Sulfamethizole attenuates poloxamer 407-induced atherosclerotic neointima formation via inhibition of mTOR in C57BL/6 mice.

Mammalian target of Rapamycin C1 (mTORC1) inhibition limits plaque progression in atherosclerosis. The present study evaluated the protective effect of sulfamethizole on poloxamer 407-induced atherosclerotic neointima formation in C57BL/6 mice via mTOR inhibition. Poloxamer 407 (P-407) (0.5 g/kg body weight) was administered intraperitoneally to male C57BL/6 mice every third day for 148 days to induce chronic hyperlipidemia. From Day 121 to 148, animals were additionally administered Sulfamethizole (5, 10, and 50 mg/kg, p.o.), Rapamycin (0.5 mg/kg, positive control), or vehicle (1 ml/kg). Plasma lipid levels were measured on Days 120 and 148. Upon sacrifice, histological studies were performed, and aortic tissue interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and mTOR levels were evaluated. A molecular docking study was carried out to mimic the interaction of sulfamethizole with mTOR protein. Chronic P-407 administration significantly (p < 0.001) elevated plasma lipid levels, compared with those of the normal control group. Chronic hyperlipidemia resulted in increased tunica intima thickness, collagen deposition, and IL-6, TNF-α, and mTOR levels. Treatment with Sulfamethizole attenuated these parameters significantly in a dose-dependent manner. Molecular docking studies showed a significant interaction of Sulfamethizole with mTOR. In conclusion, this study suggests that sulfamethizole significantly limits poloxamer 407-induced atherosclerotic neointima formation in C57BL/6 mice via mTOR inhibition.

mAKAPß signalosome: A potential target for cardiac hypertrophy.

Pathological cardiac hypertrophy is the result of a prolonged increase in the workload of the heart that activates various signaling pathways such as MAPK pathway, PKA-dependent cAMP signaling, and CaN-NFAT signaling pathway which further activates genes for cardiac remodeling. Various signalosomes are present in the heart that regulates the signaling of physiological and pathological cardiac hypertrophy. mAKAPß is one such scaffold protein that regulates signaling pathways involved in promoting cardiac hypertrophy. It is present in the outer nuclear envelope of the cardiomyocytes, which provides specificity of the target toward the heart. In addition, nuclear translocation of signaling components and transcription factors such as MEF2D, NFATc, and HIF-1α is facilitated due to the localization of mAKAPß near the nuclear envelope. These factors are required for activation of genes promoting cardiac remodeling. Downregulation of mAKAPß improves cardiac function and attenuates cardiac hypertrophy which in turn prevents the development of heart failure. Unlike earlier therapies for heart failure, knockout or silencing of mAKAPß is not associated with side effects because of its high specificity in the striated myocytes. Downregulating expression of mAKAPß is a favorable therapeutic approach toward attenuating cardiac hypertrophy and hence preventing heart failure. This review discusses mAKAPß signalosome as a potential target for cardiac hypertrophy intervention.

Experimental animal models for rheumatoid arthritis.

Rheumatoid Arthritis (RA) is an autoimmune systemic disorder of unknown etiology and is characterized by chronic inflammation and synovial infiltration of immune cells. RA is associated with decreased life expectancy and quality of life. The research on RA is greatly simplified by animal models that help us to investigate the complex system involving inflammation, immunological tolerance and autoimmunity. The animal models of RA with a proven track record of predictability for efficacy in humans include: collagen type II induced arthritis in rats as well as mice, adjuvant induced arthritis in rats and antigen induced arthritis in several species. The development of novel treatments for RA requires the interplay between clinical observations and studies in animal models. However, each model features a different mechanism driving the disease expression; the benefits of each should be evaluated carefully in making the appropriate choice for the scientific problem to be investigated. In this review article, we focus on animal models of arthritis induced in various species along with the genetic models. The review also discussed the similarity and dissimilarities with respect to human RA.

Liver X receptor: a potential target in the treatment of atherosclerosis.

