Regulation of autophagy by SARS-CoV-2: The multifunctional contributions of ORF3a.

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) regulates autophagic flux by blocking the fusion of autophagosomes with lysosomes, causing the accumulation of membranous vesicles for replication. Multiple SARS-CoV-2 proteins regulate autophagy with significant roles attributed to ORF3a. Mechanistically, open reading frame 3a (ORF3a) forms a complex with UV radiation resistance associated, regulating the functions of the PIK3C3-1 and PIK3C3-2 lipid kinase complexes, thereby modulating autophagosome biogenesis. ORF3a sequesters VPS39 onto the late endosome/lysosome, inhibiting assembly of the soluble NSF attachement protein REceptor (SNARE) complex and preventing autolysosome formation. ORF3a promotes the interaction between BECN1 and HMGB1, inducing the assembly of PIK3CA kinases into the ER (endoplasmic reticulum) and activating reticulophagy, proinflammatory responses, and ER stress. ORF3a recruits BORCS6 and ARL8B to lysosomes, initiating the anterograde transport of the virus to the plasma membrane. ORF3a also activates the SNARE complex (STX4-SNAP23-VAMP7), inducing fusion of lysosomes with the plasma membrane for viral egress. These mechanistic details can provide multiple targets for inhibiting SARS-CoV-2 by developing host- or host-pathogen interface-based therapeutics.

Can Mycobacterium tuberculosis infection lead to cancer? Call for a paradigm shift in understanding TB and cancer.

Infections are known to cause tumours though more attributed to viruses. Strong epidemiological links suggest association between bacterial infections and cancers as exemplified by Helicobacter pylori and Salmonella spp. Infection with Mycobacterium tuberculosis (M. tb), the etiological agent of tuberculosis (TB), has been reported to predispose patients to lung cancers and possibly in other organs as well. While this etiopathogenesis warrant inclusion of M. tb in IARC's (International Agency for Research on Cancer) classified carcinogenic agents, the lack of well-defined literature and direct experimental studies have barred the research community from accepting the role of M. tb as a carcinogen. The background research, case studies, and experimental data extensively reviewed in Roy et al., 2021; provoke the debate for elucidating carcinogenic properties of M. tb. Moreover, proper, timely and correct diagnosis of both diseases (which often mimic each other) will save millions of lives that are misdiagnosed. In addition, use of Anti Tubercular therapy (ATT) in misdiagnosed non-TB patients contributes to drug resistance in population thereby severely impacting TB disease control measures. Research in this arena can further aid in saving billions of dollars by preventing the superfluous use of cancer drugs. In order to achieve these goals, it is imperative to identify the underlying mechanism of M. tb infection acting as major risk factor for cancer.

Systematic Development of Solid Lipid Nanoparticles of Abiraterone Acetate with Improved Oral Bioavailability and Anticancer Activity for Prostate Carcinoma Treatment.

In the present work, an attempt was undertaken to improve the oral bioavailability and anticancer activity of abiraterone acetate. Solid lipid nanoparticles (SLNs) were developed using the quality by design (QbD) principles and evaluated through in vitro, ex vivo, and in vivo studies. Solid lipid suitability was evaluated by equilibrium solubility study, while surfactant and cosurfactant were screened based on the ability to form microemulsion with the selected lipid. SLNs were prepared by emulsion/solvent evaporation method using glyceryl monostearate, Tween 80, and Poloxamer 407 as the solid lipid, surfactant, and cosurfactant, respectively. Box-Behnken design was applied for optimization of material attributes and evaluating their impact on particle size, polydispersity index, zeta potential, and entrapment efficiency of the SLNs. In vitro drug release study was evaluated in simulated gastric and intestinal fluids. Cell culture studies on PC-3 cells were performed to evaluate the cytotoxicity of the drug-loaded SLNs in comparison to the free drug suspension. Qualitative uptake was evaluated for Rhodamine B-loaded SLNs and compared with free dye solution. Ex vivo permeability was evaluated on Wistar rat intestine and in vivo pharmacokinetic evaluation on Wistar rats for SLNs and free drug suspension. Concisely, the SLNs showed potential for significant improvement in the biopharmaceutical performance of the selected drug candidate over the existing formulations of abiraterone acetate.

Chemical Profiling of Chlorophytum comosum (Thunb.) Jaques by GC-MS/LC-ESIMS and its Antiproliferative Effects on Human Carcinoma Cell Lines.

BACKGROUND: Chlorophytum comosum, popularly known as Spider Ivy, is used as a medicinal plant in traditional Chinese medicine, however, its detailed chemical composition and biological activity are yet unexplored. OBJECTIVE: To carry out the phytochemical investigation on different parts of Chlorophytum comosum using GCMS/ LC-ESI-MS and evaluation of its antioxidant, hemolytic and antiproliferative potential on breast cancer (MCF-7), lung cancer (A549, H1299) and normal lung (L-132) cell lines. METHODS: Chemical constituents from aqueous roots and leaves extracts were identified using LC-ESI-MS/GCMS. The identified compounds were annotated based on the match of mass spectra with the literature using NIST 14 and METLIN databases. Antioxidant activity was studied using DPPH, FRAP and TPC assays. The antiproliferative effects of ethanolic roots and leaves extracts of Chlorophytum comosum were measured by MTT assay on breast cancer (MCF-7), lung cancer (A549 & H1299) and normal lung (L-132) cell lines. The toxicity studies of the extracts were carried out using Hemolysis assay. RESULTS: GC-MS analysis identified 34 metabolites in roots and 17 from leaves, while 17 compounds from roots and 7 from leaves were detected by LC-ESI-MS. Significant antiproliferative effects were observed on the A549 and MCF-7 cancer cell lines with IC50 values ranging from 56.86 µg/ml to 68.68 µg/ml while no marked response was observed against normal cell line L-132. CONCLUSION: Our study represents the first report on the detailed chemical composition and antiproliferative potential of Chlorophytum comosum against lung and breast cancer cell lines.