Synthesis, biological evaluation and theoretical studies of (E)-1-(4-sulfamoyl-phenylethyl)-3-arylidene-5-aryl-1H-pyrrol-2(3H)-ones as human carbonic anhydrase inhibitors.

A series of 20 newly designed (E)-1-(4-sulphamoylphenylethyl)-3-arylidene-5-aryl-1H-pyrrol-2(3H)-ones was synthesised and assessed as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors towards four human isoforms of pharmaceutical interest, that is, hCA I, II, IX and XII. The compounds displayed low to high nanomolar potency against all the isoforms. Introducing strong electron withdrawing groups at the para position of the arylidene ring increased the binding affinity to the enzyme. All compounds showed acceptable pharmacokinetic range and physicochemical characteristics as determined by computational ADMET analysis. Density Functional Theory (DFT) calculations of 3n were carried to gain understanding on the stability of the E and Z isomers. The energy values clearly indicate the stability of E isomer over Z isomer by -8.2 kJ mol-1. Our findings indicate that these molecules are useful as leads for discovering new CA inhibitors.

Embelin ameliorates cognitive dysfunction and progression of kindling in pentylenetetrazol-induced kindling in mice by attenuating brain inflammation.

OBJECTIVE: This study was conducted to evaluate the effect of embelin (EMB) on various epileptic models and related brain inflammation. METHODS: Male Swiss albino mice were administered EMB (5, 10, and 20 mg/kg/p.o.) in acute and chronic study for 7 days and 35 days, respectively. Acute study included increasing current electroshock (ICES) and pentylenetetrazol (PTZ)-induced seizure test. Step-down latency (SDL) and forced swim test (FST) were performed to evaluate cognitive functions and depression-like behavior, respectively. Chronic study included PTZ-induced kindling. Levels of inflammatory biomarkers, namely interleukin-1 beta (IL-1ß), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), were estimated in the hippocampus and cortex of the kindled brains by ELISA technique. Further, neurotransmitters (NTs), namely gamma aminobutyric acid (GABA), glutamate, and dopamine, were estimated by using validated liquid chromatography-mass spectrometry (LC-MS) method followed by ultra-high-performance liquid chromatography (UHPLC). RESULTS: Embelin (EMB) treatment increased the seizure threshold to hind limb extension (HLE) in the ICES test and decreased the seizure scores in the kindling experiment. Significantly low levels of IL-1ß, IL-1Ra, IL-6, and TNF-α were observed in the hippocampus of PTZ + EMB (10 and 20 mg/kg)-treated groups compared with PTZ+ vehicle-treated group. Significantly lower levels of IL-1Ra, IL-6, and TNF-α compared with PTZ+ vehicle-treated group were observed in the cortex of PTZ + EMB (10 and 20 mg/kg)-treated groups, while IL-1ß levels were found to be significantly lower only in the cortex of PTZ + EMB (20 mg/kg)-treated group. Increased levels of dopamine and GABA and decreased levels of glutamate in both hippocampus and cortex were observed in EMB + PTZ-treated groups compared with vehicle + PTZ-treated group. Latency of step down was found to be increased and immobility time in FST was decreased in EMB + PTZ groups compared with vehicle + PTZ group. CONCLUSION: Embelin suppressed epileptogenesis in the kindled mice via neurochemical modulation of neurotransmitters and inhibiting the inflammatory pathway. Further, EMB was also observed to be protecting the kindled animals from cognition and depression-like behavior.

Application of chemometric approach for development and validation of high performance liquid chromatography method for estimation of ropinirole hydrochloride.

A systematic Quality by Design approach was employed for developing an isocratic reversed-phase liquid chromatographic technique for the estimation of ropinirole hydrochloride in bulk drug and pharmaceutical formulations. LiChrospher RP 18-5 Endcapped column (25 cm × 4.6 mm id) at ambient temperature (25 ± 2°C) was used for the chromatographic separation of the drug. The screening of factors influencing chromatographic separation of the active pharmaceutical ingredient was performed employing fractional factorial design to identify the influential factors. Optimization of the selected factors was carried out using central composite design for selecting the optimum chomatographic conditions. The mobile phase employed was constituted of Solvent A/Solvent B (65:35 v/v) (Solvent A [methanol/0.05 M ammonium acetate buffer, pH 7, 80:20 v/v] and Solvent B [high performance liquid chromatography grade water]) and used at 0.6 mL/min flow rate, while UV detection was performed at 250 nm. Linearity was achieved in the drug concentration range 5-100 µg/mL (R2  = 0.9998) with limits of detection and quantification of 1.02 and 3.09 µg/mL, respectively. Method validation was performed as per ICH guidelines followed by forced degradation studies, which indicated good specificity of the developed method for detecting ropinirole hydrochloride and its possible degradation products in the bulk drug and pharmaceutical formulations.

