Obesity and Depression: Common Link and Possible Targets.

Depression is among the main causes of disability, and its protracted manifestations could make it even harder to treat metabolic diseases. Obesity is linked to episodes of depression, which is closely correlated to abdominal adiposity and impaired food quality. The present review is aimed at studying possible links between obesity and depression along with targets to disrupt it. Research output in Pubmed and Scopus were referred for writing this manuscript. Obesity and depression are related, with the greater propensity of depressed people to gain weight, resulting in poor dietary decisions and a sedentary lifestyle. Adipokines, which include adiponectin, resistin, and leptin are secretory products of the adipose tissue. These adipokines are now being studied to learn more about the connection underlying obesity and depression. Ghrelin, a gut hormone, controls both obesity and depression. Additionally, elevated ghrelin levels result in anxiolytic and antidepressant-like effects. The gut microbiota influences the metabolic functionalities of a person, like caloric processing from indigestible nutritional compounds and storage in fatty tissue, that exposes an individual to obesity, and gut microorganisms might connect to the CNS through interconnecting pathways, including neurological, endocrine, and immunological signalling systems. The alteration of brain activity caused by gut bacteria has been related to depressive episodes. Monoamines, including dopamine, serotonin, and norepinephrine, have been widely believed to have a function in emotions and appetite control. Emotional signals stimulate arcuate neurons in the hypothalamus that are directly implicated in mood regulation and eating. The peptide hormone GLP-1(glucagon-like peptide- 1) seems to have a beneficial role as a medical regulator of defective neuroinflammation, neurogenesis, synaptic dysfunction, and neurotransmitter secretion discrepancy in the depressive brain. The gut microbiota might have its action in mood and cognition regulation, in addition to its traditional involvement in GI function regulation. This review addressed the concept that obesity-related low-grade mild inflammation in the brain contributes to chronic depression and cognitive impairments.

Designing of xanthine-based DPP-4 inhibitors: a structure-guided alignment dependent Multifacet 3D-QSAR modeling, and molecular dynamics simulation study.

The DPP-4 enzyme degrades incretin hormones GLP-1 and GIP. DPP-4 inhibitors are found effective in the prevention of the degradation of incretins. Xanthine scaffold-bearing molecules are reported as potential DPP-4 inhibitors for treating type 2 diabetes mellitus, e.g. the marketed drug linagliptin. In this work, structure-guided alignment-dependent atom- and Gaussian field-based 3D-QSAR have been performed on a dataset of 75 molecules. The robustness and predictive ability of the developed multifacet 3D-QSAR models were validated on different statistical parameters and found to be statistically fit. The favorable and unfavorable pharmacophoric features were mapped for each multifacet 3D-QSAR model based on three alignment sets (1-3). A five-point common pharmacophore hypothesis was generated separately for each set of alignments. The molecular dynamics simulations (up to 100 ns) were performed for the potent molecule from each alignment set (Compounds 12, 40 and 57) compared to reference standard linagliptin to study the binding energy and stability of target-ligand complexes. The MM-PBSA calculations revealed that the binding free energy and stability of compounds 12 (-40.324 ± 17.876 kJ/mol), 40 (-80.543 ± 21.782 kJ/mol) and 57 (-50.202 ± 16.055 kJ/mol) were better than the reference drug linagliptin (-20.390 ± 63.200 kJ/mol). The generated contour maps from structure-guided alignment-dependent multifacet 3D-QSAR models offer information about the structure-activity relationship (SAR) and ligand-target binding energy and stability data from MD simulation may be utilized to design and develop target selective xanthine-based novel DPP-4 inhibitors.Communicated by Ramaswamy H. Sarma.

Epigenetic modifications in Parkinson's disease: A critical review.

