Modification of ibuprofen to improve the medicinal effect; structural, biological, and toxicological study.

Ibuprofen is classified as a non-steroidal anti-inflammatory drug (NSAID) that is employed as an initial treatment option for its non-steroidal anti-inflammatory, pain-relieving, and antipyretic properties. However, Ibuprofen is linked to specific well-known gastrointestinal adverse effects like ulceration and gastrointestinal bleeding. It has been linked to harmful effects on the liver, kidney, and heart. The purpose of the study is to create novel and potential IBU analogue with reduced side effects with the enhancement of their medicinal effects, so as to advance the overall safety profile of the drug. The addition of some novel functional groups including CH3, F, CF3, OCF3, Cl, and OH at various locations in its core structure suggestively boost the chemical as well as biological action. The properties of these newly designed structures were analyzed through chemical, physical, and spectral calculations using Density Functional Theory (DFT) and time-dependent DFT through B3LYP/6-31 g (d,p) basis set for geometry optimization. Molecular docking and non-bonding interaction studies were conducted by means of the human prostaglandin synthase protein (PDB ID: 5F19) to predict binding affinity, interaction patterns, and the stability of the protein-drug complex. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) and PASS (Prediction of Activity Spectra for Substances) predictions were employed to evaluate the pharmacokinetic and toxicological properties of these structures. Importantly, most of the analogues displayed reduced hepatotoxicity, nephrotoxicity, and carcinogenicity in comparison to the original drug. Moreover, molecular docking analyses indicated improved medicinal outcomes, which were further supported by pharmacokinetic calculations. Together, these findings suggest that the modified structures have reduced adverse effects along with improved therapeutic action compared to the parent drug.

Genetic Diversity of SARS-CoV2 and Environmental Settings: Possible Association with Neurological Disorders.

The new coronavirus (CoV), called novel coronavirus disease 2019 (COVID-19), belongs to the Coronaviridae family which was originated from the sea market in Wuhan city in China, at the end of the year 2019. COVID-19 and severe acute respiratory syndrome (SARS) are belonging to the same family (Coronaviridae). The current outbreak of COVID-19 creates public concern and threats all over the world and now it spreads out to more than 250 countries and territories. The researchers and scientists from all over the world are trying to find out the therapeutic strategies to abate the morbidity and mortality rate of the COVID-19 pandemic. The replication, spreading, and severity of SARS-CoV2 depend on environmental settings. Noteworthy, meteorological parameters are considered as crucial factors that affect respiratory infectious disorders, although the controversial effect of the meteorological parameter is exposed against COVID-19. Besides, COVID-19 accelerates the pathogenesis of the neurological disorders. However, the pathogenic mechanisms between COVID-19 and neurological disorders are still unclear. Hence, this review is focused on the genomics and ecology of SARS-CoV2 and elucidated the effects of climatic factors on the progression of COVID-19. This review also critically finds out the vulnerability between COVID-19 and neurological disorders based on the latest research data.

COVID-19 Outbreak: Pathogenesis, Current Therapies, and Potentials for Future Management.

At the end of 2019, a novel coronavirus (CoV) was found at the seafood market of Hubei province in Wuhan, China, and this virus was officially named coronavirus diseases 2019 (COVID-19) by World Health Organization (WHO). COVID-19 is mainly characterized by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) and creates public health concerns as well as significant threats to the economy around the world. Unfortunately, the pathogenesis of COVID-19 is unclear and there is no effective treatment of this newly life-threatening and devastating virus. Therefore, it is crucial to search for alternative methods that alleviate or inhibit the spread of COVID-19. In this review, we try to find out the etiology, epidemiology, symptoms as well as transmissions of this novel virus. We also summarize therapeutic interventions and suggest antiviral treatments, immune-enhancing candidates, general supplements, and CoV specific treatments that control replication and reproduction of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV).

Pumpkin (Cucurbita maxima) seeds protect against formaldehyde-induced major organ damages.