Pyridazinone substituted benzenesulfonamides as potent carbonic anhydrase inhibitors.

A series of sulfonamide derivatives (2a-l) incorporating substituted pyridazinone moieties were investigated for the inhibition of two human cytosolic carbonic anhydrase isoforms, hCA I and hCA II. All these compounds, together with the clinically used sulfonamide acetazolamide were investigated as inhibitors of the physiologically relevant isozymes I and II. These sulfonamides showed very strong inhibition against all these isoforms with K(I)'s in the range of 0.98-8.5 nM which makes such molecules possible to be used as leads for discovery of novel effective CA inhibitors targeting other isoforms with medicinal chemistry applications.

Design and synthesis of pyridazinone-substituted benzenesulphonylurea derivatives as anti-hyperglycaemic agents and inhibitors of aldose reductase - an enzyme embroiled in diabetic complications.

Thirty new aryl-pyridazinone-substituted benzenesulphonylurea derivatives (I-XXX) were synthesized and evaluated for their anti-hyperglycaemic activity in glucose-fed hyperglycaemic normal rats. Twenty-three compounds (III-XI, XIV-XVII, XIX-XXIV, XXVI and XXVIII-XXX) showed more or comparable area under the curve (AUC) reduction percentage (ranging from 21.9% to 35.5%) as compared to the standard drug gliclazide (22.0%). On the basis of docking results, 18 compounds were screened for their in vitro ability to inhibit rat lens aldose reductase. Ten compounds (III-VI, XII, XVI-XVIII, XXI and XXVII) showed ARI activity with IC50 ranging from 34 to 242 µM. Out of these, two compounds IV and V showed best ARI activity which is comparable with that of quercetin. As a result, two compounds (IV and V) possessing significant dual action (anti-hyperglycaemic and aldose reductase inhibition) were identified and may be used as lead compounds for developing new drugs.

Synthesis and Biological Evaluation of New Phthalazinone Derivatives as Anti-Inflammatory and Anti-Proliferative Agents.

The chemistry of phthalazine derivatives has been of increasing interest since many of these compounds have found many chemotherapeutic applications. So this study aims to synthesize a library of phthalazine derivatives and to investigate their anti-inflammatory and anti-proliferative activities. Sixteen new phthalazinone derivatives (2a-p) were synthesized and tested for their in vitro antiproliferative and in vivo anti-inflammatory activities. All the synthesized compounds were identified and characterized by IR, (1) H NMR, (13) C NMR spectroscopy, and MS. Two compounds, 2b and 2i, showed significant anti-inflammatory activity comparable with that of the standard drug etoricoxib in the carrageenan-induced rat paw edema model at 3 and 5 h, respectively. Three compounds (2h, 2j, and 2g) showed moderate sensitivity toward the renal cancer cell line UO-31.

Synthesis and evaluation of some new pyrazoline substituted benzenesulfonylureas as potential antiproliferative agents.

Twenty six new pyrazoline substituted benzenesulfonylureas (2a-z) were synthesized and tested for in vitro anticancer activity. Fourteen derivatives (2i, 2k-2p, 2r, 2s-2x) were screened for their antiproliferative activity towards 60 human cancer cell lines by the National Cancer Institute (USA). Among them four compounds (2i, 2n, 2v and 2x) exhibited significant growth inhibition and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 µM). The compounds 2i, 2n, 2v and 2x showed effective growth inhibition (GI50 MID) values of 2.62, 3.93, 3.33, 3.74 µM respectively beside cytostatic activity TGI (MG-MID) values of 8.42, 65.80, 24.00 and 36.06 µM respectively. The compound 2i displayed remarkable antiproliferative activity in 8 different cell lines with GI50 less than 2 µM. Compounds 2n, 2v and 2x also displayed good antiproliferative activity against 11, 18 and 14 different cell lines respectively with GI50 less than 3 µM.

