Multiple Sclerosis: Pathogenesis Mechanism and Biomarkers.

Multiple sclerosis (MS) is an unceasing, demyelinating, idiopathic inflammatory, and neurodegenerative disease of the Central Nervous System (CNS.) The disease is characterized by the occurrence of neurological symptoms over a period of days to weeks, abide by partial or absolute diminutions of various durations. In this review, a concise outline on disease activity and progression of MS, pathogenesis with the special prominence on the biomarkers for the MS as therapeutic targets has been discussed by carrying out a comprehensive literature survey employing chief websites and search engines for investigation. Cortical inflammation, neurodegeneration, demyelination, axonal injury, axonal loss, oligodendrocytes, mitochondrial dysfunction, microglia activation, oxidative and nitrosative stress are the pathological hallmarks of the MS. CNS neurofilaments, chitinase and chitinase 3-like proteins, soluble circulating form (sCD163), Chemokine ligand 13 (CXCL13), immunoglobulin M, MicroRNA (miRNA) and messenger Ribonucleic Acid (mRNA), Glial fibrillary acidic protein (GFAP), serum osteopontin, 8-iso-prostaglandin F2α (8-iso-PGF2 α), apo-Lipoprotein E and myelinreactive T cells are some of the therapeutically valuable biomarkers for such multifarious disorder. MS is one of the chronic neurodegenerative diseases with undefined etiology. The study of the pathophysiology of the disease and the involvement of certain biomarkers can help identify new targets for therapeutic intercession, identify individuals at risk of developing the disease later in life, and allow more effective treatment of progressive diseases such as MS.

Pyridazine Derivatives: Molecular Docking, ADMET Prediction, and Synthesis for Antihypertensive Activity.

INTRODUCTION: The drug discovery and development domain has witnessed remarkable advancements due to the integration of computational methods, particularly Computer-Aided Drug Design (CADD). Discovering and creating new drugs involves structural modifications to enhance their effectiveness and physical attributes. This frequently includes employing semisynthetic techniques to investigate structure-activity relationships thoroughly. Noticeable progress in molecular biology, computational chemistry, combinatorial chemistry, and highthroughput screening is steering transformative changes in the pharmaceutical industry. BACKGROUND: High blood pressure or hypertension, a significant health issue, elevates the chances of heart, kidney, and brain complications, among other health concerns. It's a leading cause of untimely mortality globally. Therefore, it is important to search for new antihypertensive compounds that have fewer side effects and higher therapeutic activity. METHODS: Following molecular docking of the pyridazine derivatives, compounds were subjected to In-silico ADMET analysis. Subsequently, a low molecular weight compound was synthesized. Among the synthesized compounds characterization procedures include TLC, FT-IR, 1HNMR, and LC-MS techniques. RESULT: Compound 8 exhibited the most favorable molecular docking results with alpha A1 and beta 1 adrenergic receptors. Compounds 3, 5, and 6 fulfilled the essential ADMET criteria. Subsequently, Compounds 3, 4, and 5 underwent additional synthesis and characterization procedures, including TLC, FT-IR, 1H-NMR, and LC-MS techniques. CONCLUSION: Similar behavior was observed in compounds 6, 8, 10, and 11, all violating Pfizer's 3/75 rules in terms of TPAS. Hydrazinolysis of these b-benzoyl propionic acids produced pyridazine, which was utilized in synthesizing pyridazine derivatives. TLC, FT-IR, 1HNMR, and LCMS have characterized the compounds.

Unveiling the Mysteries of the Blood-Brain Barrier: The Problem of the Brain/spinal Pharmacotherapy.

The most critical issue impeding the development of innovative cerebrospinal medications is the blood-brain barrier (BBB). The BBB limits the ability of most medications to penetrate the brain to the CNS. The BBB structure and functions are summarized, with the physical barrier generated by endothelial tight junctions and the transport barrier formed by transporters within the membrane and vesicular processes. The functions of connected cells, particularly the end feet of astrocytic glial cells, microglia, and pericytes, are described. The drugs that cross the blood brain barrier are explained below along with their mechanisms. Some of the associated conditions and problems are given.