Parkinson's Disease (PD) is a progressive neurodegenerative disorder expected to increase by over 50% by 2030 due to increasing life expectancy. The disease's hallmarks include slow movement, tremors, and postural instability. Impaired protein processing is a major factor in the pathophysiology of PD, leading to the buildup of aberrant protein aggregates, particularly misfolded α-synuclein, also known as Lewy bodies. These Lewy bodies lead to inflammation and further death of dopaminergic neurons, leading to imbalances in excitatory and inhibitory neurotransmitters, causing excessive uncontrollable movements called dyskinesias. It was previously suggested that a complex interplay involving hereditary and environmental variables causes the specific death of neurons in PD; however, the exact mechanism of the association involving the two primary modifiers is yet unknown. An increasing amount of research points to the involvement of epigenetics in the onset and course of several neurological conditions, such as PD. DNA methylation, post-modifications of histones, and non-coding RNAs are the primary examples of epigenetic alterations, that is defined as alterations to the expression of genes and functioning without modifications in DNA sequence. Epigenetic modifications play a significant role in the development of PD, with genes such as Parkin, PTEN-induced kinase 1 (PINK1), DJ1, Leucine-Rich Repeat Kinase 2 (LRRK2), and alpha-synuclein associated with the disease. The aberrant epigenetic changes implicated in the pathophysiology of PD and their impact on the design of novel therapeutic approaches are the primary focus of this review.

Exploring the Antioxidant Potential of Methanolic Extracts of Wild Medicinal and Edible Mushrooms from Darma Valley, Pithoragaph, Kumaun (Himalaya, India).

This study presents a comprehensive analysis of the methanolic extracts of nine species of wild edible mushrooms (WEM) native to the Darma Valley in the Kumaun Himalaya region. The investigation encompasses the assessment of various biochemical attributes, including total phenolics (TP), total flavonoids (TF), total tannins (TT) contents, the ABTS assay, and the DPPH radical scavenging assay. Among the nine WEM species examined, Clavatia craniiformis stands out for displaying the highest antioxidant capacities, indicated by exceptional TP (54.94 ± 0.54 mg gallic acid equivalenta/g dry weight) and TT (4.23 ± 0.17 mg tannic acid equivalents/g dry weight) contents, along with noteworthy ABTS (10.44 ± 0.34 mg abscorbic acid equivalents/g dw) and DPPH activity (0.335 ± 0.001 mg abscorbic acid equivalents/g dry weight). Subsequent antioxidant potential are mushrooms Ramaria fennica, Ramaria botrytis, Ramaria sanguinea, Ramaria flava, Gomphus. clavatus, Clavaria zollingeri, Pleurotus ostreatus, and Kuehneromyces mutabilis. Variations in antioxidant capacities align with distinct phenolic content. This study underscores as a remarkable source of antioxidants, suggesting its potential suitability for nutraceutical applications. The findings contribute to a deeper understanding of the antioxidant properties inherent in wild edible mushrooms, particularly emphasizing the prominence of C. craniiformis.

SMAC Mimetics for the Treatment of Lung Carcinoma: Present Development and Future Prospects.

BACKGROUND: Uncontrolled cell growth and proliferation, which originate from lung tissue often lead to lung carcinoma and are more likely due to smoking as well as inhaled environmental toxins. It is widely recognized that tumour cells evade the ability of natural programmed death (apoptosis) and facilitates tumour progression and metastasis. Therefore investigating and targeting the apoptosis pathway is being utilized as one of the best approaches for decades. OBJECTIVE: This review describes the emergence of SMAC mimetic drugs as a treatment approach, its possibilities to synergize the response along with current limitations as well as future perspective therapy for lung cancer. METHOD: Articles were analysed using search engines and databases namely Pubmed and Scopus. RESULT: Under cancerous circumstances, the level of Inhibitor of Apoptosis Proteins (IAPs) gets elevated, which suppresses the pathway of programmed cell death, plus supports the proliferation of lung cancer. As it is a major apoptosis regulator, natural drugs that imitate the IAP antagonistic response like SMAC mimetic agents/Diablo have been identified to trigger cell death. SMAC i.e. second mitochondria activators of caspases is a molecule produced by mitochondria, stimulates apoptosis by neutralizing/inhibiting IAP and prevents its potential responsible for the activation of caspases. Various preclinical data have proven that these agents elicit the death of lung tumour cells. Apart from inducing apoptosis, these also sensitize the cancer cells toward other effective anticancer approaches like chemo, radio, or immunotherapies. There are many SMAC mimetic agents such as birinapant, BV-6, LCL161, and JP 1201, which have been identified for diagnosis as well as treatment purposes in lung cancer and are also under clinical investigation. CONCLUSION: SMAC mimetics acts in a restorative way in the prevention of lung cancer.

