Biology subjects

Dhar, S. K.

Publications and source records attributed to Dhar, S. K..

3 recordsLinked to original sources

bioRxiv2023

In vitro and in vivo evidences propound therapeutic potential of Lipocalin 2 in cervical carcinoma

Cervical cancer (CC), the second most common in developing countries and the third most common in developed nations, is the fourth most common type of cancer in women overall. The HPV16 high-risk genotype of the virus, which is responsible for about 61% of cervical cancer incidences, was found to have higher LCN2 levels in advanced clinical CC stages. In this study, we assessed the impact of suppressing LCN2 activity after treatment with an anti-LCN2 monoclonal antibody (MAb) in both in vitro and in vivo settings. Anti-LCN2 antibody was found to reduce proliferation and invasion of HeLa cells, the first immortal cells from a HPV positive aggressive adenocarcinoma of the cervix. LCN2 and its ligand MMP9 was found to be highly expressed in the cells and abrogated on treatment with anti-LCN2. The five receptors of LCN2 - SLC22A17, MC1R, MC2R, MC4R and LRP2 were barely detected with or without treatment. Anti-LCN2 Mab caused tumors to regress and soften in vivo, in a xenograft mouse model. Analysis of histology images of the treated and untreated tumor established the necrotic capability of the therapeutic molecule explaining the regression and softening of the tumor. Differential gene expression analysis between untreated and treated tumor proved that LCN2 inhibition abolished the migratory, invasive, and hypoxic pathways while significantly increasing the necrosis and cell death pathways in tumor after treatment with the monoclonal antibody. LCN2 inhibition was shown molecularly to lead to tumor regression via a negative feedback loop of LCN2 through the TNF-IL17 axis exponentially increasing the effect of the anti-LCN2 monoclonal antibody. In conclusion, LCN2 appears to be a viable therapeutic target, and the monoclonal antibody used in this study can be further developed for clinical usage in cervical cancer.

cancer biology↗

bioRxiv2022

Recombinant Human ACE2-Fc : A promising therapy for SARS-CoV2 infection

SARS-CoV2 entry is mediated by binding of viral spike-protein(S) to the transmembrane Angiotensin-Converting Enzyme-2 (ACE2) of the host cell. Thus, to prevent transmission of disease, strategies to abrogate the interaction are important. However, ACE2 cannot be blocked since its normal function is to convert the Angiotensin II peptide to Angiotensin(1-7) to reduce hypertension. This work reports a recombinant cell line secreting soluble ACE2-ectopic domain (MFcS2), modified to increase binding and production efficacy and fused to human immunoglobulin-Fc. While maintaining its enzymatic activity, the molecule trapped and neutralized SARS CoV2 virus in vitro with an IC50 of 64 nM. In vivo, with no pathology in the vital organs, it inhibited the viral load in lungs in SARS-CoV2 infected Golden-Syrian-hamster. The Intravenous pharmacokinetic profiling of MFcS2 in hamster at a dose of 5 mg/Kg presented a maximum serum concentration of 23.45 {micro}g/mL with a half-life of 29.5 hrs. These results suggest that MFcS2 could be used as an effective decoy based therapeutic strategy to treat COVID19. This work also reports usage of a novel oral-cancer cell line as in vitro model of SARS-Cov2 infection, validated by over expressing viral-defence pathways upon RNA-seq analysis and over-expression of ACE2 and TMPRSS upon growth in hyperglycaemic condition.

molecular biology↗

bioRxiv2021

Anti-diabetic effects of Holarrhena antidysentrica extracts: Results from a Longitudinal Meta-analysis

BackgroundHolarrhena antidysenterica (HA), a twining shrub belonging to the Apocynaceae family is found in tropical regions of Africa and over a large part of Asia including India, Philippines and Malayan Peninsula. In Indian traditional system of medicine, HA has been used to treat gastric ailments, for wound healing and also to improve glycaemic control. Glucose lowering activity of HA root, bark, seed, leaf and fruit extract in different parts of India as well as in Chinese traditional medicine is widely reported. PurposeIn the meta-analysis reported in this article, we summarize glucose-lowering effects of HA extracts from different plant parts as reported in multiple studies involving animal models of diabetes. Our analysis helps to quantify the glucose-lowering effect of HA in comparison with standard diabetes drugs. The analysis also sheds light on differential efficacy levels of HA extracted from different plant parts. Study designThe meta-analysis was carried out following PRISMA guidelines. Literature was searched to identify studies published between years 2011 to 2019 reporting glucose-lowering effects of HA extract on rodent models of diabetes. MethodsLongitudinal meta-analysis was carried out on time-course data extracted from selected studies to calculate standardized mean change of glucose value from day 1 to days 7, 14 and 21 post-treatment by HA extract or standard anti-diabetic drug. Subgroup analysis was carried out for studies reporting effects of HA on leaf and seed extracts. Standardized mean difference in levels of cholesterol, triglycerides and serum total protein between treatment and control groups were also assessed. ResultsWe shortlisted nine articles to be used for this meta-analysis. Summarized standardized mean changes of glucose value between day 1 and day 21 post-treatment indicated glucose-lowering effects of HA extracts to be marginally lower but comparable to that of standard anti-diabetic drugs like Glibenclamide or Sitagliptin. However, subgroup analysis revealed seed extracts of HA to be more potent than leaf extracts or even standard drugs. Effects of the extract on levels of cholesterol, triglyceride and serum total protein was also commensurate with its glucose-lowering property. ConclusionsOur results, summarized over multiple studies, present a clear quantitative assessment of the anti-diabetic property of HA, in particular the seed extracts compared to standard anti-diabetic drugs. Further differential analysis of the seed extracts will be useful to arrive at a herbal formulation with superior anti-diabetic property and possibly lesser side effects than chemical entities.

plant biology↗