Targeted suppression of MEP pathway genes DXS, IspD and IspF to explore the mycobacterial metabolism and survival.

Due to the uniqueness and essentiality of MEP pathway for the synthesis of crucial metabolites- isoprenoids, hopanoids, menaquinone etc. in mycobacterium, enzymes of this pathway are considered promising anti-tubercular drug targets. In the present study we seek to understand the consequences of downregulation of three of the essential genes- DXS, IspD, and IspF of MEP pathway using CRISPRi approach combined with transcriptomics in Mycobacterium smegmatis. Conditional knock down of either DXS or IspD or IspF gene showed strong bactericidal effect and a profound change in colony morphology. Impaired MEP pathway due to downregulation of these genes increased the susceptibility to frontline anti-tubercular drugs. Further, reduced EtBr accumulation in all the knock down strains in the presence and absence of efflux inhibitor indicated altered cell wall topology. Subsequently, transcriptional analysis validated by qRT-PCR of +154DXS, +128IspD, +104IspF strains showed that modifying the expression of these MEP pathway enzymes affects the regulation of mycobacterial core components. Among the DEGs, expression of small and large ribosomal binding proteins (rpsL, rpsJ, rplN, rplX, rplM, rplS, etc), essential protein translocases (secE, secY and infA, infC), transcriptional regulator (CarD and SigB) and metabolic enzymes (acpP, hydA, ald and fabD) were significantly depleted causing the bactericidal effect. However, mycobacteria survived under these damaging conditions by upregulating mostly the genes needed for the repair of DNA damage (DNA polymerase IV, dinB), synthesis of essential metabolites (serB, LeuA, atpD) and those strengthening the cell wall integrity (otsA, murA, D-alanyl-D-alanine dipeptidase etc.).

Diabetic Retinopathy - Pathophysiology to Treatment: A Review.

Diabetic retinopathy (DR) is a microvascular disease affecting the eyes of diabetic patients, and is the most prevalent complication of diabetes mellitus. Vision improvement is not possible in the majority of DR patients. Several studies have indicated that microvascular changes, inflammation, oxidative stress, and retinal neurodegeneration are involved in the pathogenesis of DR. Therefore, there is an urgent need for the development of new and effective treatment for DR. Understanding the molecular mechanisms involved in the pathogenesis of disease will pave a way for better treatment and management of DR. This article has emphasized the molecular pathogenesis and treatment of DR.

Exploring the Therapeutic Potential of Alkaloids in Alzheimer's Disease Management.

BACKGROUND: Alkaloids are important phytoconstituents obtained from various plant sources. The study's primary goal is to assess the anti-Alzheimer potential of alkaloids using a molecular docking study. Alzheimer's disease (AD) is considered a gradual decline in memory, reasoning, decision-making, orientation to one's physical surroundings, and language. MATERIALS AND METHODS: The main target i.e. acetylcholinesterase proteins was selected for the molecular docking study. RESULTS: The structures of various alkaloids were drawn using Chem Draw Software, PDB was retrieved from the RCSB PDB database, and molecular docking study was performed on Molergo Virtual Docker. The potential alkaloids were identified with anti-Alzheimer potency. CONCLUSION: Reserpine, vinblastine, ergotamine, and tubocurarine were found to exhibit potential anti-Alzheimer potency.

Exploring the Therapeutic Potential of Phytoconstituents for Addressing Neurodegenerative Disorders.