Targeting JAK2/STAT3 for the treatment of cancer: A review on recent advancements in molecular development using structural analysis and SAR investigations.

Cancer is indeed considered a hazardous and potentially life-threatening disorder. The JAK/STAT pathway is an important intracellular signaling cascade essential for many physiological functions, such as immune response, cell proliferation, and differentiation. Dysregulation of this pathway aids in the progression and development of cancer. The downstream JAK2/STAT3 signaling cascades are legitimate targets against which newer anticancer drugs can be developed to prevent and treat cancer. Understanding the mechanisms behind JAK2/STAT3 participation in cancer has paved the way for developing innovative targeted medicines with the potential to improve cancer treatment outcomes. This article provides information on the current scenario and recent advancements in the design and development of anticancer drugs targeting JAK2/STAT3, including structural analysis and SAR investigations of synthesized molecules. Numerous preclinical and clinical trials are ongoing on these inhibitors, which are highlighted to gain more insight into the broader development prospects of inhibitors of JAK2/STAT3.

Arsenic Exposure and Amyloid Precursor Protein Processing: A Focus on Alzheimer's Disease.

BACKGROUND: Arsenic is present in above permissible safe limits in groundwater, soil, and food, in various areas of the world. This is increasing exposure to humankind and affecting health in various ways. Alternation in cognition is one among them. Epidemiological research has reflected the impact of arsenic exposure on children in the form of diminished cognition. AIMS: Considering this fact, the present study reviewed the impact of arsenic on amyloid precursor protein, which is known to cause one of the commonest cognitive disorders such as Alzheimer's disease. METHODS: The present study reviews the arsenic role in the generation of amyloid-beta from its precursor that leads to Alzheimer's disease through the published article from Pubmed and Scopus. DESCRIPTION: According to the findings, regular, long-term exposure to arsenic beginning in infancy changes numerous arsenic level-regulating regions in the rat brain, which are related to cognitive impairments. Arsenic also affects the BBB clearance route by increasing RAGE expression. Arsenic triggers the proamyloidogenic pathway by increasing APP expression and subsequently, its processing by ß-secretase and presenilin. Arsenic also affects mitochondrial dynamics, DNA repair pathway and epigenetic changes. The mechanism behind all these changes is explained in the present review article. CONCLUSION: A raised level of arsenic exposure affects the amyloid precursor protein, a factor for the early precipitation of Alzheimer's disease.

A comprehension on structure guided alignment dependent 3D-QSAR modelling, and molecular dynamics simulation on 2,4-thiazolidinediones as aldose reductase inhibitors for the management of diabetic complications.

Aldose reductase is an oxo-reductase enzyme belonging to the aldo-keto reductase class. Compounds having thiazolidine-2,4-dione scaffold are reported as potential aldose reductase inhibitors for diabetic complications. The present work uses structure-guided alignment-dependent Gaussian field- and atom-based 3D-QSAR on a dataset of 84 molecules. 3D-QSAR studies on two sets of dataset alignment have been carried out to understand the favourable and unfavourable structural features influencing the affinity of these inhibitors towards the enzyme. Using common pharmacophore hypotheses, the five-point pharmacophores for aldose reductase favourable features were generated. The molecular dynamics simulations (up to 100 ns) were performed for the potent molecule from each alignment set (compounds 24 and 65) compared to reference standard tolrestat and epalrestat to study target-ligand complexes' binding energy and stability. Compound 65 was most stable with better interactions in the aldose reductase binding pocket than tolrestat. The MM-PBSA study suggests compound 65 possessed better binding energy than reference standard tolrestat, i.e. -87.437 ± 19.728 and -73.424 ± 12.502 kJ/mol, respectively. The generated 3D-QSAR models provide information about structure-activity relationships and ligand-target binding energy. Target-specific stability data from MD simulation would be helpful for rational compound design with better aldose reductase activity.Communicated by Ramaswamy H. Sarma.

Brain-targeted Nano-architectures for Efficient Drug Delivery and Sensitization in Glioblastoma.

