Exploring the therapeutic opportunities of potassium channels for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects the synovial joint, which leads to inflammation, loss of function, joint destruction, and disability. The disease biology of RA involves complex interactions between genetic and environmental factors and is strongly associated with various immune cells, and each of the cell types contributes differently to disease pathogenesis. Several immunomodulatory molecules, such as cytokines, are secreted from the immune cells and intervene in the pathogenesis of RA. In immune cells, membrane proteins such as ion channels and transporters mediate the transport of charged ions to regulate intracellular signaling pathways. Ion channels control the membrane potential and effector functions such as cytotoxic activity. Moreover, clinical studies investigating patients with mutations and alterations in ion channels and transporters revealed their importance in effective immune responses. Recent studies have shown that voltage-gated potassium channels and calcium-activated potassium channels and their subtypes are involved in the regulation of immune cells and RA. Due to the role of these channels in the pathogenesis of RA and from multiple pieces of clinical evidence, they can be considered therapeutic targets for the treatment of RA. Here, we describe the role of voltage-gated and calcium-activated potassium channels and their subtypes in RA and their pharmacological application as drug targets.

siRNA as potential therapeutic strategy for hypertension.

Hypertension, a well-known cardiovascular disorder noticed by rise in blood pressure, poses a significant global health challenge. The development RNA interfering (RNAi)-based therapies offers a ground-breaking molecular tool, holds promise for addressing hypertension's intricate molecular mechanisms. Harnessing the power of small interfering RNA (siRNA), researchers aim to selectively target and modulate genes associated with hypertension. Furthermore, they aim to downregulate the levels of mRNA by activating cellular nucleases in response to sequence homology between the siRNA and the corresponding mRNA molecule. As a result, genes involved in the cause of disorders linked to a known genetic background can be silenced using siRNA strategy. In the realm of hypertension, siRNA therapy emerges as a potential therapy for prognostics, diagnostics and treatments. It plays an important role in execution of targeting suppression of genes involved in vascular tone regulation, sodium handling, and pathways contributing to high blood pressure. A clinical trial involving intervention like angiotensinogen siRNA (AGT siRNA) is currently being carried out to treat hypertension. Genetic correlations between uromodulin (UMOD) and hypertension are investigated as emerging Non AGT siRNA target. Furthermore, expression of UMOD is responsible for regulation of sodium by modulating the tumor necrosis factor-α and regulating the Na + -K + -2Cl-cotransporter (NKCC2) in the thick ascending limb, which makes it an important target for blood pressure regulation.

Zebrafish Experimental Animal Models for AD: A Comprehensive Review.

AD disease (AD) is a multifaceted and intricate neurodegenerative disorder characterized by intracellular neurofibrillary tangle (NFT) formation and the excessive production and deposition of Aß senile plaques. While transgenic AD models have been found instrumental in unravelling AD pathogenesis, they involve cost and time constraints during the preclinical phase. Zebrafish, owing to their simplicity, well-defined behavioural patterns, and relevance to neurodegenerative research, have emerged as a promising complementary model. Zebrafish possess glutaminergic and cholinergic pathways implicated in learning and memory, actively contributing to our understanding of neural transmission processes. This review sheds light on the molecular mechanisms by which various neurotoxic agents, including okadaic acid (OKA), cigarette smoke extract, metals, and transgenic zebrafish models with genetic similarities to AD patients, induce cognitive impairments and neuronal degeneration in mammalian systems. These insights may facilitate the identification of effective neurotoxic agents for replicating AD pathogenesis in the zebrafish brain. In this comprehensive review, the pivotal role of zebrafish models in advancing our comprehension of AD is emphasized. These models hold immense potential for shaping future research directions and clinical interventions, ultimately contributing to the development of novel AD therapies.

An Overview of Recent Findings that Shed Light on the Connection between Fat and Cancer.

