Effectiveness of estrogen and its derivatives over dexamethasone in the treatment of COVID-19.

Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus and dexamethasone is a glucocorticoid widely used for its treatment. Dexamethasone is not used in non-severe cases due to its immunosuppressant action. So, considering this, Estrogen and Estetrol were tested for the treatment of COVID-19 as they all possess a common steroid ring and dislike dexamethasone, they are immunoenhancer. Virtual screening of test ligands was performed through molecular docking, MM-GBSA, simulations, in silico ADMET and drug-likeness prediction to identify their potential to inhibit the effects of SARS-CoV-2. Results showed that test ligands possess drug-like properties and they are safe as drug candidates. The protein-ligand interaction study revealed that they bind with the amino acid residues at the active site of the target proteins and the test ligands possess better binding potential than Dexamethasone. With protein Mpro, Estetrol and Estrogen showed docking score of -7.240 and -5.491 kcal/mol, and with protein ACE2, Estetrol and Estrogen showed docking score of -5.269 and -4.732 kcal/mol, respectively. Further, MD Simulation was carried out and most of the interactions of molecular docking are preserved during simulation. The prominent interactions that our test ligands showed during MD Simulation are similar to drugs that possess in vitro anticovid activity as shown in recent studies. Hence, our test ligands possessed potential for anticovid activity and they should be further tested through in vitro and in vivo studies for their activity against COVID-19.Communicated by Ramaswamy H. Sarma.

Explicit mechanistic insights of Prosopis juliflora extract in streptozotocin-induced diabetic rats at the molecular level.

Background: The Ancient system of medicine showed the limelight on the use of herbal remedies and was found to possess minimal side effects and acceptable therapeutic outcomes. In this context, Prosopis juliflora gained importance in managing chronic diseases such as cancer, dermatological diseases, and chronic inflammatory disorders. Hence, P. juliflora was selected for further investigation associated with diabetes and inflammation. Aim: The present study aimed to evaluate the anti-diabetic activity in chemically induced experimental rats and explore the nature of phytocomponents that may produce this activity. Methods: Experimentally, diabetes was induced by a single administration of streptozotocin at 50 mg/kg intraperitoneally in Wistar rats. The animals were treated orally with P. juliflora at low and high doses (200 and 400 mg/kg) for 10 days. Blood collected from the retro-orbital plexus was analyzed for parameters like blood glucose levels, insulin, adiponectin, Keap1 and Nrf2. PPAR-γ, AMPK and GLUT 2 levels were analyzed in the pancreatic tissue. Besides, at the end of the experiment, animals were sacrificed, and the pancreatic tissue sections were subjected for histopathological, morphometrical and immune histochemical exploration. The phytochemical composition of the plant was investigated by GC-MS. Results: The administration of P. juliflora higher dose showed a significant decrease (**p< 0.001) in blood glucose levels with a rise in adiponectin, PPARγ, Keap1, Nrf2, Glut 2, and AMPK significantly (**p< 0.001). The inflammatory cytokine TNFα was also estimated and was found to be lowered significantly (**p< 0.001) in test drug-treated animals. Furthermore, in the pancreatic tissue, the number of Islets, the area, and the number of ß-cells were improved significantly with the sub-chronic treatment of P. juliflora extract. The structure and function of ß-cells were also revamped. Conclusion: The study results demonstrated a significant effect of P. juliflora on glycemic status, inflammatory condition, and the architecture of pancreatic tissue. In the identification and isolation process by GC MS, it was noticed that P. juliflora contained few phytochemical constituents from which it might be considered a promising drug for type 2 diabetes mellitus.

Trastuzumab-Mediated Cardiotoxicity and Its Preventive Intervention by Zingerone through Antioxidant and Inflammatory Pathway in Rats.