Synthesis and blood glucose lowering activity of some novel benzenesulfonylthiourea derivatives substituted with 4-aryl-1-oxophthalazin-2(1H)yl-ones.

Some new benzenesulfonylthiourea derivatives substituted with phthalazones (2a-q) were synthesized by refluxing the appropriate 4-aryl-1-oxophthalazin-2(1H)yl benzenesulfonamides with isothiocyanate in dry acetone over anhydrous K2CO3. All the synthesized compounds were characterized on the basis of IR, (1)H NMR, MS data and elemental analysis. These synthesized compounds (2a-q) at the dose of 20 mg/kg were tested for antihyperglycemic activity in the glucose-fed hyperglycemic normal rat model and among these compounds 2f and 2m showed modest antihyperglycemic activity.

Palladium Nanoparticles and Lung Health: Assessing Morphology-Dependent Subacute Toxicity in Rats and Toxicity Modulation by Naringin - Paving the Way for Cleaner Vehicular Emissions.

The release of palladium nanoparticles (PdNPs) from autocatalytic converters has raised concerns regarding public health and the environment due to their emergence as anthropogenic contaminants. With growing vehicular population, there is an urgent need for comprehensive toxicological studies of PdNPs to mitigate their risk. The present study aims to investigate the effects of spherical PdNPs with average sizes of 20 and 80 nm, as well as Pd nanorods, on the lung function of female Wistar rats following oral exposure to environmentally relevant doses (1 and 10 µg/kg) over a period of 28 days. Various biological parameters were evaluated, including liver and kidney biochemical changes, lung oxidative stress markers (SOD, CAT, GSH, LPO), lung inflammatory markers (IL-1ß, IL-8, IL-6, and TNF-α), and histopathological alterations in the lungs. Additionally, the potential mitigating effects of naringin on PdNPs-induced toxicity were examined. The results demonstrate a significant increase in oxidative stress, the onset of inflammation, and histological changes in lung alveolar sacs upon exposure to all tested particles. Specifically, 20@PdNPs and PdNRs exhibited higher cytotoxicity and pro-inflammatory properties compared to 80@PdNPs. Naringin effectively attenuated the pulmonary toxicity induced by PdNPs by modulating oxidative and inflammatory pathways. These findings contribute to the sustainable development of PdNPs for their future applications in the biomedical and environmental sectors, ensuring the advancement of safe and sustainable nanotechnology.

Synthesis and anti-inflammatory activity of celecoxib like compounds.

Nine novel 4-[3-(4-Dimethylamino-phenyl)-5-aryl-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamides (2a-i) were synthesized and evaluated for their anti-inflammatory and antiproliferative activities. These compounds (2a-i) showed moderate to strong anti-inflammatory activity in carrageenan rat paw oedema test. Compounds 2b, 2d and 2g showing comparable anti-inflammatory activity to that of reference drug celecoxib were evaluated for their ulcerogenic and analgesic activities. The effect of 2b, 2d and 2g on the content of NO, TNF-α and PGE2 in exudates from rat paw stimulated by carrageenan was also evaluated. The compound 2c showed considerable antitumor activities against all 60 human tumor cell lines with effective GI50 (MG-MID) value of 3.63 µM. It exhibited maximum activity against melanoma (LOX IMVI and SK-MEL-5) cancer cell lines with GI50 value less than 2 µM.

Synthesis and biological evaluation of 4-arylphthalazones bearing benzenesulfonamide as anti-inflammatory and anti-cancer agents.