Exposures to hazardous chemicals including formaldehyde are harmful to human health. In this study, the authors investigate the protective effects of pumpkin seed oil (PSO) extract against formaldehyde-induced major organ damages in mice. Administration of formaldehyde (FA) caused significant elevation of serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), serum creatinine, etc. Histopathological examinations of liver, kidney, and brain tissues showed the degenerations of those organs. Mice pretreated with PSO extract significantly attenuated the FA-induced elevation of SGOT (39.0 ± 1.30 vs 20.5 ± 0.65 IU/L; FA-group vs PSO treatment group), SGPT (91.8 ± 1.65 vs 51.0 ± 1.29 IU/L), serum creatinine (1.05 ± 0.07 vs 0.65 ± 0.07 IU/L), and preserved the normal histology of organ tissues. The FA-induced elevation of malondialdehyde (MDA) in the brain, liver, and kidneys was suppressed by pretreatment with PSO extract. The extract also attenuated the FA-induced reduction of endogenous antioxidant pools. In vitro phytochemical analyses showed that PSO extract possesses free radical scavenging and total antioxidant activities due to the presence of phenolic and flavonoid compounds. Thus, PSO extract has significant protective effects against FA-induced organ toxicities by scavenging oxidative stress and inhibiting lipid peroxidation.

Pharmacological screening of fenofibrate-loaded solid dispersion in fructose-induced diabetic rat.

OBJECTIVES: Hyperlipidaemia is a common phenomenon in diabetes mellitus. Fenofibrate (FF) is a good candidate for the treatment of lipid abnormalities in patients with type 2 diabetes. But the bioavailability as well as therapeutic efficacy of this drug is limited to its dissolution behaviour. Here, the authors assess the therapeutic efficacy of a newly formulated solid dispersion of fenofibrate (SDF) having enhanced dissolution profiles in contrast to pure FF using fructose-induced diabetic rat model. METHODS: Fructose-induced diabetic rat model was developed to assess the pharmacological efficacy of the formulated SDF, and the results were compared with the effects of conventional FF therapy. KEY FINDINGS: The 14 days treatment showed better improvement in lipid-lowering potency of SDF than pure FF. SDF containing one-third dose of pure FF showed similar effect in terms of triglyceride, total cholesterol and low-density lipoprotein lowering efficacy, whereas increased high-density lipoprotein at same extent. The similar dose of SDF produced more prominent effect than FF. Histological studies also demonstrated the enhanced lipid clearance from liver by SDF than FF that was concordant with the biochemical results. CONCLUSIONS: This newly formulated SDF would be a promising alternative for conventional fenofibrate in treating hyperlipidaemia.

Circadian and sleep dysfunction in Alzheimer's disease.

Alzheimer's disease (AD) is a devastating and irreversible cognitive impairment and the most common type of dementia. Along with progressive cognitive impairment, dysfunction of the circadian rhythms also plays a pivotal role in the progression of AD. A mutual relationship among circadian rhythms, sleep, and AD has been well-recommended. The etiopathogenesis of the disturbances of the circadian system and AD share some general features that also unlock the outlook of observing them as a mutually dependent pathway. Indeed, the burden of amyloid ß (Aß), neurofibrillary tangles (NFTs), neuroinflammation, oxidative stress, and dysfunction of circadian rhythms may lead to AD. Aging can alter both sleep timings and quality that can be strongly disrupted in AD. Increased production of Aß and reduced Aß clearance are caused by a close interplay of Aß, sleep disturbance and raised wakefulness. Besides Aß, the impact of tau pathology is possibly noteworthy to the sleep deprivation found in AD. Hence, this review is focused on the primary mechanistic complexities linked to disruption of circadian rhythms, sleep deprivation, and AD. Furthermore, this review also highlights the potential therapeutic strategies to abate AD pathogenesis.

Curcumin ameliorates liver damage and progression of NASH in NASH-HCC mouse model possibly by modulating HMGB1-NF-κB translocation.

Curcumin, a phenolic compound, has a wide spectrum of therapeutic effects such as antitumor, anti-inflammatory, anti-cancer and so on. The study aimed to investigate the underlying mechanisms of curcumin to protect liver damage and progression of non-alcoholic steatohepatitis (NASH) in a novel NASH-hepatocellular carcinoma (HCC) mouse model. To induce this model neonatal C57BL/6J male mice were exposed to low-dose streptozotocin and were fed a high-fat diet (HFD) from the age of 4weeks to 14weeks. Curcumin was given at 100mg/kg dose daily by oral gavage started at the age of 10weeks and continued until 14weeks along with HFD feeding. We found that curcumin improved the histopathological changes of the NASH liver via reducing the level of steatosis, fibrosis associated with decreasing serum aminotransferases. In addition, curcumin treatment markedly reduced the hepatic protein expression of oxidative stress, pro-inflammatory cytokines, and chemokines including interferon (IFN) γ, interleukin-1ß and IFNγ-inducible protein 10, in NASH mice. Furthermore, curcumin treatment significantly reduced the cytoplasmic translocation of high mobility group box 1 (HMGB1) and the protein expression of toll like receptor 4. Nuclear translocation of nuclear factor kappa B (NF-κB) was also dramatically attenuated by the curcumin in NASH liver. Curcumin treatment effectively reduced the progression of NASH to HCC by suppressing the protein expression of glypican-3, vascular endothelial growth factor, and prothrombin in the NASH liver. Our data suggest that curcumin reduces the progression of NASH and liver damage, which may act via inhibiting HMGB1-NF-κB translocation.