Trastuzumab (TZB) is a new medicine, used to treat cancers of the breast and stomach. However, the cardiotoxic potential of this drug edges out its clinical advantages. The present study was designed to find out the effect of zingerone against trastuzumab-mediated cardiotoxicity in rats. In this study, five groups of rats with eight animals in each group were used. Group 1 was treated with normal saline, as a normal control (NC); Group 2 was treated with TZB (6 mg/kg/week-for five weeks) intraperitoneally as a toxic control. Groups 3 and 4 were pre-treated with zingerone (50 and 100 mg/kg, as per their body weight orally) along with five doses of TZB for five weeks, and Group 5 was treated with zingerone (100 mg/kg, body weight orally) as a control. TZB treatment showed cardiotoxicity as evidenced by increased levels of aspartate aminotransferase (AST), creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), and lipid peroxidation (LPO) and decreased level of glutathione (GSH), and antioxidant enzymes such as glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-s- transferase (GST), catalase (CAT), and superoxide dismutase (SOD) activities. Zingerone pre-treatment significantly decreased the levels of AST, CK-MB, LDH, and LPO and increased GSH and antioxidant enzymes content toward their normal level. In the TZB-alone administered group, inflammatory cytokines (IL-2 and TNF-α) levels were also elevated. Pre-treatment with zingerone restored the level of IL-2 and TNF-α toward normal level. The current findings undoubtedly demonstrated zingerone's cardioprotective nature against TZB-mediated cardiotoxicity in rats with the evidence of histopathological recall.

Synthesis, in-Silico studies and biological evaluation of pyrimidine based thiazolidinedione derivatives as potential anti-diabetic agent.

Despite the advancements in the management of Diabetes mellitus, the design and synthesis of drug molecule which ameliorates the hyperglycemia and associated secondary complications in diabetic patients, still remains a challenge. Herein, we report the synthesis, characterization and anti-diabetic evaluation of pyrimidine-thiazolidinedione derivatives. The synthesized compounds were characterized by 1H NMR, 13C NMR, FTIR and Mass Spectroscopic analytical techniques. The in-silico ADME studies depicted that the compounds were within the permissible limits of the Lipinski's rule of five. The compounds 6e and 6m showing the best results in OGTT were evaluated for in-vivo anti-diabetic evaluation in STZ induced diabetic rats. Administration of 6e and 6m for four weeks decreased the blood glucose levels significantly. Compound 6e (4.5 mg/kg p.o.) was the most potent compound of the series. It reduced the level of blood glucose to 145.2 ± 1.35 compared to the standard Pioglitazone (150.2 ± 1.06). Moreover, the 6e and 6m treated group did not show increase in bodyweight. The biochemical estimations showed that the levels of ALT, ASP, ALP, urea, creatinine, blood urea nitrogen, total protein and LDH restored to normal in 6e and 6m treated groups as compared to STZ control group. The histopathological studies supported the results obtained in biochemical estimations. Both the compounds did not show any toxicity. Moreover, the histopathological studies of pancreas, liver, heart and kidney revealed that the structural integrity of these tissues restored to almost normal in 6e and 6m treated groups as compared to STZ control group. Based upon these findings it can be concluded that the pyrimidine-based thiazolidinedione derivatives represent novel anti-diabetic agents with least side effects.

Mitochondrial oxidative damage by co-exposure to bisphenol A and acetaminophen in rat testes and its amelioration by melatonin.

OBJECTIVE: Human exposure to multiple xenobiotics, over various developmental windows, results in adverse health effects arising from these concomitant exposures. Humans are widely exposed to bisphenol A, and acetaminophen is the most commonly used over-the-counter drug worldwide. Bisphenol A is a well-recognized male reproductive toxicant, and increasing evidence suggests that acetaminophen is also detrimental to the male reproductive system. The recent recognition of male reproductive system dysfunction in conditions of suboptimal reproductive outcomes makes it crucial to investigate the contributions of toxicant exposures to infertility and sub-fertility. We aimed to identify toxicity in the male reproductive system at the mitochondrial level in response to co-exposure to bisphenol A and acetaminophen, and we investigated whether melatonin ameliorated this toxicity. METHODS: Male Wistar rats were divided into six groups (n=10 each): a control group and groups that received melatonin, bisphenol A, acetaminophen, bisphenol A and acetaminophen, and bisphenol A and acetaminophen with melatonin treatment. RESULTS: Significantly higher lipid peroxidation was observed in the testicular mitochondria and sperm in the treatment groups than in the control group. Levels of glutathione and the activities of catalase, glutathione peroxidase, glutathione reductase, and manganese superoxide dismutase decreased significantly in response to the toxicant treatments. Likewise, the toxicant treatments significantly decreased the sperm count and motility, while significantly increasing sperm mortality. Melatonin mitigated the adverse effects of bisphenol A and acetaminophen. CONCLUSION: Co-exposure to bisphenol A and acetaminophen elevated oxidative stress in the testicular mitochondria, and this effect was alleviated by melatonin.