INTRODUCTION: Liver X receptors (LXRs) are master regulators of atherogenesis. Their anti-atherogenic potential has been attributed to their role in the inhibition of macrophage-mediated inflammation and promotion of reverse cholesterol transport. Owing to the significance of their anti-atherogenic potential, it is essential to develop and test new-generation LXR agonists, both synthetic and natural, to identify potential LXR-targeted therapeutics for the future. AREAS COVERED: This review describes the role of LXRs in atherosclerotic development, and provides a summary of LXR agonists and future directions for atherosclerosis research. We searched PubMed, Scopus, and Google Scholar for relevant reports, from last 10 years, using atherosclerosis, liver X receptor, and LXR agonist as keywords. EXPERT OPINION: LXRα has gained widespread recognition as a regulator of cholesterol homeostasis and expression of inflammatory genes. Further research using models of cell type-specific knockout and specific agonist-targeted LXR isoforms is warranted. Enthusiasm for therapeutic value of LXR agonists has been tempered due to LXRα-mediated induction of hepatic lipogenesis. LXRα agonism and LXRß targeting, gut-specific inverse LXR agonists, investigations combining LXR agonists with other lipogenesis-mitigating agents, like IDOL antagonists and synthetic HDL, and targeting ABCA1, M2 macrophages, and LXRα phosphorylation remain as promising possibilities.

Cytokine storm associated coagulation complications in COVID-19 patients: Pathogenesis and Management.

INTRODUCTION: SARS-CoV-2, the causative agent of COVID-19, attacks the immune system causing an exaggerated and uncontrolled release of pro-inflammatory mediators (cytokine storm). Recent studies propose an active role of coagulation disorders in disease progression. This hypercoagulability has been displayed by marked increase in D-dimer in hospitalized patients. AREAS COVERED: This review summarizes the pathogenesis of SARS-CoV-2 infection, generation of cytokine storm, the interdependence between inflammation and coagulation, its consequences and the possible management options for coagulation complications like venous thromboembolism (VTE), microthrombosis, disseminated intravascular coagulation (DIC), and systemic and local coagulopathy. We searched PubMed, Scopus, and Google Scholar for relevant reports using COVID-19, cytokine storm, and coagulation as keywords. EXPERT OPINION: A prophylactic dose of 5000-7500 units of low molecular weight heparin (LMWH) has been recommended for hospitalized COVID-19 patients in order to prevent VTE. Treatment dose of LMWH, based on disease severity, is being contemplated for patients showing a marked rise in levels of D-dimer due to possible pulmonary thrombi. Additionally, targeting PAR-1, thrombin, coagulation factor Xa and the complement system may be potentially useful in reducing SARS-CoV-2 infection induced lung injury, microvascular thrombosis, VTE and related outcomes like DIC and multi-organ failure.

Targeting Matrix Metalloproteinases for Diabetic Retinopathy: The Way Ahead?

Diabetic retinopathy (DR) is a severe sight-threatening complication of diabetes. It causes progressive damage to the retina and is the most common cause of vision impairment and blindness among diabetic patients. DR develops as a result of various changes in the ocular environment. Such changes include accelerated mitochondrial dysfunction, apoptosis, reactive oxygen species production, and formation of acellular capillaries. Matrix metalloproteinases (MMPs) are one of the major culprits in causing DR. Under physiological conditions, MMPs cause remodeling of the extracellular matrix in the retina, while under pathological conditions, they induce retinal cell apoptosis. This review focuses on the roles of various MMPs, primarily MMP-2 and MMP-9 in DR and also their participation in oxidative stress, mitochondrial dysfunction, and apoptosis, along with their involvement in various signaling pathways. This review also underscores different strategies to inhibit MMPs, thus suggesting that MMPs may represent a putative therapeutic target in the treatment of DR.

Therapeutic Approaches for the Treatment of Epidermal Growth Factor Receptor Mutated Lung Cancer.