Antidiabetic, antihyperlipidemic and antioxidant properties of ethanol extract of Grewia asiatica Linn. bark in alloxan-induced diabetic rats.

BACKGROUND: Inspite of introduction of oral hypoglycemic agents, diabetes and its related complications remains to be a major clinical problem. The aim of this study was to investigate the antidiabetic, antihyperlipidemic and antioxidant activities of Grewia asiatica (Linn) stem bark in alloxan induced diabetic rats. METHODS: Diabetes was induced by a single dose of intraperitoneal injection of alloxan (110 mg/kg) in Norwegian Long Evans rats. Ethanol extract of barks from Grewia asiatica (GAE 200 and 400 mg/kg) and metformin (150 mg/kg) were orally administered once daily for 15 days. Blood glucose levels and body weights of rats were measured on 0, 5, 10 and 15 days of oral treatment. At the end of the experiment the rats were sacrificed and blood sample were collected for the measurement of total cholesterol (TC), triglycerides (TG), very low density lipoproteins (VLDL), low density lipoproteins (LDL), high density lipoproteins (HDL), SGOT and CK-MB. Analysis of liver glycogen content and histopathlogy of pancreas were carried out. In vitro DPPH free radical scavenging activity, total phenolic and total flavonoid content of GAE were also determined. RESULTS: After 15 days of oral administration of GAE at doses of 200 and 400 mg/kg increased survival rate and showed a significant attenuation in blood glucose and lipid profile in diabetic rats. Oral ingestion of GAE significantly reduced the SGOT and CK-MB levels and restored liver glycogen content when compared to diabetic control. The effects of GAE on SGOT, CK-MB and liver glycogen content were dose-dependent. The diabetic rats treated with GAE showed significant improvement in normal cellular population size of islets. Phytochemical screening of GAE revealed the presence of flavonoid, steroid, tannin and phenolic compounds. Total phenolic content was 44.65 ± 3.17 mg of gallic acid equivalent per gm of GAE extract and the total flavonoid content was 39.11 ± 4.65 mg of quercetin equivalent per gm of GAE extract. In DPPH scavenging assay, IC50 values of GAE and ascorbic acid were found 76.45 and 12.50 µg/ml, respectively. CONCLUSION: We demonstrated that ethanol extract of barks from G. asiatica possess glucose, lipid lowering efficacy, restored liver glycogen and protects pancreas from oxidative damage in alloxan-induced diabetic rats. Thus, the results of the present study provide a scientific rationale for the use of G. asiatica in the management of diabetes and its related complications.

Attenuation of Endoplasmic Reticulum Stress-Mediated Liver Damage by Mulberry Leaf Diet in Streptozotocin-Induced Diabetic Rats.

Endoplasmic reticulum stress (ERS) plays a crucial role in the development of insulin resistance and diabetes mellitus. Although antidiabetic use of mulberry leaves (MLs) has been popular due to their many anti-oxidative flavonoid compounds and free radical scavenging effects, ML's effects on ERS in experimental diabetic hepatocyte injury remain unknown. To investigate how ML affect ERS in diabetic liver, Sprague-Dawley (SD) rats were assigned to induce diabetes by a single intraperitoneal injection of streptozocin (STZ; 55 mg/kg) and fed with either normal chow or a diet containing 25% mulberry leaf powder diet (MLD) and examined for 56 days. We observed that MLD improved the rats' morphological and histopathological changes. Levels of ERS markers such as phosphorylated double-stranded RNA-dependent protein kinase-like endoplasmic reticulum kinase (PERK) and X-box binding protein 1 (XBP1) and the protein expression of glucose regulated protein 78 (GRP78) were significantly higher in the diabetic liver compared to normal liver. MLD for 8 weeks significantly reduced all of these markers. MLD also significantly decreased hepatocyte apoptosis, hepatic macrophage recruitment, cellular infiltration, and CCAAT/enhancer-binding protein homologous protein (CHOP), tumor necrosis factor receptor associated factor 2 (TRAF2), interleukin 1[Formula: see text] (IL-1[Formula: see text]) and sterol regulatory element binding protein isoform 1c (SREBP 1c) levels in diabetic liver. These results may suggest that MLs can preserve hepatic function in experimental diabetes by modulating ERS mediated apoptosis and liver damage.