Capsaicin Ameliorates the Cyclophosphamide-Induced Cardiotoxicity by Inhibiting Free Radicals Generation, Inflammatory Cytokines, and Apoptotic Pathway in Rats.

Cyclophosphamide is an antineoplastic agent that has a broad range of therapeutic applications; however, it has numerous side effects, including cardiotoxicity. Furthermore, chili peppers contain a substance called capsaicin, having antioxidant and anti-inflammatory effects. Thus, this research paper focuses on the potential mechanism of capsaicin's cardioprotective activity against cyclophosphamide-induced cardiotoxicity by measuring the expression of oxidative and inflammatory marker such as interleukins and caspases. The following groups of rats were randomly assigned: only vehicle given for 6 days (control group); cyclophosphamide 200 mg/kg intraperitoneal on 4th day only (positive control group); capsaicin 10 mg/kg orally given for 6 days followed by cyclophosphamide 200 mg/kg on 4th day of treatment; capsaicin 20 mg/kg orally for six days followed by cyclophosphamide 200 mg/kg on 4th day of treatment; and maximum amount of capsaicin alone (20 mg/kg) orally for six days. Using ELISA kits, it was found that the cyclophosphamide administration significantly increased the levels of lactate dehydrogenase, troponin-I (cardiac cell damage marker), lipid peroxidation, triglyceride, interleukin-6, tumor necrosis factor-alpha, and caspase 3. However, it markedly reduced the antioxidant enzymes catalase and glutathione levels. Both doses of capsaicin could reverse cardiac cell damage markers, as shown by a significant decline in (lactate dehydrogenase and troponin-I). In addition, capsaicin significantly reduced the cytokine levels (interleukin-6 and tumor necrosis factor-alpha), caspase 3, lipid peroxidation, and triglycerides. However, capsaicin treatment significantly raised the antioxidant content of enzymes such as glutathione and catalase. The capsaicin-treated group restored the oxidative parameter's imbalance and generated considerable protection against cardiomyocyte harm from cyclophosphamide in male Wistar rats. These protective effects might be beneficial against the negative impacts of cyclophosphamide when used to treat cancer and immune-mediated diseases.

Therapeutic Potential of Capsaicin against Cyclophosphamide-Induced Liver Damage.

Cyclophosphamide (CPM) is a classical alkylating agent used in different cancer chemotherapy regimens and is restricted due to severe adverse effects, including hepatotoxicity. Natural or plant-derived antioxidants such as capsaicin were utilized in this study to examine the hepatoprotective benefits against cyclophosphamide-induced hepatotoxicity. The rats were divided into five groups: a normal control group, a toxic group (CPM), an intraperitoneal injection of a single dose of 200 mg/kg b.w. on the fourth day, a pretreated group with two doses of CPS (10 mg and 20 mg/kg b.w.) orally for six consecutive days, and an intraperitoneal administration of 200 mg/kg b.w. on the fourth day of treatment. The fifth group was administered with the highest dose of CPS (20 mg/kg b.w.) orally for six consecutive days. After 24 h of administration of CPS, the rats were anesthetized, blood was collected, and the serum enzyme toxicity was evaluated. After the blood sampling and euthanasia of all the animals, the liver was isolated for further toxicity and histopathological examination. The results revealed that serum liver markers (AST, ALT, ALP, BLI) significantly increased after CPM administration, but were subsequently restored after CPS treatment with both doses. In addition, lipid peroxidation (MDA), inflammatory cytokines (IL-1ß, TNF-α), and apoptotic markers (Caspase-3) increased, and antioxidant enzymes (GSH, CAT, SOD) were significantly decreased after CPM administration, and it was re-established by CPS treatment. However, CPS effectively protected against the CPM-induced histopathological architects of liver tissues. In conclusion, CPS attenuates CPM-induced hepatotoxicity via modulating oxidative stress, apoptotic signals, and cytokine pathway. Therefore, CPS could play a significant role as a supplement during the chemotherapy of patients.

