Current pharmacotherapy and putative disease-modifying therapy for Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease of the central nervous system correlated with the progressive loss of cognition and memory. ß-Amyloid plaques, neurofibrillary tangles and the deficiency in cholinergic neurotransmission constitute the major hallmarks of the AD. Two major hypotheses have been implicated in the pathogenesis of AD namely the cholinergic hypothesis which ascribed the clinical features of dementia to the deficit cholinergic neurotransmission and the amyloid cascade hypothesis which emphasized on the deposition of insoluble peptides formed due to the faulty cleavage of the amyloid precursor protein. Current pharmacotherapy includes mainly the acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor agonist which offer symptomatic therapy and does not address the underlying cause of the disease. The disease-modifying therapy has garnered a lot of research interest for the development of effective pharmacotherapy for AD. ß and γ-Secretase constitute attractive targets that are focussed in the disease-modifying approach. Potentiation of α-secretase also seems to be a promising approach towards the development of an effective anti-Alzheimer therapy. Additionally, the ameliorative agents that prevent aggregation of amyloid peptide and also the ones that modulate inflammation and oxidative damage associated with the disease are focussed upon. Development in the area of the vaccines is in progress to combat the characteristic hallmarks of the disease. Use of cholesterol-lowering agents also is a fruitful strategy for the alleviation of the disease as a close association between the cholesterol and AD has been cited. The present review underlines the major therapeutic strategies for AD with focus on the new developments that are on their way to amend the current therapeutic scenario of the disease.

Structural effect of the H992D/H418D mutation of angiotensin-converting enzyme in the Indian population: implications for health and disease.

The Non synonymous SNPs (nsSNPs) of the renin-angiotensin-system (RAS) pathway, unique to the Indian population were investigated in view of its importance as an endocrine system. nsSNPs of the RAS pathway genes were mined from the IndiGenome database. Damaging nsSNPs were predicted using SIFT, PredictSNP, SNP and GO, Snap2 and Protein Variation Effect Analyzer. Loss of function was predicted based on protein stability change using I mutant, PremPS and CONSURF. The structural impact of the nsSNPs was predicted using HOPE and Missense3d followed by modeling, refinement, and energy minimization. Molecular Dynamics studies were carried out using Gromacsv2021.1. 23 Indian nsSNPs of the RAS pathway genes were selected for structural analysis and 8 were predicted to be damaging. Further sequence analysis showed that HEMGH zinc binding motif changes to HEMGD in somatic ACE-C domain (sACE-C) H992D and Testis ACE (tACE) H418D resulted in loss of zinc coordination, which is essential for enzymatic activity in this metalloprotease. There was a loss of internal interactions around the zinc coordination residues in the protein structural network. This was also confirmed by Principal Component Analysis, Free Energy Landscape and residue contact maps. Both mutations lead to broadening of the AngI binding cavity. The H992D mutation in sACE-C is likely to be favorable for cardiovascular health, but may lead to renal abnormalities with secondary impact on the heart. H418D in tACE is potentially associated with male infertility.Communicated by Ramaswamy H. Sarma.

Recent Development of DNA Gyrase Inhibitors: An Update.

Antibiotic or antimicrobial resistance is an urgent global public health threat that occurs when bacterial or fungal infections do not respond to the drug regimen designed to treat these infections. As a result, these microbes are not evaded and continue to grow. Antibiotic resistance against natural and already-known antibiotics like Ciprofloxacin and Novobiocin can be overcome by developing an agent that can act in different ways. The success of agents like Zodiflodacin and Zenoxacin in clinical trials against DNA gyrase inhibitors that act on different sites of DNA gyrase has resulted in further exploration of this target. However, due to the emergence of bacterial resistance against these targets, there is a great need to design agents that can overcome this resistance and act with greater efficacy. This review provides information on the synthetic and natural DNA gyrase inhibitors that have been developed recently and their promising potential for combating antimicrobial resistance. The review also presents information on molecules that are in clinical trials and their current status. It also analysed the SAR studies and mechanisms of action of enlisted agents.

Cytokine database of stress and metabolic disorders (CdoSM): a connecting link between stress and cardiovascular disease, hypertension, diabetes and obesity.