Nine 4-arylphthalazones bearing benzenesulfonamide (2a-i) were synthesized by the condensation of the appropriate 2-aroylbenzoic acid (1a-i) and 4-hydrazinobenzenesulfonamide in ethanol. The structures of these compounds were elucidated by elemental analysis, IR, ¹H NMR, ¹³C NMR, and MS spectroscopy. Two compounds, 2b and 2i, showed significant anti-inflammatory activity comparable to that of the standard drug celecoxib in the carrageenan-induced rat paw edema model. These compounds (2b and 2i) had selective inhibitory activity towards the COX-2 enzyme. Compound 2b had a better selectivity ratio (COX-1/COX-2) compared to that of celecoxib and can be used as a novel template for the design of selective COX-2 inhibitors. Compounds 2d and 2i were screened for their antiproliferative activity toward 60 human cancer cell lines by the National Cancer Institute (USA). The compounds 2d and 2i displayed mild activity toward the renal cancer cell line UO-31.

Fisetin provides neuroprotection in pentylenetetrazole-induced cognition impairment by upregulating CREB/BDNF.

OBJECTIVES: Fisetin is a flavonoid molecule known to be neuroprotective by its multiple mechanisms. The present study was designed to explore the effect of fisetin in the pentylenetetrazole (PTZ) kindling-induced cognitive dysfunction in mice. METHODS: Kindling was established by the intraperitoneal administration of PTZ in a subconvulsive dose (25 mg/kg). Mice were administered fisetin (5, 10, and 20 mg/kg, p.o.) to study its probable cognition-enhancing effect. The kindled mice were evaluated for cognition using behavioral tests-elevated plus maze and passive avoidance response. Then, the oxidative stress markers, gene expressions and neurotransmitters levels were estimated in the hippocampus and cortex of mice. RESULTS: Passive avoidance response and elevated plus maze paradigms showed that fisetin administration improved the cognitive function in kindled mice. The increased levels of lipid peroxidation and protein carbonyl were modulated upon fisetin administration through increasing the levels of antioxidants (reduced glutathione, glutathione reductase, glutathione peroxidase, superoxide dismutase, and catalase) in the hippocampus and cortex of kindled mice. Upregulated gene expressions of cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were observed in the hippocampus and cortex of fisetin-administered mice which play a crucial role in cognitive function. Furthermore, alterations of neurotransmitter levels (dopamine, GABA, and glutamate) and acetylcholinesterase (AchE) were ameliorated by fisetin administration in the hippocampus and cortex of kindled mice. CONCLUSION: Our findings suggest a therapeutic potential of fisetin against cognitive dysfunction associated with PTZ-induced kindling.

Magnoflorine-Loaded Chitosan Collagen Nanocapsules Ameliorate Cognitive Deficit in Scopolamine-Induced Alzheimer's Disease-like Conditions in a Rat Model by Downregulating IL-1ß, IL-6, TNF-α, and Oxidative Stress and Upregulating Brain-Derived Neurotrophic Factor and DCX Expressions.

Dementia or the loss of cognitive functioning is one of the major health issues in elderly people. Alzheimer's disease (AD) is one of the common forms of dementia. Treatment chiefly involves the use of acetylcholinesterase (AChE) inhibitors in AD. However, oxidative stress has also been found to be involved in the proliferation of the disease. Magnoflorine is one of the active compounds of Coptidis Rhizoma and has high anti-oxidative properties. Active principle-loaded nanoparticles have shown increased efficiency for neurodegenerative diseases due to their ability to cross the blood-brain barrier more easily. An in vitro study involving magnoflorine-loaded chitosan collagen nanocapsules (MF-CCNc) has shown them to possess inhibitory effects against oxidative stress and to some extent on AChE as well. In the current study, both nootropic and anti-amnesic effects of magnoflorine and MF-CCNc on scopolamine-induced amnesia in rats were evaluated. The treatment was done intraperitoneally (i.p.) once daily for 17 consecutive days with MF-CCNc (0.25, 0.5, and 1 mg), magnoflorine (1 mg), and donepezil (1 mg). To induce amnesia, hence, cognitive deficit rats were induced with scopolamine (1 mg/kg) daily for the last 9 days. Novel object recognition (NOR) and elevated plus maze (EPM) behavioral analysis were done to assess memory functioning. Hippocampal tissues were extracted to study the effect on biochemicals (AChE, MDA, SOD, and CAT), pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α), and immunohistochemistry (brain-derived neurotrophic factor (BDNF) and DCX). MF-CCNc showed memory-enhancing effects in nootropic as well as chronic scopolamine-treated rats in NOR and an increase in inflexion ratio in EPM. MF-CCNc reduced the levels of AChE and MDA while increasing SOD and CAT levels in the hippocampus. MF-CCNc further lowered the levels of pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α. These nanocapsules further increased the expression of BDNF and DCX that are necessary for adult neurogenesis. From the research findings, it can be concluded that MF-CCNc has high anti-amnesic properties and could be a promising candidate for the treatment of AD.