Neurodegenerative disorder is a serious condition that is caused by abnormal or no neurological function. Neurodegenerative disease is a major growing cause of mortality and morbidity worldwide, especially in the elderly. After World War Ⅱ, eugenics term was exterminated from medicines. Neurodegenerative disease is a genetically inherited disease. Lifestyle changes, environmental factors, and genetic modification, together or alone, are involved in the occurrence of this disorder. The major examples of neurodegenerative disorders are Alzheimer's and Parkinson's disease, in which apoptosis and necrosis are the two major death pathways for neurons. It has been determined from various studies that the etiology of the neurodegenerative disease involves the role of oxidative stress and anti-oxidant defence system, which are prime factors associated with the activation of signal transduction pathway that is responsible for the formation of synuclein in the brain and manifestation of toxic reactions in the form of functional abnormality, which ultimately leads to the dysfunction of neuronal pathway or cell. There has not been much success in the discovery of effective therapy to treat neurodegenerative diseases because the main cause of abnormal functioning or death of neurons is not well known. However, the use of natural products that are derived from plants has effective therapeutic potential against neurodegenerative disease. The natural compounds with medicinal properties to prevent neurological dysfunction are curcumin, wolfberry, ginseng, and Withania somnifera. The selection and use of natural compounds are based on their strong anti-inflammatory and anti-oxidant properties against neurodegenerative disease. Herbal products have active constituents that play an important role in the prevention of communication errors between neurons and neurotransmitters and their respective receptors in the brain, which influence their function. Considering this, natural products have great potential against neurodegenerative diseases. This article reviews the natural compounds used to treat neurodegenerative diseases and their mechanisms of action.

Pesticides: An alarming detrimental to health and environment.

Pesticides are chemical substances of natural or synthetic origin that are used to eradicate pests and insects. These are indispensable in the agricultural processes for better crop production. Pesticide use aims to promote crop yield and protect the crops from diseases and damage. Pesticides must be handled carefully and disposed of appropriately because they are dangerous to people and other species by default. Environmental pollution occurs when pesticide contamination spreads away from the intended plants. Older pesticides such as lindane and dichlorodiphenyltrichloroethane (DDT) may remain in water and soil for a longer time. These accumulate in various parts of the food chain and cause damage to the ecosystem. Biological techniques in the management of pest control such as importation, augmentation, and conservation, and the accompanying procedures are more efficient, less expensive, and ecologically sound than other ways. This review mainly focuses on the consequences on the targeted and non-targeted organisms including the health and well-being of humans by the use of pesticides and their toxicity. The side effects that occur when a pesticide's LD50 exceeds the accepted limit through oral or skin penetration due to their binding to various receptors such as estrogen receptors, GABA, EGFR, and others. These pesticide classes include carbamates, pyrethroids, organochlorides, organophosphorus, and others. The current study seeks to highlight the urgent requirement for a novel agricultural concept that includes a major reduction in the use of chemical pesticides.

Concise Review on Scientific Approaches to Burns and Scars.

Burns are large open surgical lesions bathed in virulent pus that result in rupturing of the cutaneous membrane, which has serious consequences such as an extensive loss of proteins, and body fluids, increased chances of infections, and sometimes death. These can be classified based on their penetration levels, i.e., first-degree burns penetrating the epidermis, second-degree burns including both epidermis and dermis, third-degree burns to both layers including the hair follicular cells, sweat glands and various core tissues, fourth-degree burns to adipose tissue, fifth stage burns to muscles, and sixth stage burns to bones. Wound healing/wound repair is a very perplexing process in which the tissues of the affected/burnt area repairs themselves to attain their original form and functionality but develop a scar at the wound site. This article mainly focuses on the algorithms to differentiate various degrees of burns, general first aid approaches to burns and scars, the rationale of treatment of burns, basic mechanisms highlighting the healing processes in humans in terms of free from scar formation as well as with scar formation at their elementary levels including cellular as well as biochemical levels, utility, and progression of pre-clinical data to humans and finally approaches for the improvement of scar formation in man.

Supersaturation Behavior: Investigation of Polymers Impact on Nucleation Kinetic Profile for Rationalizing the Polymeric Precipitation Inhibitors.