Nephroprotective Effect of Diosmin against Cisplatin-Induced Kidney Damage by Modulating IL-1ß, IL-6, TNFα and Renal Oxidative Damage.

Cisplatin (CP) is a platinum compound of the alkylating agent class that is used for the treatment of various types of cancer. However, CP treatments in cancer patients are accountable for nephrotoxicity, as it is a major adverse effect. Hence, this research study was proposed to investigate the nephroprotective effect of diosmin, a flavonoid glycoside of hesperidin derivatives against cisplatin-induced kidney damage. Wistar rats received a single intraperitoneal (i.p) injection of CP (7.5 mg/kg, i.p) to induce nephrotoxicity. The administration of CP significantly (p < 0.001) increased the markers of kidney function test (creatinine, blood urea nitrogen, and uric acid) and demonstrated histopathological changes in the kidney of the CP-treated nephrotoxic group. In addition, the CP-treated nephrotoxic group demonstrated a significant (p < 0.001) increase in lipid peroxidation (LPO) levels and depleted activities of reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and catalase (CAT).However, diosmin (100 and 200 mg/kg) treatments significantly reduced the elevated levels of kidney function test parameters and restored structural changes in the kidney (p < 0.001). The administration of diosmin (100 and 200 mg/kg) significantly (p < 0.001) reduced LPO levels, increased GSH content and showed improvements in the activities of GPx, GR, SOD and CAT. The markers of inflammatory cytokines such as IL-1ß, IL-6 and TNFα significantly (p < 0.001) increased in the CP-treated nephrotoxic group, whereas diosmin (100 and 200 mg/kg) treatments significantly (p < 0.001) reduced the elevated levels of these cytokines. The findings of this research demonstrate the nephroprotective effect of diosmin against CP-induced kidney damage. Therefore, we conclude that diosmin may be used as a supplement in the management of nephrotoxicity associated with CP treatments in cancer patients.

Hepatoprotective potential of diosmin against hepatotoxic effect of isoniazid and rifampin in wistar rats.

OBJECTIVE: The treatment of tuberculosis with isoniazid and rifampin is associated with hepatocellular damage. Therefore, the study was designed to evaluate the hepatoprotective potential of diosmin against hepatotoxic effect of isoniazid and rifampin in Wistar rats. METHODS: Hepatotoxicity was induced by administering isoniazid and rifampin (100 mg/kg), whereas diosmin was given as treatment control. Markers of liver function (ALT, AST, ALP and bilirubin), inflammatory cytokines (TNFα, IL-6 and IL-1ß), apoptosis (caspase-3), oxidative stress parameters (LPO, GSH, CAT and SOD) and histological changes in liver were assessed in normal, hepatotoxic control and treatment groups. RESULTS: The administration of isoniazid and rifampin significantly increased markers of liver dysfunction (ALT, AST, ALP and bilirubin), cytokines (TNFα, IL-6 and IL-1ß) and apoptosis (caspase-3). However, daily dosing of diosmin significantly reduced these markers of liver dysfunction, inflammatory cytokines and apoptosis to near normal levels. Additionally, markers of hepatocellular oxidative stress parameters were significantly altered as evident from increased LPO level and decreased endogenous antioxidants such as GSH, SOD and CAT in isoniazid-and rifampin-treated hepatotoxic group. It was observed that diosmin treatment reduced high levels of LPO and demonstrated significant improvement in antioxidant levels. Histological studies of liver also supported our biochemical findings, which are also manifested as diosmin treatment exhibited protection against hepatocellular degeneration and inflammation. CONCLUSION: Results of the present study demonstrate hepatoprotective potential of diosmin against isoniazid-and rifampin-treated hepatotoxicity. Thus, we conclude that diosmin may be used along with anti-tubercular drugs (isoniazid and rifampin) in tuberculosis patients to overcome their hepatotoxic adverse effect.