Design, synthesis and evaluation of 5-chloro-6-methylaurone derivatives as potential anti-cancer agents.

A series of novel 5-chloro-6-methylaurone derivatives (6a-p) were synthesized and characterized by various spectroscopic techniques. The synthesized compounds were tested for anticancer activity against 60-human cancer cell line panel derived from nine cancer types at NCI, Bethesda, USA. Among the synthesized compounds, six compounds (6e, 6f, 6h, 6i, 6k and 6 m) exhibited growth inhibition and cytotoxic activity against various human cancer cell lines in one-dose data. The most potent compound among the series, 6i was active against 55 out of 60 human cancer cell lines. Compound 6i showed remarkable % growth inhibition and cytotoxicity against various cancer cell lines exhibiting % GI in the range 36.05-199.03. The compound 6i was further evaluated for five dose assay and exhibited GI50 1.90 µM and 2.70 µM against melanoma and breast cancer cell lines respectively. Further evaluation of 6i for five-dose assay exhibited a diverse spectrum of anti-cancer activity towards all the 60 human cancer cell line panel with the selectivity index ratio ranging 0.854-1.42 and 0.66-1.35 for GI50 and TGI respectively. Based on one-dose and five-dose data compound 6i was further evaluated for cell apoptosis against MDA-MB-468 breast cancer cell line and was found to induce early apoptosis in cells explaining its mode of action. The in-silico studies for the synthesized compounds as LSD1 inhibitors (2H94) have shown better docking score and binding energy comparable to vafidemstat. All the compounds followed Lipinski rule of five. These findings concluded that the compound 6i could lead to the development of a promising therapeutic anticancer agent.

Synthesis, Molecular Docking, and Biological Evaluation of a New Series of Benzothiazinones and Their Benzothiazinyl Acetate Derivatives as Anticancer Agents against MCF-7 Human Breast Cancer Cells and as Anti-Inflammatory Agents.

Six 1,4-benzothiazin-3-ones (2a-f) and four benzothiazinyl acetate derivatives (3a-d) were synthesized and characterized by various spectroscopic methods, namely, 1H NMR, 13C NMR, IR, MS, and elemental analysis. The cytotoxic effects of the compounds were assessed against MCF-7, a human breast cancer cell line, along with their anti-inflammatory activity. Molecular docking studies performed against the VEGFR2 kinase receptor displayed a common binding orientation of the compounds in the catalytic binding pocket of the receptor. The generalized Born surface area (GBSA) studies of compound 2c with the highest docking score also proved its stability in binding to the kinase receptor. Compounds 2c and 2b showed better results against VEGFR2 kinase with IC50 values of 0.0528 and 0.0593 µM, respectively, compared to sorafenib. All of the compounds (2a-f and 3a-d) showed effective growth inhibition having (IC50) values of 2.26, 1.37, 1.29, 2.30, 4.98, 3.7, 5.19, 4.50, 4.39, and 3.31 µM, respectively, against the MCF-7 cell line compared to standard 5-fluorouracil (IC50 = 7.79 µM). However, compound 2c displayed remarkable cytotoxic activity (IC50 = 1.29 µM), suggesting it as a lead compound in the cytotoxic assay. Additionally, compounds 2c and 2b showed better results against VEGFR2 kinase with IC50 values of 0.0528 and 0.0593 µM, respectively, compared to sorafenib. It also inhibited hemolysis by stabilizing the membrane comparable to that of diclofenac sodium, a standard used in the human red blood cell membrane stabilization assay and hence can act as a template for designing novel anticancer and anti-inflammatory agents.

Halogen substituted aurones as potential apoptotic agents: synthesis, anticancer evaluation, molecular docking, ADMET and DFT study.