Lung cancer surfaces to be the predominant determinant of mortality worldwide constituting 13% and 19% of all new cancer cases and deaths related to cancer respectively. Molecular profiling has now become a regular trend in lung cancer to identify the driver mutations. Epidermal Growth Factor Receptor (EGFR) is the most regular driver mutation encountered in Non-Small Cell Lung Cancer (NSCLC). Targeted therapies are now available for the treatment of EGFR mutant NSCLC. EGFR mutation is more frequently expressed in adenocarcinoma than squamous cell carcinoma. This article presents a detailed molecular insight of the therapeutic approaches for the treatment of EGFR mutant lung cancer. The article delineates molecular mechanism of the drugs that are approved, the drugs that are in clinical trial and the drugs that have not entered a clinical trial but shows promising future in the treatment of EGFR mutant lung cancer. Furthermore, this article provides concise information on relevant combinational or monotherapy clinical trials that have been completed for various approaches.

Gastrointestinal hormones in regulation of memory.

The connection between the gastrointestinal hormones and the brain has been established many years ago. This relation is termed the gut-brain axis (GBA). The GBA is a bidirectional communication which not only regulates gastrointestinal homeostasis but is also linked with higher emotional and cognitive functions. Hypothalamus plays a critical role in the regulation of energy metabolism, nutrient partitioning and control of feeding behaviors. Various gut hormones are released inside the gastrointestinal tract on food intake. These hormones act peripherally and influence the different responses of the tissues to the food intake, but do also have effects on the brain. The hypothalamus, in turn, integrates visceral function with limbic system structures such as hippocampus, amygdala, and cerebral cortex. The hippocampus has been known for its involvement in the cognitive function and the modulation of synaptic plasticity. This review aims to establish the role of various gut hormones in learning and memory, through the interaction of various receptors in the hippocampus. Understanding their role in memory can also aid in finding novel therapeutic strategies for the treatment of the neurological disorders associated with memory dysfunctions.

Beta-blocking activity of PP-34, a newly synthesized aryloxypropanolamine derivative, and its cardioprotective effect against ischaemia/reperfusion injury in laboratory animals.

Beta-adrenoceptor antagonists are widely used in cardiovascular medicine. However, the main side effect of these drugs is due to antagonism of beta(2)-adrenoceptors in the airways, resulting in bronchospasm. Therefore, more cardioselective beta-blockers have been developed to offer a lower side effect profile. We have studied a new aryloxypropanolamine derivative (PP-34) with more cardioselectivity and efficacy against ischaemia/reperfusion injury in rats. Oxalate salts of 1-(tert-butylamino)-3-(5-tert-butylaminomethyl-2-methoxyphenoxy) propan-2-ol (PP-34) is a novel beta-adrenoceptor antagonist. In-vitro studies in rat isolated right atria, guinea-pig trachea and rat distal colon preparations were carried out to investigate the potency of PP-34 towards different beta-adrenoceptor subtypes. pA(2)/pK(B) values of PP-34 for beta(1), beta(2), and beta(3) adrenoceptor were 7.89+/-0.15, 6.13+/-0.09 and 6.30+/-0.19, respectively. The beta(1)/beta(2) selectivity ratio calculated was in the order of PP-34 > atenolol > propranolol. Pre-ischaemic administration (20 min before coronary occlusion) of PP-34 (0.3 or 1 mg kg(-1)) showed cardioprotective effects against ischaemia/reperfusion injury in rats and significantly reduced arrhythmias, infarct area and necrosis induced by ischaemia/reperfusion injury. The efficacy of PP-34 was found to be greater then atenolol. In conclusion, PP-34 is a cardioselective beta-adrenoceptor antagonist, possessing potent anti-arrhythmic and cardioprotective effects against ischaemia/reperfusion injury in rats.

Neuropeptides: A promising target for treating seizures.