Zingerone Attenuates Carfilzomib-Induced Cardiotoxicity in Rats through Oxidative Stress and Inflammatory Cytokine Network.

Carfilzomib (CFZ) is an anticancer medication acting as a selective proteasome inhibitor. However, it can cause cardiovascular problems, increasing mortality and morbidity. This study aimed to investigate whether zingerone (ZRN) could help reduce carfilzomib-induced cardiotoxicity in Wistar albino rats. Rats were divided into five groups of six animals each. The first group received normal saline as a control (NC); the second group received multiple doses (six) of CFZ (4 mg/kg) intraperitoneally (IP); the third and fourth groups received zingerone (50 mg/kg and 100 mg/kg oral) along with six doses of CFZ for 16 days; and the fifth group received only 100 mg/kg zingerone orally. Hematological, biochemical, oxidative stress, and histopathological studies confirmed the findings of CFZ-induced cardiotoxicity. We found that ZRN significantly attenuated the effects of CFZ on oxidative stress by enhancing the antioxidant properties of glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Additionally, ZRN reduces inflammatory cytokines and apoptotic markers, such as IL-1ß, IL-6, TNFα, and caspase-3. Overall, zingerone prevents carfilzomib-induced cardiotoxicity in rats, as evidenced by histopathological studies.

The Protective Effects of Sesamin against Cyclophosphamide-Induced Nephrotoxicity through Modulation of Oxidative Stress, Inflammatory-Cytokines and Apoptosis in Rats.

Cyclophosphamide is an anticancer drug with a wide spectrum of clinical uses, but its typical side effects are multiple complications, including nephron toxicity. The possible molecular mechanism of the nephroprotective action of sesamin (SM) against cyclophosphamide (CP) induced renal toxicity was investigated in rats by understanding oxidative stress and inflammatory cytokines. In this study, rats were arbitrarily grouped into the following four groups: a normal control group (CNT); a CP-induced toxicity group; a treatment group with two doses of sesamin SM10 and SM20; a group with sesamin (SM20) alone. A single dose of CP (150 mg/kg body, i.p.) was administered on day 4 of the experiments, while treatment with SM was given orally for seven days from day 1. The group treated with SM showed a significant protective effect against CP-induced renal damage in rats. Treatment with SM significantly increased the antioxidant enzymes (GSH, CAT, and SOD) and reduced malondialdehyde (MDA) levels. Thus, SM significantly overcame the elevated kidney function markers (creatinine, blood urea nitrogen, and uric acid) by attenuating oxidative stress. The SM also significantly reduced the elevated cytokines (IL-1ß and TNFα) and caspase-3 in the treated group. Histopathological studies confirmed the protective effect of sesamin (SM) on CP-induced nephrotoxicity. In conclusion, the current findings support the nephroprotective effect of sesamin against CP-induced renal injury.

Heterocyclic Moieties as HDAC Inhibitors: Role in Cancer Therapeutics.

'Epigenetic' regulation of genes via post-translational modulation of proteins is a wellexplored approach for disease therapies, particularly cancer chemotherapeutics. Histone deacetylases (HDACs) are one of the important epigenetic targets and are mainly responsible for balancing the acetylation/deacetylation of lysine amino acids on histone/nonhistone proteins along with histone acetyltransferase (HAT). HDAC inhibitors (HDACIs) have become important biologically active compounds for the treatment of cancers due to cell cycle arrest, differentiation, and apoptosis in tumor cells, thus leading to anticancer activity. Out of the four classes of HDAC, i.e., Class I, II, III, and IV, HDACIs act on Class IV (Zinc dependent HDAC), and various FDA-approved drugs belong to this category. The required canonical pharmacophore model (zinc-binding group, surface recognition cap, and appropriate linker) supported by HDACIs, various heterocyclic moieties containing compounds exhibiting HDAC inhibitory activity, and structure-activity relationship of different synthetic derivatives reported during the last twelve years have been summarized in this review.

Effect of thymoquinone on high fat diet and STZ-induced experimental type 2 diabetes: A mechanistic insight by in vivo and in silico studies.