BACKGROUND: Although nucleation kinetic data is quite important for the concept of supersaturation behavior, its part in rationalizing the crystallization inhibitor has not been well understood. OBJECTIVE: This study aimed to investigate the nucleation kinetic profile of Dextromethorphan HBr (as an ideal drug, BCS-II) by measuring liquid-liquid phase segregation, nucleation induction time, and Metastable Zone width. METHODS: Surfeit action was examined by a superfluity assay of the drug. The concentration was scrutinized by light scattering techniques (UV spectrum (novel method) and Fluorometer (CL 53)). RESULTS: The drug induction time was 20 min without polymer and 90 and 110 min with polymers, such as HPMC K15M and Xanthan Gum, respectively. Therefore, the order of the polymer's ability to inhibit nucleation was Xanthan Gum > HPMC K15M in the medium (7.4 pH). Similarly, the drug induction time was 30 min without polymer and 20, 110, and 90 min with polymers, such as Sodium CMC, HPMC K15M, and Xanthan Gum, respectively. Therefore, the order of the polymer's ability to inhibit nucleation was HPMC K15M > Xanthan Gum > Sodium CMC in SIFsp (6.8 pH), which synchronizes the polymer's potentiality to interdict the drug precipitation. CONCLUSION: The HPMC K15M and xanthan Gum showed the best crystallization inhibitor effect for the maintenance of superfluity conditions till the drug absorption time. The xanthan gum is based on the "glider" concept, and this shows the novelty of this preliminary research. The screening methodology used for rationalizing the best polymers used in the superfluity formulations development successfully.

In-Silico Investigation of Ginseng Phytoconstituents as Novel Therapeutics Against MAO-A.

BACKGROUND: Ginseng (Panax ginseng) is a herb of medicinal and nutritional importance. Ginseng has been used since ancient times for the treatment of numerous ailments as it has many therapeutic properties. Several phytoconstituents are present in Panax ginseng that possess a variety of beneficial pharmacological properties. OBJECTIVE: To explore the potential of phytoconstituents of Panax ginseng in the treatment of depression, a molecular modeling technique was utilized targeting monoamine oxidase-A (MAOA). METHODS: A total of sixty-one phytoconstituents of ginseng were drawn with the help of ChemBioDraw Ultra 12.0 software and PDBs for MAO-A enzyme were retrieved from the RCSB PDB database. The prepared ligands were screened for MAO-A properties using the software Molegro Virtual Docker (MVD 2010.4.1.0). All the prepared ligands were evaluated for drug-likeliness properties using Swiss ADME. RESULT: Among the docking studies of 60 Ginseng phytochemicals including one standard, 15 phytoconstituents with the highest dock score and better binding interactions were selected further for absorption, distribution, metabolism and excretion (ADME) studies. Stachyose (-227.287, 17 interactions), Raffinose (-222.157, 14 interactions), and Ginsenoside Rg1 (-216.593, 10 interactions) were found to possess better interactions as compared to Clorgyline taken as a standard drug. CONCLUSION: Stachyose was found to be the most potent inhibitor of MAO-A enzyme under investigation and can be a potential lead molecule for the development of newer phytochemical-based treatment of depression.

Alkaloids as Potential Anti-HIV Agents.

BACKGROUND: Alkaloids are nitrogen-containing compounds that are naturally occurring and have a variety of biological activities, including antimicrobial properties. In this study, the authors used a molecular docking approach to evaluate the anti-HIV potential of 64 alkaloids. METHODS: The authors used the Molegro Virtual Docker software to dock the alkaloids into the active sites of three HIV enzymes: protease, integrase, and non-nucleoside reverse transcriptase (NNRT). The docking scores were used to assess the potential of the alkaloids to inhibit the enzymes. RESULTS: The results showed the alkaloids to have good potential to inhibit the enzymes. Tubocurarine and reserpine were found to be the most potent alkaloids, with docking scores of -123.776 and - 114.956, respectively. CONCLUSION: The authors concluded that tubocurarine and reserpine could be further promoted as potential lead molecules for the development of new anti-HIV drugs.

Targeted Approach to Enhance the Solubility of Weakly Soluble Drugs by Nanocrystal Technology.