Seizures are serious neurological disorders affecting nearly 50 million people worldwide. Seizures are characterized by abnormal, repetitive and synchronised firing of the neurons which is produced as a result of imbalance in the levels of the excitatory and inhibitory neurotransmitters. Neuropeptides are found to regulate seizures by rectifying this imbalance. These neuropeptides are stored in the dense core synaptic vesicles, and are released on excitation. This review focuses on certain neuropeptides which can alleviate both, the effects of seizures as well as epileptogenesis. Thus making it an attractive target for the management of seizures.

Oncolytic Herpes Simplex Viral Therapy: A Stride toward Selective Targeting of Cancer Cells.

Oncolytic viral therapy, which makes use of replication-competent lytic viruses, has emerged as a promising modality to treat malignancies. It has shown meaningful outcomes in both solid tumor and hematologic malignancies. Advancements during the last decade, mainly genetic engineering of oncolytic viruses have resulted in improved specificity and efficacy of oncolytic viruses in cancer therapeutics. Oncolytic viral therapy for treating cancer with herpes simplex virus-1 has been of particular interest owing to its range of benefits like: (a) large genome and power to infiltrate in the tumor, (b) easy access to manipulation with the flexibility to insert multiple transgenes, (c) infecting majority of the malignant cell types with quick replication in the infected cells and (d) as Anti-HSV agent to terminate HSV replication. This review provides an exhaustive list of oncolytic herpes simplex virus-1 along with their genetic alterations. It also encompasses the major developments in oncolytic herpes simplex-1 viral therapy and outlines the limitations and drawbacks of oncolytic herpes simplex viral therapy.

Biomarkers for Parkinson's Disease: Recent Advancement.

As a multi-factorial degenerative disease, Parkinson's disease (PD) leads to tremor, gait rigidity, and hypokinesia, thus hampering normal living. As this disease is usually detected in the later stages when neurons have degenerated completely, cure is on hold, ultimately leading to death due to the lack of early diagnostic techniques. Thus, biomarkers are required to detect the disease in the early stages when prevention is possible. Various biomarkers providing early diagnosis of the disease include those of imaging, cerebrospinal fluid, oxidative stress, neuroprotection, and inflammation. Also, biomarkers, alone or in combination, are used in the diagnosis and evolution of PD. This review encompasses various biomarkers available for PD and discusses recent advances in their development.

Management of bipolar depression with lamotrigine: an antiepileptic mood stabilizer.

The efficacy of lamotrigine in the treatment of focal epilepsies have already been reported in several case reports and open studies, which is thought to act by inhibiting glutamate release through voltage-sensitive sodium channels blockade and neuronal membrane stabilization. However, recent findings have also illustrated the importance of lamotrigine in alleviating the depressive symptoms of bipolar disorder, without causing mood destabilization or precipitating mania. Currently, no mood stabilizers are available having equal efficacy in the treatment of both mania and depression, two of which forms the extreme sides of the bipolar disorder. Lamotrigine, a well established anticonvulsant has received regulatory approval for the treatment and prevention of bipolar depression in more than 30 countries worldwide. Lamotrigine, acts through several molecular targets and overcomes the major limitation of other conventional antidepressants by stabilizing mood from "below baseline" thereby preventing switches to mania or episode acceleration, thus being effective for bipolar I disorder. Recent studies have also suggested that these observations could also be extended to patients with bipolar II disorder. Thus, lamotrigine may supposedly fulfill the unmet requirement for an effective depression mood stabilizer.

Enhancement of matrix metalloproteinase 2 and 9 inhibitory action of minocycline by aspirin: an approach to attenuate outcome of acute myocardial infarction in diabetes.