Obesity and cancer have been found to have a direct link in epidemiological studies. Obesity raises the risk of cancer and associated chronic disorders. Furthermore, an imbalance of adipokines, like leptins, plays a crucial role in neoplasm pathogenesis, cell migration, and thereby, cancer metastasis. Also, leptin increases human epidermal growth factor receptor 2 (HER2) protein levels through the STAT3-mediated (signal transducer and activator of transcription) upregulation of heat shock protein (Hsp90) in breast cancer cells. It has been noticed that insulin and insulin-like growth factors (IGFs) act as mitosis activators in the host and cancerous breast epithelial cells. The condition of hyperinsulinemia explains the positive association between colorectal cancer and obesity. Furthermore, in prostate cancer, an alteration in sex hormone levels, testosterone and dihydrotestosterone, has been reported to occur, along with increased oxidative stress, which is the actual cause of the tumors. Whereas, there have been two interconnected factors that play a crucial role in the psychological cycle concerned with lung cancer. The review article focuses on all the prospects of etiological mechanisms that have found linkage with obesity and breast, colon, lung, and prostate cancers. Furthermore, the article has also highlighted how these new insights into the processes occur and, due to which reasons, obesity contributes to tumorigenesis. This review provides a detailed discussion on the progression, which can assist in the development of new and innovative techniques to interfere in this process, and it has been supported with insights based on evidence literature on approved clinical treatments for obesity and cancer.

Understanding Glycogen Synthase Kinase-3: A Novel Avenue for Alzheimer's Disease.

Alzheimer's Disease (AD) is the most prevalent form of age-related dementia. Even though a century has passed since the discovery of AD, the exact cause of the disease still remains unknown. As a result, this poses a major hindrance in developing effective therapies for treating AD. Glycogen synthase kinase-3 (GSK-3) is one of the kinases that has been investigated recently as a potential therapeutic target for the treatment of AD. It is also known as human tau protein kinase and is a proline-directed serine-threonine kinase. Since dysregulation of this kinase affects all the major characteristic features of the disease, such as tau phosphorylation, amyloid formation, memory, and synaptic function, it is thought to be a major player in the pathogenesis of AD. In this review, we present the most recent information on the role of this kinase in the onset and progression of AD, as well as significant findings that identify GSK-3 as one of the most important targets for AD therapy. We further discuss the potential of treating AD by targeting GSK-3 and give an overview of the ongoing studies aimed at developing GSK-3 inhibitors in preclinical and clinical investigations.

Behavioral and Neurological Effects of Edaravone and Noscapine in Albino Wistar Rats.

OBJECTIVE: The purpose of the study was to explore Edaravone and Noscapine in anAlCl3-induced Alzheimer's disease (AD) model. METHODS: Morris Water Maze (MWM), Novel Object Recognition (NOR), andY-maze tests with TNF-α, IL-1, IL-6, amyloid-ß, CAT, SOD and MDAlevels were performed, followed by brain histology. RESULTS: On the probe trial, the MWM demonstrated a decrease in escape latencyfollowed by an increase in the target quadrant. The NOR showeddiscrimination and recognition index scores and Y-maze, revealed arise in spontaneous alterations. TNF-α, IL-1, IL-6, amyloid-ß, CATand MDA levels increased, while SOD levels dropped. The results werefound to be significant for combination full and half doses (***p <0.001, **p < 0.01). The treated group's histology ofbrain revealed mild neurodegeneration with hippocampal pyknoticnuclei. CONCLUSIONS: Thus, Edaravone and Noscapine can be used for thetreatment of AD. .

Abbreviations: AlCl3: Aluminium chloride; AD: Alzheimer's disease; Aß: Amyloid plaques; APP: amyloid precursor protein; BACE 1: Serum beta-secretase 1; GSK3ß: Glycogen synthase kinase 3 ß; CDK 5: cyclin-dependent kinase-5; NFTs: neurofibrillary tangles; ROS: reactive oxygen species; JNK: c Jun N-terminal kinases; MWM: Morris Water Maze; NOR: Novel Object Recognition (NOR); TNF-α: Tumor necrosis factor -α; CAT: Catalase; SOD: Superoxide Dismutase; MDA: Malondialdehyde.

Deciphering the role of metal and non-metals in the treatment of epilepsy.