The aim was to investigate whether thymoquinone (TQ) attenuates hyperglycemia-induced insulin resistance in experimental type 2 diabetes. Type 2 diabetes mellitus (T2DM) was induced by injection of streptozotocin (STZ, 40 mg/kg) in high fat diet (HFD) rats. The levels of glucose, insulin, area under curve (AUC) of glucose, lipid profile parameters, homeostasis model assessment of insulin resistance (HOMA-IR), peroxisome proliferator-activated receptor-γ (PPARγ), and dipeptidyl peptidase peptidase-IV (DPP-IV) were evaluated in HFD + STZ-induced type 2 diabetic rats. TQ treatment significantly reduced elevated levels of glucose, AUC of glucose, insulin, and DPP-IV in diabetic-treated groups. In addition, TQ treatment significantly reduced high levels of triglycerides (TG) and cholesterols (total, low-density and very low-density lipoprotein) accompanied by significant augmentation in high-density lipoprotein (HDL) levels in diabetic-treated groups. However, TQ treatment significantly improved insulin sensitivity in diabetic-treated groups, which was confirmed by increased level of PPARγ and decreased level of HOMA-IR. Molecular docking of TQ exhibited substantial binding affinity with PPARγ and DPP-IV target proteins, which is supported by in vivo results. These results demonstrate that TQ attenuates hyperglycemia-induced insulin resistance by counteracting hyperinsulinemia, improving lipid profile, insulin sensitivity, and inhibiting DPP-IV. PRACTICAL APPLICATIONS: T2DM results in relentless hyperglycemia which eventually progress to a state of insulin resistance. TQ is an active principle compound found in Nigella sative seed, having myriad of traditional medicinal values. Administration of TQ significantly prevented hyperglycemia, hyperinsulinemia, hyperlipidemia, insulin resistance, and inhibited DPP-IV in experimental type 2 diabetes. The in vivo results are also supported by molecular docking study of PPARγ and DPP-IV target proteins. Thus, we hypothesize that TQ can be used as an alternative natural drug in the management of hyperglycemia-induced insulin resistance in T2DM.

Modulatory effect of zingerone against STZ-nicotinamide induced type-2 diabetes mellitus in rats.

The objective of this research was to explore the role of zingerone on hyperglycemia, hyperlipidemia, insulin level, oxidative biochemical markers and histological alterations in ß-cells of type-2 diabetic rats. The outcome of this study illustrates reduction in glucose and insulin levels significantly in zingerone-treated diabetic groups. Lipid parameters were resumed to normal in zingerone-treated diabetic group as demonstrated by significant reduction in triglycerides, cholesterols (total, low-density and very low-density) levels along with significant increase high-density cholesterols levels. Zingerone-treated diabetic groups exhibited significant reduction in LPO levels and restoration of GSH contents. Administration of zingerone to treated diabetic groups indicated improvement in antioxidant enzymes (GPx, GR, GST, SOD and CAT). Administration of zingerone to treated diabetic groups minimized degeneration of pancreatic ß-cells as witnessed from histopathological studies. Our results demonstrate that zingerone modulates hyperglycaemia, hyperlipidaemia, oxidative biochemical markers and degenerative changes in ß-cells of treated diabetic groups.

Hepatoprotective Potential of Sargassum muticum against STZ-Induced Diabetic Liver Damage in Wistar Rats by Inhibiting Cytokines and the Apoptosis Pathway.

Liver inflammation and necrosis are the foremost problems interlinked with diabetes mellitus (DM). The methanolic extract of Sargassum muticum (MESM) plays a hepatoprotective role in streptozotocin- (STZ-) induced hepatic injury. In this study, STZ exposure induced diabetes that augmented hepatic damage, which was reflected in serum enzyme markers, the cytokine network, and caspase-3 and caspase-9 levels in Group 2. Exposure to the MESM tremendously modulated the levels of hepatic enzyme markers ALP, ACP, ALT, and AST in Groups 3 and 4. The cytokine network was well regulated by suppressing the release of cytokines, and the levels of caspase-3 and caspase-9 were also reduced in Groups 3 and 4. The present study suggests that MESM treatment at 200 and 500 mg protected the liver and also minimizes the glucose level. Thus, the MESM plays a key role in rejuvenating the liver and can modulate diabetes's pathogenic effect by reducing the glucose level.