Antidiabetic and antioxidant activities of ethanolic extract of Semecarpus anacardium (Linn.) bark.

BACKGROUND: Diabetes mellitus is a global health problem and constantly increasing day by day. The number of diabetic people in world is expected to rise to 366 million in 2030. The available drugs for diabetes, insulin or oral hypoglycemic agents have one or more side effects and search for new antidiabetic drugs with minimal or no side effects from medicinal plants is a challenging for us. The present study was undertaken to investigate the antidiabetic and antioxidant activity of Semecarpus anacardium (Linn.) (abbreviated as SF). METHODS: The antidiabetic activity was determined by using alloxan-induced diabetic rats. After 15 days of treatment, serum biochemical parameters such as TC, TG, LDL, HDL, SGOT and SGPT were estimated. The survival rate, body weight, organ weight, liver glycogen and blood parameters (RBC and Hb) were also measured. The antioxidant activity was measured by DPPH free radical scavenging assay. Phytochemical screening, total phenolic and total flavonoid content were determined by using standard methods. RESULTS: The results showed that the survival rate was 100% in rats of Group SA 400. The effect of extract on blood glucose level in Groups SA 100, SA 200 and SA 400 were dose-dependent throughout the treatment period. No significant changes in organ weight to body weight ratio were observed, liver weights significantly improved in Groups SA 200 and SA 400. The bark extract exhibited significant (p < 0.05) anti-diabetic activity with lowering TC, TG, LDL level dose-dependently and protected liver which may be partially explained by attenuation of SGOT and SGPT levels and increases liver glycogen. The percentage of Hb and RBC counts were negatively correlated with the doses of extracts. In DPPH scavenging assay, IC50 values of SA extract and ascorbic acid were found 72.24 µg/ml and 17.81 µg/ml, respectively. Phytochemical screening showed the presence of steroids, triterpenoids, flavonoids, glycosides, saponins, and tannins that were contribute to biological activity. CONCLUSIONS: These results indicated that stem barks of S. anacardium possess strong anti-diabetic and antioxidant potentials and support traditional medicinal use for the treatment of diabetes mellitus and good source for natural antioxidants.

Development of highly stable nifedipine solid-lipid nanoparticles.

To improve the solubility of the drug nifedipine (NI), highly stabilized solid-lipid nanoparticles (SLNs) of nifedipine (NI-SLNs) were prepared by high pressure homogenization using two phospholipids, followed by lyophilization with individual sugar moieties (four monosaccharides and four disaccharides). The mean particle diameter, polydispersity index (PDI), zeta potential, drug loading, and the encapsulation efficiency of the NI-SLN suspension were determined to be 68.5 nm, 0.3, -62.1 mV, 2.7%, and 97.5%, respectively. In comparison with the NI-SLNs, the NI-SLNs lyophilized with trehalose (NI-SLN-Tre) showed a slight increase in the particle size from 68.5 to 107.7 nm, but the PDI decreased from 0.38 to 0.33, and no significant change in zeta potential was observed. Aqueous re-dispersibility study demonstrated that NI-SLNs lyophilized with trehalose had the maximum concentration (14.7 µg/mL) at 5 min, compared with lyophilized SLNs using other sugars; the use of other sugars also resulted in significant changes in the particle size, PDI, and zeta potential. A trehalose concentration of 2.5% w/v and a two-fold dilution of the SLN suspension were found to be the best conditions for lyophilization. Data from lyophilized SLNs using differential scanning calorimetry, powder X-ray diffraction, Fourier-transform infrared spectroscopy, and scanning electron microscopy indicated eventual transformation of NI-SLN-Tre from a crystalline to an amorphous state during the homogenization process. Finally, a stability study was performed with NI-SLN-Tre for up to 6 months at 30°C and 65% relative humidity, with no significant deterioration observed, suggesting that trehalose might be a useful cryoprotectant for NI-SLNs.