Metals and non-metals have known to play a significant role in various physiological roles in the body including the central nervous system (CNS). The alterations in their concentration in the CNS leads to abnormalities in the normal functions which may lead to various neurological conditions including epilepsy. Manganese is a cofactor required for antioxidant enzymes such as Superoxide dismutase, Glutamine synthetase, etc. The accumulation of iron leads to formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) which have the potential to cause ferroptosis, one of the reasons for epileptogenesis. Zinc has biphasic response, both neurotoxic and neuroprotective, based on concentration levels in the CNS. Selenium is a main element for selenoproteins which is responsible for the regulation of oxidative state and antioxidant defence mechanism. The reduction in the phosphorous levels in the CNS is widely observed after generalised tonic clonic seizures (GTC), which can be a potential diagnostic biomarker. Copper acts in the CNS in an identical manner, i.e., by blocking both AMPA mediated and GABA mediated neuronal transmission. Magnesium blocks calcium channels in the NMDA receptor and prevents glutamatergic transmission, thus inhibiting excitotoxicity. Lithium acts as a proconvulsive agent and is used in combination with pilocarpine to induce seizures. The identified potential of metals and non-metals in epilepsy can be utilised in order to devise new adjuvant therapies for the management of epilepsy. The article summaries in depth the role of metals and non-metals in the treatment of epilepsy supported with special paragraph on author perspective on to the topic. Furthermore, an update of preclinical and clinical evidences are discussed in the review to give evidence on metal and non-metal based therapies in epilepsy.

Exploring Cytokines as Potential Target in Peptic Ulcer Disease: A Systematic Update.

Peptic ulcer disease (PUD) is a widespread condition that affects millions of people each year, with an incidence rate of 0.1%-1.5%, and has a significant impact on human health. A range of stimuli, such as Helicobacter pylori, non-steroidal anti-inflammatory drugs, hyperacidity, stress, alcohol, smoking, and idiopathic disease states, can produce a sore in the gastrointestinal mucosal layer. For individuals infected with H. pylori, 2%-3% remain asymptomatic throughout their life. Although PUD treatments are available, genetic variations occurring in individuals because of geographical dissimilarity and antibiotic resistance pose limitations. Specifically, inflammatory cytokine gene polymorphisms have received immense attention in recent years because they appear to affect the severity and duration of stomach inflammation, which is induced by H. pylori infection, contributing to the initiation of PUD. In such a context, in-depth knowledge of interleukins may aid in the discovery of new targets and provide precautionary approaches for the treatment of PUD. This review aims to give insights into the importance of several interleukins that cognate with PUD and contribute to ulcer progression or healing by activating or dampening the host immunity. Furthermore, the available targets with clinical evidence have been explored in this review.

Update on Oxytocin, Phosphodiesterase, Neurokinin, Glycine as a Therapeutic Approach in the Treatment of Schizophrenia.

BACKGROUND: Schizophrenia is a chronic psychiatric disorder characterized by disrupted thoughts, perception, mood, and behavior. It has a heterogeneous genetic and neurobiological background and affects about 0.5-1% of the adult population worldwide. Herein, we review the current approaches and advances in schizophrenia. The potential therapeutic compounds for the treatment of schizophrenia act on the oxytocin receptor, phosphodiesterase system, neurokinin receptor, and glycine transport 1 receptor. Therefore, this article provides an update on the pharmacology of different receptors in addition to the dopaminergic system. These findings would guide the readers on novel targets for schizophrenia with the potential to be therapeutic agents in the future. OBJECTIVE: To provide the researchers an update on the emerging role of oxytocin, phosphodiesterase, neurokinin, and glycine which can be explored as potential pharmacotherapeutic targets in the treatment of schizophrenia. METHODS: An extensive literature search was conducted using PubMed, Science Direct, and NCBI with the following keywords: schizophrenia, novel receptors, oxytocin, phosphodiesterase, neurokinin, and glycine. Furthermore, to provide insights into newer drug treatments for Schizophrenia, Furthermore, Clinicaltrials.gov website was searched for newer receptor-based drugs. RESULTS: Current literature supported by preclinical and clinical provides substantial evidence that oxytocin, phosphodiesterase, neurokinin, and glycine play a crucial role in Schizophrenia. CONCLUSION: Our findings indicate that though multiple antipsychotic drugs are prescribed to treat schizophrenia, novel approaches and/or mechanisms are plausible. Moreover, sensitive and specific diagnostic tools and safe and effective interventions, including novel therapeutic agents, are required to yield substantially improved future outcomes.

Deciphering the Role of ß-Lactamase Inhibitors, Membrane Permeabilizers and Efflux Pump Inhibitors as Emerging Targets in Antibiotic Resistance.