About 90% of the newly discovered drugs are poorly soluble in water, to overcome this problem, nanocrystal technology is used. Nanocrystal technology is a modern technique that is specially used to increase the solubility of less soluble drugs. Production of a nanocrystal on a large scale can be done by techniques like homogenization (high-pressure), precipitation, and milling methods. Using this technique, saturation solubility, the adhesiveness of a drug molecule to the surface cell, and the dissolution velocity is enhanced. This technology is better than the traditional method because it provides certain other benefits like increased drug loading capability, fantastic reproducibility of oral retention, further developed proportionality of portion bioavailability and expanded patient compliance. This audit makes sense of the various kinds of techniques for the arrangement of nanocrystals, benefits, drawbacks, a system of solvency improvement, clinical applications, and future imminent. This review article also provides further guidelines for studies about nanocrystal technology.

Erratum: Addendum: Effect of pre-operative medication with paracetamol and ketorolac on the success of inferior alveolar nerve block in patients with symptomatic irreversible pulpitis: a double-blind randomized clinical trial.

[This corrects the article on p. 441 in vol. 21, PMID: 34703893.].

Imidazole and Derivatives Drugs Synthesis: A Review.

Imidazoles have long held a special place in heterocyclic chemistry, and their derivatives have piqued interest in recent years due to their diverse chemistry and pharmacology features. Imidazole is a biologically and pharmaceutically important nitrogen-containing heterocyclic ring. As a result, researchers have been interested in imidazole molecules. For a century and a half, purine, histamine, and other natural compounds all contained the imidazole ring. A number of imidazole drugs have been prepared and marketed for the treatment of various diseases. In view of this, we herein report a detailed account of synthetic procedures for various imidazole drugs.

Chemical Constituents Based Approach for the Management of Diabetes.

BACKGROUND: A number of complexities in compliance with long-term diabetes have been elicited. It has become a global concern without any convincing medicinal, therapeutical methodology. Both hyperglycaemia and oxidative pressure are major notable parts that play a significant role in the initialization of diabetic inconvenience. Natural medications have gained a lot of attention in recent years as expected restorative specialists in the prevention and treatment of diabetic complications due to their many objectives and less poisonous outcomes. This survey means to evaluate the accessible information on therapeutic spices for constriction and the executives of diabetic complications. MATERIALS AND METHODS: Bibliographic investigation was accomplished by checking old-style course books and papers, directing overall bases of logical information (SCOPUS, PUBMED, SCIELO, Google Scholar, NISCAIR,) to recapture accessible distributed writing. For the assessment of plants with the potential in calming diabetic complications, several inclusion models rely on the numerous medicinal spices as well as their crucial mixes. Furthermore, several models, including plants, have been considered, each of which has a suitable impact on increasing oxidative pressure in diabetes. RESULTS: Different therapeutic plants/plant withdrawals containing alkaloids, terpenoids, phenolic compounds, flavonoids, saponins, and phytosterol-type synthetic constituents were uncovered that are profitable in the administration of diabetic complexities. Results may be attributed to the improvement of oxidative pressure, constant hyperglycemia, and twitch of different metabolic pathways related to the pathogenesis of diabetic confusions. CONCLUSION: An optimistic approach for new medication terminology to treat diabetic confusion is screening compound competitors from homegrown medication. Investigation of the activity of different plant extracts as well as their potency profile and to determine their job in the treatment of diabetic inconveniences must be there. In addition, an ideal rat model which imitates human diabetic complications ought to be created.

Diabetic Neuropathy: A Repercussion of Vitamin D Deficiency.

Diabetes mellitus is a crucial health issue worldwide. The worldwide ubiquity is 8.8% among adults, which is predicted to rise to 10.4% by 2040. Diabetic neuropathy is a long-term complication associated with the diabetes mellitus condition, which primarily targets Schwann cells, peripheral axons and cell bodies (perikarya) in DRG (dorsal root ganglia). It can be accompanied by different factors such as metabolic factors such as insulin resistance, hypertension, obesity, low HDL level, and hypertriglyceridemia. The etiology of DPN is multifactorial. It is caused by hyperglycemia, micro-angiopathy, HbA1c, duration of diabetes, smoking status, high-density lipoprotein cholesterol and hypertension. Also, increased glucose conditions decrease vitamin D levels. Vitamin D, which is involved in neurotrophins such as NGF (nerve growth factor) and NCH (neuronal calcium homeostasis), plays a neuroprotective role in peripheral nerves. Depletionleads to vitamin D deficiency which further develops peripheral neuropathy in diabetic patients. Accumulation of AGEs (advanced glycation end product) plays a significant role in the pathogenesis of sensory neuronal damage. It contributes to microangiopathy and endoneurial vascular dysfunction in peripheral nerves. With vitamin D supplementation, the neuropathy pain scores were improved.

