoid, and phenolic contents were determined. Moreover, the molecular binding affinity of the bioactive component of the plant has been analyzed using PyRx AutoDock Vina, Chimera, and Discovery Studio software. The plant extract showed dose-dependent hepatoprotective potential (p < 0.05, 0.01, 0.001) as well as strong antioxidant properties. Moreover, hepatoprotective and antioxidant molecular docking studies revealed a result varying from −2.90 kcal/mol to −10.1 kcal/mol. 4,5-dicaffeoylquinic acid and chlorogenic acid revealed the highest binding affinity among the selected molecules. However, the plant showed portent antioxidant and hepatoprotective properties in the in vitro, in vivo, and in silico models, and it is presumed that the hepatoprotective properties of the plant extract have occurred due to the presence of the vast bioactive chemical compounds as well as their antioxidant properties. Therefore, advanced studies are recommended to elucidate the pharmacological properties of the plant extracts.

mTORC1-Inhibition Potentiating Metabolic Block by Tyrosine Kinase Inhibitor Ponatinib in Multiple Myeloma.

Studies in targeting metabolism in cancer cells have shown the flexibility of cells in reprogramming their pathways away from a given metabolic block. Such behavior prompts a combination drug approach in targeting cancer metabolism, as a single compound may not address the tumor intractability. Overall, mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated as enabling metabolic escape in the case of a glycolysis block. From a library of compounds, the tyrosine kinase inhibitor ponatinib was screened to provide optimal reduction in metabolic activity in the production of adenosine triphosphate (ATP), pyruvate, and lactate for multiple myeloma cells; however, these cells displayed increasing levels of oxidative phosphorylation (OXPHOS), enabling them to continue generating ATP, although at a slower pace. The combination of ponatinib with the mTORC1 inhibitor, sirolimus, blocked OXPHOS; an effect also manifested in activity reductions for hexokinase 2 (HK2) and glucose-6-phosphate isomerase (GPI) glycolysis enzymes. There were also remarkably higher levels of reactive oxygen species (ROS) produced in mouse xenografts, on par with increased glycolytic block. The combination of ponatinib and sirolimus resulted in synergistic inhibition of tumor xenografts with no overt toxicity in treated mice for kidney and liver function or maintaining weight.

Reversing the HDAC-inhibitor mediated metabolic escape in MYCN-amplified neuroblastoma.

In MYCN-amplified neuroblastoma (NB), we noticed that the single compound treatment with the HDAC inhibitor vorinostat led to a reprogramming of the glycolytic pathway in these cells. This reprogramming was upregulation of fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS), allowing the cells to generate ATP, albeit at a reduced rate. This behavior was dependent on reduced levels of MYCN and a corresponding increase in the levels of PPARD transcription factors. By integrating metabolic and functional studies in NB cells and mouse xenografts, we demonstrate a compensatory upregulation of FAO/OXPHOS metabolism that promotes resistance to HDAC inhibitors. From the additional compounds that could reverse this metabolic reprogramming, the mTORC1 inhibitor sirolimus was selected. Besides both a block of glycolysis and OXPHOS, the HDAC/mTORC1 inhibitor combination produced significantly higher levels of reactive oxygen species (ROS) in the treated cells and in xenograft tumor samples, also a consequence of increased glycolytic block. The lead compounds were also tested for changes in the message levels of the glycolytic enzymes and their pathway activity, and HK2 and GPI glycolytic enzymes were most affected at their RNA message level. This combination was seen with no overall toxicity in treated mice in terms of weight loss or liver/kidney function.

Network Pharmacology Study to Reveal the Potentiality of a Methanol Extract of Caesalpinia sappan L. Wood against Type-2 Diabetes Mellitus.

Caesalpinia sappan L. (CS) is widely used to treat diabetic complications in south-east Asia, specifically in traditional Chinese medicine. This study intends to explain the molecular mechanism of how chemical constituents of CS interrelate with different signaling pathways and receptors involved in T2DM. GC-MS was employed to identify the chemical compounds from the methanol extract of CS wood (MECSW). Lipinski's rule of five was applied, and 33 bioactive constituents have been screened from the CS extract. After that, 124 common targets and 26 compounds associated with T2DM were identified by mining several public databases. Protein-protein interactions and compound-target network were constructed using the STRING database and Cytoscape tool. Protein-protein interactions were identified in 121 interconnected nodes active in T2DM and peroxisome proliferator-activated receptor gamma (PPARG) as key target receptors. Furthermore, pathway compound target (PCT) analysis using the merger algorithm plugin of Cytoscape revealed 121 nodes from common T2DM targets, 33 nodes from MECSW compounds and 9 nodes of the KEGG pathway. Moreover, network topology analysis determined "Fisetin tetramethyl ether" as the key chemical compound. The DAVID online tool determined seven signaling receptors, among which PPARG was found most significant in T2DM progression. Gene ontology and KEGG pathway analysis implied the involvement of nine pathways, and the peroxisome proliferator-activated receptor (PPAR) pathway was selected as the hub signaling pathway. Finally, molecular docking and quantum chemistry analysis confirmed the strong binding affinity and reactive chemical nature of fisetin tetramethyl ether with target receptors exceeding that of the conventional drug (metformin), PPARs agonist (rosiglitazone) and co-crystallized ligands, indicating that fisetin could be a potential drug of choice in T2DM management. This study depicts the interrelationship of the bioactive compounds of MECSW with the T2DM-associated signaling pathways and target receptors. It also proposes a more pharmaceutically effective substance, fisetin tetramethyl ether, over the standard drug that activates PPARG protein in the PPAR signaling pathway of T2DM.