A series of halogen-substituted aurone derivatives (2a-k) were synthesized and evaluated for an anti-proliferative study against NCI 60 cancer cell line panel and showed that most of the compounds predominantly exhibited promising activity against MCF-7. Compound 2e exhibited promising anticancer activity against the MCF-7 cancer cell line with 84.98% percentage growth inhibition in a single dose assay of 10 µM with an IC50 value of 8.157 ± 0.713 µM. In apoptotic assay, the effect of compound 2e on the cell cycle progression indicated that exposure of MCF-7 cells to compound 2e induced a significant disruption in the cell cycle profile including a time-dependent decrease in the cell population at G0/G1 and G2/M phase and arrests the cell cycle at the S phase. In silico, molecular docking ADME and toxicity studies of all compounds were also carried out. The docking study revealed that all the aurone derivatives displayed good docking scores ranging from -7.066 to -8.573. The results of Molecular Electrostatic Potential Mapping (MESP) and Density Functional Theory (DFT) studies of the most active compound 2e and least active compound 2k also favoured the experimental results.

Resveratrol-Loaded Glutathione-Coated Collagen Nanoparticles Attenuate Acute Seizures by Inhibiting HMGB1 and TLR-4 in the Hippocampus of Mice.

Epilepsy is a relatively complicated neurological disorder that results in seizures. The use of resveratrol in treating seizures has been reported in recent studies. However, the low bioavailability of resveratrol and the difficulty of reaching the targeted location in the brain reduce its efficacy considerably. The side effects due to the higher concentration of drugs are another matter of concern. The purpose of the present study is to enhance the antiepileptic potential of resveratrol by delivering it to the brain's targeted location by encapsulating it in glutathione-coated collagen nanoparticles. The collagen nanoparticles increase the bioavailability of resveratrol, while the transport of resveratrol to its target location in the brain is facilitated by glutathione. By encapsulating resveratrol in glutathione-coated collagen nanoparticles, the concentration also substantially decreases. Resveratrol encapsulated in synthesized nanoparticles is referred to as nanoresveratrol. In the present study, nanoresveratrol effectiveness was studied through PTZ-induced seizures (PTZ-IS) and the increasing current electroshock (ICES) test. The efficacy of nanoresveratrol was further established using biochemical analysis, histopathological examinations, ELISA and real-time-PCR tests, and immunohistochemistry examination of the hippocampus of mice. Hence, this study is unique in the sense that it synthesized nanoresveratrol by using glutathione-coated collagen nanoparticles, followed by its application to treating seizures. On the basis of the study results, nanoresveratrol was found to be effective in preventing cognitive impairment in the mice and controlling epilepsy seizures to a greater extent than resveratrol. The proposed nanoformulation also reduces the concentration of resveratrol considerably. The present study results show that even 0.4 mg/kg of nanoresveratrol outperforms 40 mg/kg of resveratrol.

Nanonization of Magnoflorine-Encapsulated Novel Chitosan-Collagen Nanocapsules for Neurodegenerative Diseases: In Vitro Evaluation.

Neurodegeneration is one of the most common diseases in the aged population, characterized by the loss in the function of neuronal cells and their ultimate death. One of the common features in the progression of this type of diseases is the oxidative stress. Drugs which are currently being used have been found to show lateral side effects, which is partly due to their inefficiency to cross blood-brain barrier. Nanoencapsulation of bioactive compounds is a profound approach in this direction and has become a method of choice nowadays. This study involved the evaluation of the anti-oxidative properties of magnoflorine (MF), which is an aporphine quaternary alkaloid, and synthesis of MF-loaded chitosan-collagen nanocapsules (MF-CCNc) for its better efficacy as a potent anti-oxidant. Physiochemical characterization of the synthesized nanocapsules was done by using dynamic light scattering and transmission electron microscopy. It revealed that the synthesized nanocapsules are of small size range, as small as 12 ± 2 nm, and are more or less of spherical shape. Sustained release was shown by MF in the in vitro drug release studies. Both MF and MF-CCNc were found to have good anti-oxidant potential with IC50 < 25 µg/mL. No major cytotoxicity was shown by the synthesized nanocapsules on SH-SY5Y cells. In silico anti-acetylcholinesterase (AChE) studies were also done, and they revealed that MF can be a potent inhibitor of AChE.

Neuroprotective Effect of Fisetin Through Suppression of IL-1R/TLR Axis and Apoptosis in Pentylenetetrazole-Induced Kindling in Mice.