Due to ineffective diagnosis and analysis, glioblastoma multiforme (GBM), is still the most aggressive form of all cancers. Standard therapy for GBM comprises resection surgery following chemo and radiotherapy, which offers less efficacious treatment to the malignant nature of glioma. Several treatment strategies involving gene therapy, immunotherapy, and angiogenesis inhibition have been employed recently as alternative therapeutics. The main drawback of chemotherapy is resistance, which is mainly due to the enzymes involved in the therapeutic pathways. Our objective is to provide a clear insight into various nano-architectures used in the sensitization of GBM and their importance in drug delivery and bioavailability. This review includes the overview and summary of articles from Pubmed and Scopus search engines. The present era's synthetic and natural drugs used in the treatment of GBM are facing poor Blood Brain Barrier (BBB) permeability issues due to greater particle size. This problem can be resolved by using the nanostructures that showcase high specificity to cross the BBB with their nano-scale size and broader surface area. Nano-architectures act as promising tools for effective brain-targeted drug delivery at a concentration well below the final dose of free drug, thus resulting in safe therapeutic effects and reversal of chemoresistance. The present review focuses on the mechanisms involved in the resistance of glioma cells to chemotherapeutic agents, nano-pharmacokinetics, diverse types of nano-architectures used for potent delivery of the medicine and sensitization in GBM, their recent clinical advances, potential challenges, and future perspective.

Potential Targets in Constipation Research: A Review.

BACKGROUND: Constipation is one of the most frequent abnormalities of the gastrointestinal system that affects the patient's quality of life. Constipation is more common in women and affects them more frequently as they get older. Many constipated patients take over-the-counter drugs for treatment, but some do not respond to these medicines and need newer, more expensive drugs. Still, many patients are not completely satisfied with these medicines. Unlike other areas, constipation research is not given much importance. OBJECTIVE: This review discusses targets such as ClC-2, CFTR, opioid receptors, and 5HT-4 receptors, which are important in constipation therapy. The recent focus is also on the gut microbiome with the help of various randomized controlled trials. Pharmacological advances have also added novel targets such as IBAT, PAR-2, and intestinal NHE-3 for constipation treatment. METHODS: This review summarises the research on these targets collected from various databases. ClC-2 and CFTR are involved in intestinal chloride secretion followed by sodium or water, which increases stool passage. Non-cancer pain treatment with opioids targeting opiate receptors is considered in 40-90% of patients, which causes constipation as a side effect. On activation, 5HT-4 receptors increase gastrointestinal motility. IBAT is responsible for transporting bile acid into the liver. Bile acid will reach the colon by inhibiting IBAT, stimulating colonic motility, and providing a laxative effect. Activation of the ghrelin receptor results in prokinetic activity in both animals and humans. Intestinal NHE-3 mediates the absorption of Na+ and the secretion of hydrogen into the intestine. Many reports show that PAR-2 is involved in the pathogenesis of gastrointestinal diseases. The gut microbiota influences the peristaltic action of the intestine. CONCLUSION: Drugs working on these targets positively impact the treatment of constipation, as do the drugs that are currently in clinical trials acting on these targets. The results from the ongoing clinical trials will also provide some valuable information regarding whether these medications will meet the patients' needs in the future.

Epigenetic basis for PARP mutagenesis in glioblastoma: A review.

Several modifications in the glioblastoma genes are caused by epigenetic modifications, which are crucial in appropriate developmental processes such as self-renewal and destiny determination of neural stem cells. Poly (ADP-ribose)polymerase (PARP) is an essential cofactor involved in DNA repair as well as several other cellular functions such as transcription and chromatin shape modification. Inhibiting PARP has evolved for triggering cell damage in cancerous cells when paired with certain other anticancer drugs including temozolomide (TMZ). PARP1 is involved with in base excision repair (BER) pathway, however its functionality differs across types of tumours. Epigenomics as well as chromosomal statistics have contributed to the growth of main subgroups of glioma, which serve as foundation for the categorization of central nervous system (CNS) tumours as well as a unique classification based only on DNA methylation information, which demonstrates extraordinary diagnostic accuracy. Unfortunately, not all patients respond to PARP inhibitors (PARPi), and there is no way to anticipate who will and who will not. In this field, PARPi are one of the innovative medicines currently being explored. As a result, cancer cells that also have a homologous recombination defect become fatal synthetically. As well as preparing the tumour microenvironment for immunotherapy, PARPi may enhance the lethal effects of chemotherapy and radiotherapy. This article analyzes the justification and clinical evidence for PARPi in glioma to offer potential therapeutic approaches. Despite the effectiveness of these targeted drugs, researchers have looked into a number of resistance mechanisms as well as the growing usage of PARPi in clinical practice for the treatment of various malignancies.