BACKGROUND AND AIMS: Diabetes is a risk factor for exacerbated outcome after acute myocardial infarction (AMI) and doubles the risk of mortality after MI. Increased levels of MMP-2 and MMP-9 in diabetes cause vascular remodelling, which leads to cardiovascular complications of diabetes. We hypothesized that inhibition of MMP-2 and MMP-9 can reduce worsening of myocardial ischemia in diabetic patients. Further, we hypothesized that minocycline induced MMP-2 and MMP-9 inhibition will be potentiated by aspirin and the combination of both drugs will prevent worsening of MI in diabetic patients. In the present study, efficacy of combination of minocycline and aspirin to attenuate exacerbation of myocardial ischemia/reperfusion (I/R) injury in diabetic rats was evaluated. METHODS: Diabetes was induced in male Wistar rats by streptozotocin (55 mg/kg i.p.). Three weeks after diabetes induction, rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of 3 weeks. At the end of week 6, I/R injury was induced by ligating the left anterior descending coronary artery for 30 min followed by 2 h reperfusion. RESULTS: Percentage infarct volume, arrhythmias, mortality, collagen level and MMP-2 and MMP-9 level were significantly increased in vehicle-treated diabetic group when compared with normoglycemic rats. Treatment with a combination of minocycline and aspirin decreased percentage infarct volume, arrhythmias, mortality and collagen level when compared with vehicle-treated diabetic controls and showed reduced levels of MMP-2 and MMP-9. CONCLUSIONS: Results of the present study suggest that the combination of minocycline and aspirin prevent worsening of AMI in diabetic rats.

Potentiation of aspirin-induced cerebroprotection by minocycline: a therapeutic approach to attenuate exacerbation of transient focal cerebral ischaemia.

Cerebrovascular disease is a major cause of mortality and disability in adults. Diabetes mellitus increases the risk of cerebral ischaemia and is associated with worse clinical outcome following an event. Upregulation of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in diabetes appears to play a role in vascular complications of diabetes. We hypothesised that inhibition of MMP-2 and MMP-9 by minocycline can be potentiated by aspirin through inhibition of cyclooxygenase-2 and tissue plasminogen activator, resulting in amelioration of clinical cerebral ischaemia in diabetes. In the present study, cerebral ischaemia/reperfusion injury was induced in streptozotocin diabetic rats by 1 h middle cerebral artery occlusion and 24 h reperfusion. Infarct volume, cerebral oedema, neurological severity score and blood-brain barrier disruption were significantly increased in diabetic animals compared with the normoglycemic control group. The combination of aspirin and minocycline treatment significantly improved these parameters in diabetic animals. Moreover, this therapy was associated with significantly lower mortality and reduction in MMP-2 and MMP-9 levels. Our data indicate that combination of aspirin and minocycline therapy protects from the consequences of cerebral ischaemia in animal models of diabetes and is associated with inhibition of MMP-2 and MMP-9. Therefore, this combination therapy may represent a novel strategy to reduce the neurological complications of cerebral ischaemia in diabetes.

Cardioprotective and ß-adrenoceptor antagonistic activity of a newly synthesized aryloxypropanolamine derivative PP-36.

The present study was performed to evaluate the cardioprotective effects and pharmacological characterization of newly synthesized ß-adrenoreceptor antagonists 3-(3-tert-butylamino-2-hydroxypropoxy)-4-methoxybenzaldehyde (PP-36) in the rat model of coronary artery occlusion and reperfusion. Pre-ischemic administration (20 minutes before coronary occlusion) of PP-36 showed cardioprotective effects against ischemia/reperfusion injury in rats. PP-36 (6 mg kg(-1)) significantly reduced arrhythmia score (6.33 ± 0.55, P < 0.05), infarct size/left ventricle size (38.9 ± 3.2, P < 0.05) and no mortality compared to vehicle-treated control group (14.17 ± 1.83, 44.9 ± 4.6 and 17% respectively). In-vitro studies in rat isolated right atria, guinea-pig trachea and rat distal colon preparations, were carried out to investigate the potency of PP-36 towards different ß-adrenoceptor subtypes. pA2/pKB values of PP-36 for ß1-ß2-and ß3-adrenoceptors were 6.904 ± 0.190, 6.44 ± 0.129 and 5.773 ± 0.129, respectively. In conclusion, PP-36 is a ß-adrenoceptor antagonist possessing potent anti-arrhythmic and cardioprotective effects against ischemia/reperfusion injury in rats.