Antimicrobial drugs have been noticed to have reduce activity effective due to upsurge witnessed in resistance of microbes. To deal with viewpoint of such a circumstance, we must seek ways to prevent it or atleast mitigate its effects in order to provide its activity against the microbes. Hence, novel antimicrobials are the one of the most promising solution for ending antimicrobial resistance. Furthermore, due to the less development of newer antimicrobials in recent years, the only way to combat microbial resistance are various synergistic approaches of exploring antimicrobial drug combinations. This combination's efficacy is due to a synergistic chemical that re-sensitizes the resistant microbial strain. It has been observed that classes of ß-lactamases inhibitors, efflux pump inhibitors and membrane permeabilizers are of particular relevance, since they can break resistance to the most commonly used antimicrobials. This review explains the readers that how these synergistic combinations can help to reduce or eliminate the microbial resistance supported with clinical evidence. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-022-01045-6.

An Update On Proficiency of Voltage-gated Ion Channel Blockers in the Treatment of Inflammation-associated Diseases.

Inflammation is the body's mechanism to trigger the immune system, thereby preventing bacteria and viruses from manifesting their toxic effect. Inflammation plays a vital role in regulating inflammatory mediator levels to initiate the wound healing process depending on the nature of the stimuli. This process occurs due to chemical release from white blood cells by elevating blood flow to the site of action, leading to redness and increased body temperature. Currently, there are numerous Non-steroidal anti-inflammatory drugs (NSAIDs) available, but these drugs are reported with adverse effects such as gastric bleeding, progressive kidney damage, and increased risk of heart attacks when prolonged use. For such instances, alternative options need to be adopted. The introduction of voltage-gated ion channel blockers can be a substantial alternative to mask the side effects of these currently available drugs. Chronic inflammatory disorders such as rheumatoid and osteoarthritis, cancer and migraine, etc., can cause dreadful pain, which is often debilitating for the patient. The underlying mechanism for both acute and chronic inflammation involves various complex receptors, different types of cells, receptors, and proteins. The working of voltage-gated sodium and calcium channels is closely linked to both inflammatory and neuropathic pain. Certain drugs such as carbamazepine and gabapentin, which are ion channel blockers, have greater pharmacotherapeutic activity for sodium and calcium channel blockers for the treatment of chronic inflammatory pain states. This review intends to provide brief information on the mechanism of action, latest clinical trials, and applications of these blockers in treating inflammatory conditions.

An update on novel therapeutic intervention in Rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder that is slow progressive destruction of the joints and is caused by autoantibodies that target a variety of organs thereby leading to auto-destruction. Patients diagnosed with RA develop deformity of joints and show gradual functional impairment if they do not receive treatment within the desired timeline. The availability of biological treatments and the introduction of treat-to-target regimens have dramatically enhanced the outcome for patients treated with RA conditions. Nevertheless, there is still attention required for RA because patients do not respond adequately to currently available treatment regimens. Over the past few decades, newer therapy methods are evolving to better understand the in-depth literature behind the actual cause of RA. Thus, getting an insight into the importance of RA there is a need for a shift in the existing treatment. This article focuses on a comprehensive review of the therapeutic potential of newer targets such as Janus Kinase-signal transducer and activator of transcription pathway, Granulocyte macrophage-colony stimulating factor, Bruton's Tyrosine Kinase Pathway, Phosphoinositide-3-kinase Pathway, Dendritic cells, Neuropathway, Receptor activator of nuclearfactor-kappa-Β ligand (RANKL) Inhibitors, Mesenchymal Stem Cells and Synovial Anatomy emphasizing on Synovial fibroblasts Myeloid Cells which have been summarized. In addition, novel therapeutic targets such as proteins, small molecular metabolites, and epigenetics are described in this article. Cytokines, chemokines, and other protein targets are among the protein target. Prostaglandins, leukotrienes, platelet-activating factor, cannabinoids, and specific fatty acid amide hydrolase are all examples of small molecular metabolites. DNA, RNA, and Histone Modification are epigenetic targets. Furthermore, the article provides an in-depth understanding of the exact mechanism in underlying pathophysiology in RA and thereby substantiating their evident therapeutic effect with ongoing clinical trials. Nevertheless, these newer targets would help to bring and paradigm shift in the treatment of this ancient autoimmune disorder.