Unveiling novel diphenyl-1H-pyrazole based acrylates tethered to 1,2,3-triazole as promising apoptosis inducing cytotoxic and anti-inflammatory agents.

Meagre and suboptimal therapeutic response along with the side effect profile associated with the existing anticancer therapy have necessitated the development of new therapeutic modalities to curb this disease. Bearing in mind the current scenario, a series of 1,2,3-triazole linked 3-(1,3-diphenyl-1H-pyrazol-4-yl)acrylates was synthesized following a multi-step reaction scheme. Initial screening for anticancer potential was done by in vitro sulforhodamine B assay against four human cancer cell lines- MCF-7 (breast), A549 (Lung) and HCT-116 and HT-29 (Colon). On evaluation, several compounds showed promising growth inhibition against all the cell lines, particularly compounds 6e, 6f and 6n. Among them, compound 6f displayed IC50 values of 1.962, 3.597, 1.764 and 4.496 µM against A549, HCT-116, MCF-7 and HT-29 cell lines respectively. Furthermore, the apoptosis inducing potential of the compounds was determined by Hoechst staining and DNA fragmentation assay. Colony formation inhibition assay was also carried out to determine the long term cytotoxic potential of the molecules. Moreover, compounds 6e, 6f and 6n were also evaluated for anti-inflammatory activity by protein albumin denaturation assay and red blood cell membrane stabilizing assay.

Thymoquinone and fluoxetine alleviate depression via attenuating oxidative damage and inflammatory markers in type-2 diabetic rats.

The study was designed to find out the effect of thymoquinone (TQ) alone and combination of TQ + fluoxetine in depression of type-2 diabetic rats. Glucose level was significantly decreased in TQ alone treated group, whereas no significant change was recorded when TQ was combined with fluoxetine. Administration of TQ alone and combination of TQ and fluoxetine significantly decreased immobility time, increased latency to immobility and increased locomotor activity. Treatment with TQ alone significantly decreased level of TBARS, increased GSH and restored the activities of antioxidant enzymes (GPx, GR & CAT). However, TQ and fluoxetine combination reduced TBARS level, increased GSH content but no change in the antioxidant enzymes activities. Inflammatory markers (IL-1ß, IL-6 & TNF-α) levels were significantly reduced after the administration of TQ alone and TQ + fluoxetine. The study suggests that combination of TQ and fluoxetine can be used to control depression in type-2 diabetes mellitus.

The combination of canagliflozin and omega-3 fatty acid ameliorates insulin resistance and cardiac biomarkers via modulation of inflammatory cytokines in type 2 diabetic rats.

The present study was carried out with the hypothesis that combination of canagliflozin and omega-3 fatty acid may have potential effect on insulin level, insulin resistance, cardiac biomarkers, inflammatory cytokines and histological studies in type 2 diabetes mellitus (DM). Type 2 DM was induced by injecting nicotinamide (120 mg/kg, i.p.) 15 min before STZ (60 mg/kg) injection. Canagliflozin (5 and 10 mg/kg) and omega-3 fatty acid (300 mg/kg) were given for 28 days after confirmation of diabetes. Biochemical estimations revealed elevated levels of glucose, insulin, HOMA-R and inflammatory cytokines in diabetic group. Daily dosing of alone canagliflozin and omega-3 fatty acid slightly reduced elevated levels of glucose, insulin, HOMA-R and inflammatory cytokines (IL-1ß, IL-2, and TNFα), whereas canagliflozin and omega-3 fatty acid combination has reduced these biochemical parameters significantly when compared with diabetic group. Similarly in diabetic group the levels of cardiac biomarkers such as lipid profile, LDH, CKMB and troponin were significantly increased. Elevated levels of cardiac biomarkers were significantly reduced after daily dosing of alone canagliflozin and omega-3 fatty acid. Canagliflozin and omega-3 fatty acid combination has offered better improvement in cardiac biomarkers compared to alone canagliflozin and omega-3 fatty acid. Histopathological analysis also supported the above hypothesis that combination therapy (canagliflozin and omega-3 fatty acid) offered better protection against degenerative changes in ß-cells of pancreas as compared to alone treatment with these drugs. Thus the present study revealed that canagliflozin and omega-3 fatty acid can be used as potential combination therapy in type 2 DM along with cardiac complication.