Effect of pre-operative medication with paracetamol and ketorolac on the success of inferior alveolar nerve block in patients with symptomatic irreversible pulpitis: a double-blind randomized clinical trial.

BACKGROUND: The efficacy of local anesthesia decreases in patients with symptomatic irreversible pulpitis. Therefore, it was proposed that the use of premedication with an anti-inflammatory drug might increase the success rate of pulpal anesthesia in mandibular posterior teeth with vital inflamed pulp. METHODS: One hundred thirty-four patients who were actively experiencing pain willingly participated in this study. The Heft Parker (HP) visual analog scale (VAS) was used to record the initial pain intensity. Patients were randomly allocated to receive a placebo, 10 mg of ketorolac, and 650 mg of paracetamol. The standard inferior alveolar nerve block (IANB) was administered to all patients using 2% lidocaine with 1:200,000 adrenaline after one hour of medication. After 15 min, the patient was instructed to rate the discomfort during each step of the treatment procedure, such as access to remaining dentin, access to the pulp chamber, and during canal instrumentation on the HP VAS. IANB was considered successful if the patient reported no or mild pain during access preparation and instrumentation. Moderate or severe pain was classified as a failure of IANB and another method of anesthesia was used before continuing the treatment. RESULTS: The rate of successful anesthesia in the placebo, paracetamol, and ketorolac groups was 29%, 33%, and 43%, respectively, and no statistically significant difference was found between the groups. CONCLUSION: Preoperative administration of paracetamol or ketorolac did not significantly affect the success rate of IANB in patients with irreversible pulpitis. No significant difference was observed between the paracetamol and ketorolac groups.

Current and Future Prospective of a Versatile Moiety: Imidazole.

Imidazole containing compounds have been a very much explored field since ancient times. Subsequently, it constitutes a significant moiety for the new drug development. A variety of compounds having imidazole moiety have been synthesized, evaluated and marketed for the treatment of various diseases such as antifungal, antiepileptic, ACE inhibitors and so on, as shown in the figure. The search for imidazole containing compounds with more selective biological potency with low side effects continues to be an active area of research in medicinal chemistry. This review is in an effort to highlight the marketed drugs with imidazole ring. The article also demonstrates the future prospective of marketed imidazoles as antifungal with potential activity targeting 14α-demethylase enzyme.

Molecular Modeling Studies of Halogenated Imidazoles against 14α- Demethylase from Candida Albicans for Treating Fungal Infections.

BACKGROUND: Imidazole is one of the most explored and marketed azole utilized for the treatment of fungal infections. Lanosterol 14α-demethylase (Cytochrome P450DM) is the active target site for azole antifungals. AIM AND OBJECTIVE: This study emphasized on evaluation of a series of halogenated imidazole analogues using molecular docking studies for anti-Candidal activity. Furthermore, the model was refined by molecular dynamic simulation. METHODS: Halogenated imidazole analogues (PS1-PS30) were obtained from literature for the study. The imidazole analogues were prepared using Chem sketch and molecular docking was performed using Molergo Virtual Docker program and ADMET study was carried out by using Accelry's Accord for Excel programme. RESULTS: The docking study indicated that all the imidazole analogues (PS1-PS30) and standard drugs i.e., Ketoconazole, Miconazole and Clotrimazole possessed interaction with protein residue, heme cofactor and water molecule positioned above Heme cofactor of 14α-demethylase. Further, the ADMET study indicated that most of the halogenated imidazoles possessed good absorption, human intestinal absorption, aqueous solubility and blood brain penetration. CONCLUSION: Halogenated imidazole analogues may be used as potential lead molecules as 14α- demethylase inhibitors.