The risk of metabolic diseases is greatly increased by both chronic and acute stress. Irrespective of the cause, chronic or acute stress has the capacity to alter an individual's cytokine profile. For instance, it has been observed that stress significantly increased concentrations of IL 1 beta, IL 6 and TNF alpha. Alteration in cytokine profiles increase the likelihood of dysregulated metabolism, which subsequently acts as a driving force in the development of disorders, such as cardiovascular disease (CVD), hypertension, diabetes and obesity. Considering the dynamic and versatile role of cytokines in health and disease, an in-depth computational analysis (qualitative and quantitative) was performed to study the role of cytokines as an immuno-molecular link between rising stress levels and an increase in CVD, hypertension, diabetes and obesity. Upon a qualitative comparative analysis of cytokine profiles, a total of 14 cytokines (IL-6, TNF-alpha, IFN-gamma, IL-10, etc.) were observed to be commonly involved in stress and aforementioned four metabolic disorders. Further analysis of quantitative studies has revealed that the cytokine profile for coronary artery disease (CAD) showed remarkable increase in a couple of cytokines. IL 9 registered an increase of 67 percent to reach a concentration of 75 pg/mL. IL 3, on the other hand, was absent in control candidates but reached 56 ± 14 pg/mL in CAD patients. In case of diabetes, IFN-gamma showed an increase of 290 pg/mL. For obesity it was observed that both MCP-1 and IL-1 beta fell by 12.2 pg/mL to reach 44.4 pg/mL in obese patients. A fall of approximately 50 pg/mL was observed in the concentration of VEGF in obese patients. Similarly, hypertension was marked by reduction in concentration of several cytokines - MCP-1 and VEGF being a couple of them. Apart from performing an analysis of cytokine profiles, an innovative database [Cytokine database of Stress and Metabolic disorders (CdoSM)-https://www.akbi-nsut.co.in/] has also been created comprising cytokines involved in stress and the aforementioned metabolic disorders. Upon accessing the database, a user can find the list cytokines associated with a particular condition along with information on cytokine receptor/s; related research articles; cytokine concentration in control v/s diseased candidates for some specific cytokines and the Uniprot ID for the respective cytokine. Database can be accessed by the link-https://www.akbi-nsut.co.in/. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03375-0.

Ameliorative effects of amide derivatives of 1,3,4-thiadiazoles on scopolamine induced cognitive dysfunction.

The present study reports the effect of amide derivatives of 1,3,4-thiadizoles on scopolamine induced deficit cholinergic neurotransmission and oxidative stress serving as promising leads for the therapeutics of cognitive dysfunction. Fourteen compounds (2c-8d) have been synthesised and evaluated against behavioural alterations using step down passive avoidance protocol and morris water maze and at a dose of 0.5 mg/kg with reference to the standard, Rivastigmine. All the synthesised compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme. Biochemical estimation of markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione, plasma nitrite, catalase) has also been carried out to assess the role of synthesised molecules on the oxidative damage induced by scopolamine. The compounds 5c, 6c and 8c displayed appreciable activity with an IC50 value of 3 µM, 3.033 µM and 2.743 µM, respectively towards acetylcholinesterase inhibition. These compounds also decreased scopolamine induced oxidative stress, thus serving as promising leads for the amelioration of oxidative stress induced cognitive decline. The molecular docking study performed to predict the binding mode of the compounds also suggested that these compounds bind appreciably with the amino acids present in the active site of recombinant human acetylcholinesterase (rhAChE). The results indicated that these compounds could be further traversed as inhibitors of AChE and oxidative stress for the treatment of cognitive dysfunction.

Deciphering Transcriptional Programming during Pod and Seed Development Using RNA-Seq in Pigeonpea (Cajanus cajan).

Seed development is an important event in plant life cycle that has interested humankind since ages, especially in crops of economic importance. Pigeonpea is an important grain legume of the semi-arid tropics, used mainly for its protein rich seeds. In order to understand the transcriptional programming during the pod and seed development, RNA-seq data was generated from embryo sac from the day of anthesis (0 DAA), seed and pod wall (5, 10, 20 and 30 DAA) of pigeonpea variety "Asha" (ICPL 87119) using Illumina HiSeq 2500. About 684 million sequencing reads have been generated from nine samples, which resulted in the identification of 27,441 expressed genes after sequence analysis. These genes have been studied for their differentially expression, co-expression, temporal and spatial gene expression. We have also used the RNA-seq data to identify important seed-specific transcription factors, biological processes and associated pathways during seed development process in pigeonpea. The comprehensive gene expression study from flowering to mature pod development in pigeonpea would be crucial in identifying candidate genes involved in seed traits directly or indirectly related to yield and quality. The dataset will serve as an important resource for gene discovery and deciphering the molecular mechanisms underlying various seed related traits.