Comparative effects of pranidipine with amlodipine in rats with heart failure.

The aim of the present study was to compare the cardioprotective properties of long-acting calcium channel antagonist pranidipine with amlodipine in rat model of heart failure induced by autoimmune myocarditis. Twenty-eight days after immunization the surviving rats were randomized for the oral administration of low-dose amlodipine (1 mg/kg/day), high-dose amlodipine (5 mg/kg/day), pranidipine (0.3 mg/kg/day) or vehicle (0.5% methylcellulose). After oral administration for 1 month, the animals underwent echocardiography and hemodynamic analysis. Histopathology, immunohistochemistry, and Western immunoblotting were carried out in the heart samples. Both pranidipine and high-dose amlodipine increased survival rate. Although the heart rate did not differ among the four groups, left ventricular end-diastolic pressure was significantly decreased and +/-dP/dt was increased in the pranidipine- and high-dose amlodipine-treated rats, but not in low-dose amlodipine-treated rats. In comparison to amlodipine treatment, pranidipine treatment significantly reduced myocyte size and central venous pressure. Furthermore, both pranidipine and high-dose amlodipine treatment significantly reduced myocardial protein levels of atrial natriuretic peptide and inducible nitric oxide synthase, whereas pranidipine only significantly decreased tumor necrosis factor-alpha, and improved sarcoplasmic reticulum Ca2+ ATPase2 protein levels. We conclude that pranidipine ameliorates the progression of left ventricular dysfunction and cardiac remodeling in rats with heart failure after autoimmune myocarditis in a lower dose when compared to amlodipine and which may be a clinically potential therapeutic agent for the treatment of heart failure.

Effects of eplerenone, a selective aldosterone blocker, on the progression of left ventricular dysfunction and remodeling in rats with dilated cardiomyopathy.

Aldosterone blockade reduces morbidity and mortality in patients with heart failure. We studied the effects of eplerenone, a novel aldosterone blocker, on the progression of left ventricular dysfunction and remodeling in rats with dilated cardiomyopathy after autoimmune myocarditis. Twenty-eight days after immunization, the surviving Lewis rats were randomized to 1 month's oral treatment with low-dose eplerenone (group L), high-dose eplerenone (group H) or vehicle (group V). Five of 15 (33%) rats in group V and 3 of 15 (20%) rats in group L died during the course of treatment. High-dose eplerenone significantly reduced cardiomyocyte hypertrophy, heart weight and heart weight to body weight ratio. Eplerenone improved left ventricular function in a dose-dependent manner. Central venous pressure and left ventricular end-diastolic pressure were lower, and +/-dP/dt and fractional shortening were higher in group H than group V. Eplerenone also attenuated myocardial fibrosis and reduced left ventricular mRNA expressions of TGF-beta(1) and collagen-III. Our results indicate that treatment with eplerenone improved left ventricular dysfunction and attenuated left ventricular remodeling in rats with heart failure.

Effects of pranidipine, a novel calcium channel antagonist, on the progression of left ventricular dysfunction and remodeling in rats with heart failure.

The cardioprotective properties of pranidipine were studied in a rat model of heart failure after autoimmune myocarditis. Twenty-eight days after immunization the surviving rats were divided into three groups and received oral treatment of 0.03 mg/kg/day (group 0.03) or 0.3 mg/kg/day (group 0.3) of pranidipine or vehicle (group V) for 1 month. High-dose pranidipine (group 0.3) improved the survival rate, and significantly reduced heart weight, heart weight to body weight ratio, myocardial fibrosis, central venous pressure and left ventricular end-diastolic pressure than low-dose pranidipine (group 0.03) and group V. Pranidipine at high dose also decreased the left ventricular systolic and diastolic dimensions, and increased fractional shortening compared with group V. The increase in level of TGF-beta1 and collagen-III mRNA were suppressed by pranidipine in a dose-dependent manner. Our results indicated that pranidipine has cardioprotective effects on heart failure, and that the beneficial effect can be partly explained by attenuation of fibrotic response through suppression of TGF-beta1 and collagen-III mRNA expression, and regression of myocyte hypertrophy.