The Possible Role of Selected Vitamins and Minerals in the Therapeutic Outcomes of Leishmaniasis.

Leishmaniasis is a protozoal disease declared as an endemic in areas suffering from severe malnutrition and poverty. The factors associated with poverty like low income, ecological factors, and malnutrition cause disruption in immunity and host defense increasing risk of infection. Altered resistance to infection and host susceptibility are associated with low micronutrient levels in undernourished patients. Malnutrition has been recognized as a poor predictive marker for leishmaniasis, in particular the deficiency of trace elements like zinc, iron, and vitamin A, B, C, D which has a prominent function in the regulation of innate and adaptive immunity, cell proliferation, human physiology, etc. Malnourishment can exacerbate host sensitivity and pathophysiologic intensity to infection in variety of ways, whereas infection can enhance underlying poor nutrition or enhance host vulnerability and sandfly's urge to attack specific hosts. The intensity of leishmaniasis can be influenced by body mass and micronutrient availability in the blood. Vitamin D, C, zinc, and iron are proved effective in inhibiting the growth of leishmaniasis in both amastigote or promastigote forms, either directly or by acting as precursor for a pathway which inhibits the parasite growth. This article elucidates a new perception to the crucial role of micronutrients and their probable role in the therapeutic outcomes of leishmaniasis. Since there is requirement of novel drugs to fight drug resistance and relapse of leishmaniasis, this article may pave way to understand the importance of micronutrients and their role in therapeutic outcomes of leishmaniasis.

Role of PARP Inhibitors in Glioblastoma and Perceiving Challenges as Well as Strategies for Successful Clinical Development.

Glioblastoma multiform is the most aggressive primary type of brain tumor, representing 54% of all gliomas. The average life span for glioblastoma multiform is around 14-15 months instead of treatment. The current treatment for glioblastoma multiform includes surgical removal of the tumor followed by radiation therapy and temozolomide chemotherapy for 6.5 months, followed by another 6 months of maintenance therapy with temozolomide chemotherapy (5 days every month). However, resistance to temozolomide is frequently one of the limiting factors in effective treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors have recently been investigated as sensitizing drugs to enhance temozolomide potency. However, clinical use of PARP inhibitors in glioblastoma multiform is difficult due to a number of factors such as limited blood-brain barrier penetration of PARP inhibitors, inducing resistance due to frequent use of PARP inhibitors, and overlapping hematologic toxicities of PARP inhibitors when co-administered with glioblastoma multiform standard treatment (radiation therapy and temozolomide). This review elucidates the role of PARP inhibitors in temozolomide resistance, multiple factors that make development of these PARP inhibitor drugs challenging, and the strategies such as the development of targeted drug therapies and combination therapy to combat the resistance of PARP inhibitors that can be adopted to overcome these challenges.

Diabetic nephropathy: A twisted thread to unravel.

Diabetic nephropathy (DN), a persistent microvascular problem of diabetes mellitus is described as an elevated level of albumin excretion in urine and impaired renal activity. The morbidity and mortality of type-1 diabetics and type-2 diabetics due to end stage renal disease is also a result of the increased prevalence of DN. DN typically occurs as a consequence of an association among metabolic and hemodynamic variables, activating specific pathways leading to renal injury. According to current interventions, intensive glucose regulation decreases the threat of DN incidence and growth, and also suppressing the renin-angiotensin system (RAS) is a significant goal for hemodynamic and metabolism-related deformities in DN. However, the pathogenesis of DN is multifactorial so novel approaches other than glucose and blood pressure control are required for treatment. This review briefly summarizes the reported pathogenesis of DN, current interventions for its treatment, and possible novel interventions to unweave the thread of DN.