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Biology subjects

Mandal, S. M.

Publications and source records attributed to Mandal, S. M..

2 recordsLinked to original sources

Fermented polyherbal formulation restored ricinoleic acid-induced diarrhea in Sprague Dawley rats and exhibited in vitro antibacterial effect on multiple antibiotics resistant gastric pathogens

The involvement of multiple antibiotics resistant gastric pathogens in diarrhea aggravates the disease condition uncontrollably. Current study was aimed at finding and developing a suitable formulation utilizing multiple natural components from known plant sources to augment current therapeutic outcomes. Hydro-ethanolic extraction method was applied through boiling and fermentation, on ancient observation based efficacious plant parts for developing antidiarrheal polyherbal formulation AP-01. Animal study model of diarrhea was used to evaluate safety and efficacy of the formulation. The formulation was tested in vitro on four different multiple antibiotics resistant gastric pathogens collected from national repository. The formulation depicted no cytotoxicity on normal gut cells and was efficacious at 10 ml/Kg single dose in relieving symptoms of diarrhea by 79.71%, in comparison with standard drug showing reduction of symptoms by 83.01%. AP-01 exhibited delaying the gastric motility. Symptoms of diarrhea ceased to occur within 321 minutes with AP-01, where the standard drug took 308 minutes. AP-01 was found successful at a viable dosage regimen of 75 to 100 microliter per ml, in inhibiting growth of different pathogens from Enterobacteriaceae family possessing resistance against several classes of antibiotics, in culture media. Chemical analysis revealed different alkaloids, flavonoids and polyphenols those probably work in unison through multiplex modes of action to arrest diarrhea and inhibit pathogens at the same time. These promising results shown by AP-01 should definitely evoke an effort to dive deep into research and development for better therapeutic formulations for infectious diarrhea by harvesting the arsenal of nature.

microbiology↗

A glycolytic metabolite restores DNA repair activity of polynucleotide kinase 3-phosphatase in polyglutamine (PolyQ) diseases

Huntingtons disease (HD) and spinocerebellar ataxia type 3 (SCA3) are the two most prevalent polyglutamine (polyQ) neurodegenerative diseases, caused by CAG (encoding glutamine) repeat expansion in the coding region of the huntingtin (HTT) and ataxin-3 (ATXN3) proteins, respectively. We have earlier reported that the activity, but not the protein level, of an essential DNA repair enzyme, polynucleotide kinase 3-phosphatase (PNKP), is severely abrogated in both HD and SCA3 resulting in accumulation of double-strand breaks in patients brain genome. While investigating the mechanistic basis for the loss of PNKP activity and accumulation of DNA double-strand breaks leading to neuronal death, we observed that PNKP interacts with the nuclear isoform of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3). Depletion of PFKFB3 markedly abrogates PNKP activity without changing its protein level. Notably, the levels of both PFKFB3 and its product fructose-2,6 bisphosphate (F2,6BP), an allosteric modulator of glycolysis, are significantly lower in the nuclear extracts of post-mortem brain tissues of HD and SCA3 patients. Supplementation of F2,6BP restored PNKP activity in the nuclear extracts of patients brain. Moreover, intracellular delivery of F2,6BP restored both the activity of PNKP and the integrity of transcribed genome in neuronal cells derived from striatum of HD mouse. Importantly, supplementing F2,6BP rescued the HD phenotype in Drosophila, suggesting F2,6BP to serve in vivo as a cofactor for the proper functionality of PNKP and thereby, of brain health. Our results thus provide a compelling rationale for exploring the therapeutic use of F2,6BP and structurally related compounds for treating polyQ diseases. SignificanceTo unravel the biological basis for the loss of PNKP activity in HD and SCA3, the two most prevalent polyglutamine neurodegenerative disorders, we analyzed PNKP interactome and found that the nuclear isoform of a glycolytic enzyme PFKFB3 associated with PNKP and other repair proteins forming a multiprotein complex. Surprisingly, we found that PFKFB3 and its biosynthetic product, F2,6BP are significantly low in the affected region of patients brain. Exogenous addition of F2,6BP restored PNKP activity in patients brain nuclear extract. Moreover, supplementing F2,6BP in HD cells and fruit flies restored genome integrity and rescued the disease symptoms. While there is no curative therapy for HD/SCA3, except symptom management, our discovery suggests that F2,6BP supplementation would be a promising therapeutic option.

biochemistry↗