Therapeutic potential of Vanillylacetone against CCl4 induced hepatotoxicity by suppressing the serum marker, oxidative stress, inflammatory cytokines and apoptosis in Swiss albino mice.

The aim of this research was to investigate the therapeutic potential of Vanillylacetone against carbon tetrachloride (CCl4) induced hepatotoxicity in mice through understanding the serum marker, oxidative stress mechanism and cytokine networks. Carbon tetrachloride is highly hepatotoxic used as research based on animal model. The mice were classified into five groups and each had eight mice. Group-I was controlled and the vehicle was given orally. Group-II was toxic and carbon tetrachloride (1.5 ml/kg) twice a week for 15 days was administered by intra-peritoneal injections. Group- III and IV were pre-treated with Vanillylacetone 50 & 100 mg kg-1 body weight given every day p.o. while, Group-V received only Vanillylacetone (100 mg kg-1 body weight) for 15 days orally. The finding indicates that the administration of CCl4 causes significant elevation of enzyme markers, oxidative stress, inflammatory cytokine and apoptotic markers in Group-II as compared to Group-I. The administration of Vanillylacetone (50 and100 mg kg-1) significantly suppresses the elevated serum enzymes, oxidative stress (TBARS), an inflammatory cytokine (IL2 and TNFα) and apoptotic markers (Caspase-3 and 9) in Group-III and IV as compared to Group-II. It was also noticed that the higher dose of Vanillylacetone (100 mg) is more effective than lower dose of Vanillylacetone (50 mg). There were no significant changes observed with higher dose of Vanillylacetone (100 mg kg-1) in Group-V as compared to Group-I. Histopathological analysis also supported the above findings. Overall, this results shows that Vanillylacetone has a good antioxidant and therapeutic properties which can help in preventing the chemically (CCl4) induced hepatotoxicity.

Thymoquinone Ameliorates Doxorubicin-Induced Cardiotoxicity in Swiss Albino Mice by Modulating Oxidative Damage and Cellular Inflammation.

Thymoquinone is the active constituent of Nigella sativa, having antioxidant and anti-inflammatory actions. In present study, we have analyzed the effects of thymoquinone on doxorubicin (DOX) induced cardiotoxicity in mice. In this experiment, thirty mice (25-35 gm) were divided into five groups (Groups A, B, C, D, and E) each containing six animals. Normal saline was given to a control group (Group A) for 14 days. Cardiotoxicity was induced by DOX (15 mg/kg, i.p.) in Group B, once on the 13th day of the study, and Groups C and D also received DOX (15 mg/kg, i.p.) and were then treated with thymoquinone (10 and 20 mg/kg, b/w, p.o.), respectively, for 14 days. Group E was given only thymoquione (20 mg/kg b/w, p.o.). A blood serum marker (AST, ALT, CK-MB, and LDH) and oxidative stress marker (LPO, GSH, CAT, SOD, GPx, GR, and GST) were evaluated. Results revealed that serum enzyme marker like aspartate aminotransferase (AST), creatinine kinase-MB (CKMB), and lactate dehydrogenase (LDH) were significantly elevated in Group B as compare to Group A. Similarly, the oxidative stress marker lipid peroxidation (LPO) was also elevated in Group B while the antioxidant enzyme catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase (CAT, SOD, GPx, GR, and GST) were also decreased in Group B. The treatment with thymoquinone 10 and 20 mg/kg resulted in a significant decrease in the serum marker and increase in the antioxidant enzymes. In this study, we have found that thymoquinone prevented DOX-induced cardiotoxicity by accelerating heart antioxidant defense mechanisms and down regulating the LPO levels towards normalcy in Groups C and D. The effect of doxorubicin increases the inflammatory cytokine (IL2) in Group B as compared to Group A, and it overcomes by the thymoquinone in Groups C and D. Thus, thymoquinone may have utility as a potential drug for cardiomyopathy.