Epilepsy is a complex neurological disorder, characterized by frequent electrical activity in brain regions. Inflammation and apoptosis cascade activation are serious neurological sequelae during seizures. Fisetin (3, 3',4',7-tetrahydroxyflavone), a flavonoid molecule, is considered for its effective anti-inflammatory and anti-apoptotic properties. This study investigated the neuroprotective effect of fisetin on experimental epilepsy. For acute studies, increasing current electroshock (ICES) and pentylenetetrazole (PTZ)-induced seizure tests were performed to evaluate the antiseizure activity of fisetin. For the chronic study, the kindling model was established by the administration of PTZ in subconvulsive dose (25 mg/kg, i.p.). Mice were treated with fisetin (5, 10, and 20 mg/kg, p.o.) to study its probable antiseizure mechanism. The kindled mice were evaluated for seizure scores. Their hippocampus and cortex were assessed for neuronal damage, inflammation, and apoptosis. Histological alterations were observed in the hippocampus of the experimental mice. Levels of high mobility group box 1 (HMGB1), Toll-like receptor-4 (TLR-4), interleukin-1 receptor 1 (IL-1R1), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were assessed in the hippocampus and cortex by ELISA. The immunoreactivity and mRNA expressions of nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), cytochrome C, and caspase-3 were quantified by immunohistochemical analysis and real-time PCR. Phosphorylation ELISA was performed to evaluate AkT/mTOR (mammalian target of rapamycin) activation in the hippocampus and cortex of the kindled mice. The results showed that fisetin administration increased the seizure threshold current (STC) in the ICES test. In PTZ-induced seizures, fisetin administration increased the latency for myoclonic jerks (MJs) and generalized seizures (GSs). In the PTZ-induced kindling model, fisetin administration dose-dependently suppressed the development of kindling and the associated neuronal damage in the experimental mice. Further, fisetin administration ameliorated kindling-induced neuroinflammation as evident from decreased levels of HMGB1, TLR-4, IL-1R1, IL-1ß, IL-6, and TNF-α in the hippocampus and cortex of the kindled mice. Also, the immunoreactivity and mRNA expressions of inflammatory molecules, NF-κB, and COX-2 were decreased with fisetin administration in the kindled animals. Decreased phosphorylation of the AkT/mTOR pathway was reported with fisetin administration in the hippocampus and cortex of the kindled mice. The immunoreactivity and mRNA expressions of apoptotic molecules, cytochrome C, and caspase-3 were attenuated upon fisetin administration. The findings suggest that fisetin shows a neuroprotective effect by suppressing the release of inflammatory and apoptosis molecules and attenuating histological alterations during experimental epilepsy.

Impact of cardiovascular diseases on severity of COVID-19 patients: A systematic review.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) cases are increasing rapidly worldwide. Similar to Middle East respiratory syndrome where cardiovascular diseases were present in nearly 30% of cases, the increased presence of cardiovascular comorbidities remains true for COVID-19 as well. The mechanism of this association remains unclear at this time. Therefore, we reviewed the available literature and tried to find the probable association between cardiovascular disease with disease severity and mortality in COVID-19 patients. METHODS: We searched Medline (via PubMed) and Cochrane Central Register of Controlled Trials for articles published until Sept 5, 2020. Nineteen articles were included involving 6,872 COVID-19 patients. RESULTS: The random-effect meta-analysis showed that cardiovascular disease was significantly associated with severity and mortality for COVID-19: odds ratio (OR) 2.89, 95% confidence interval (CI) 1.98-4.21 for severity and OR 3.00, 95% CI 1.67-5.39 for mortality, respectively. Risk of COVID-19 severity was higher in patients having diabetes, hypertension, chronic obstructive pulmonary disease, malignancy, cerebrovascular disease and chronic kidney disease. Similarly, patients with diabetes, hypertension, chronic liver disease, cerebrovascular disease and chronic kidney disease were at higher risk of mortality. CONCLUSION: Our findings showed that cardiovascular disease has a negative effect on health status of COVID-19 patients. However, large prevalence studies demonstrating the consequences of comorbid cardiovascular disease are urgently needed to understand the extent of these concerning comorbidities.