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Background Previous studies have shown the effect of bacterial lipopolysaccharide (LPS) on enhanced cancer cells’ growth and metastasis. However, the effect of LPS on prostate cancer (PCa) cells metastasis has not been investigated in details. This study aimed to investigate the functional role of LPS on PCa cells metastasis and determine the effect of dexamethasone (DEX) on this event. Methods Two different PCa reporter cells lines (DU145‐NF‐κB‐Luc and MAT‐LyLu‐ NF‐κB‐Luc) were used to assess the direct effect of LPS on NF‐κB activation in PCa cells. Plasma collected from LPS‐stimulated human and rodent blood were used to check the indirect effect of LPS on NF‐κB activation in PCa cells. Trans‐well migration assay and two different orthotopic PCa animal models were used to investigate the effect of LPS on DU145 and MAT‐LyLu cells migration or metastasis in vitro and in vivo, respectively. In all the studies DEX was used with or without LPS stimulation. Results LPS and secretory factors present in plasma collected from LPS‐stimulated blood, significantly activated NF‐κB in DU145, and MAT‐LyLu cells and enhanced their migration in vitro. DEX significantly suppressed LPS‐mediated activation of cancer and blood cells and abrogated the direct and indirect pro‐migratory effect of LPS on PCa cells. Systemic administration of LPS activated NF‐κB in DU145 cells in vivo; however, failed to alter the metastatic properties of these cells. On the other hand, systemic administration of LPS to MAT‐LyLu tumor bearing animals significantly enhanced the incidence of metastasis without altering the overall growth of primary tumors. Unexpectedly, though DEX significantly suppressed MAT‐LyLu primary tumor weights, it aggravated metastasis of cancer cells in presence and absence of LPS. Moreover, consecutive DEX pre‐treatment enhanced experimental peritoneal metastasis of MAT‐LyLu cells. At the molecular level, LPS, and/or DEX induced overexpression of immunosuppressive molecules in MAT‐LyLu tumors. Conclusions Overall, our study has shown that LPS and/or LPS induced inflammation can increase PCa metastasis and immunosuppressive dose of DEX might further enhance cancer metastasis.

The Syrian golden hamster (Mesocricetus auratus) has recently been demonstrated as a clinically relevant animal model for SARS-CoV-2 infection. However, lack of knowledge about the tissue-specific expression pattern of various proteins in these animals and the unavailability of reagents like antibodies against this species hampers these models’ optimal use. The major objective of our current study was to analyze the tissue-specific expression pattern of angiotensin-converting enzyme 2, a proven functional receptor for SARS-CoV-2 in different organs of the hamster. Using two different antibodies (MA5-32307 and AF933), we have conducted immunoblotting, immunohistochemistry, and immunofluorescence analysis to evaluate the ACE2 expression in different tissues of the hamster. Further, at the mRNA level, the expression of Ace2 in tissues was evaluated through RT-qPCR analysis. Both the antibodies detected expression of ACE2 in kidney, small intestine, tongue, and liver. Epithelium of proximal tubules of kidney and surface epithelium of ileum expresses a very high amount of this protein. Surprisingly, analysis of stained tissue sections showed no detectable expression of ACE2 in the lung or tracheal epithelial cells. Similarly, all parts of the large intestine were negative for ACE2 expression. Analysis of tissues from different age groups and sex didn’t show any obvious difference in ACE2 expression pattern or level. Together, our findings corroborate some of the earlier reports related to ACE2 expression patterns in human tissues and contradict others. We believe that this study’s findings have provided evidence that demands further investigation to understand the predominant respiratory pathology of SARS-CoV-2 infection and disease.

AbstractRecently, the Syrian golden hamster (Mesocricetus auratus) has been demonstrated as a clinically relevant animal model for SARS-CoV-2 infection. However, lack of knowledge about the tissue-specific expression pattern of various proteins in these animals and the unavailability of reagents like antibodies against this species hampers optimal use of these models. The major objective of our current study was to analyze the tissue-specific expression pattern of angiotensin□converting enzyme 2 (ACE2), a proven functional receptor for SARS-CoV-2 in different organs of the hamster. We have adapted immunoblot analysis, immunohistochemistry, and immunofluorescence analysis techniques to evaluate the ACE2 expression pattern in different tissues of the Syrian golden hamster. We found that kidney, small intestine, esophagus, tongue, brain, and liver express ACE2. Epithelium of proximal tubules of kidney and surface epithelium of ileum expresses a very high amount of this protein. Surprisingly, analysis of stained tissue sections for ACE2 showed no detectable expression of ACE2 in the lung or tracheal epithelial cells. Similarly, all parts of the large intestine (caecum, colon, and rectum) were negative for ACE2 expression. Together, our findings corroborate some of the earlier reports related to ACE2 expression pattern in human tissues and also contradicts some others. We believe that the findings of this study will enable the appropriate use of the Syrian golden hamster to carryout SARS-CoV-2 related studies.

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An effective drug delivery system (DDS) relies on an efficient cellular uptake and faster intracellular delivery of theranostic agents, bypassing the endosomal mediated degradation of the payload. The use of viral nanoparticles (VNPs) permits such advancement, as the viruses are naturally evolved to infiltrate the host cells to deliver their genetic material. As a proof of concept, we bioengineered the vesicular stomatitis virus glycoprotein (VSV-G)-based near-infrared (NIR) active viral nanoconstructs (NAVNs) encapsulating indocyanine green dye (ICG) for NIR bioimaging. NAVNs are spherical in size and have the intrinsic cellular-fusogenic properties of VSV-G. Further, the NIR imaging displaying higher fluorescence intensity in NAVNs treated cells suggests enhanced cellular uptake and delivery of ICG by NAVNs compared to the free form of ICG. The overall study highlights the effectiveness of VSV-G-based VNPs as an efficient delivery system for NIR fluorescence imaging.

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Dendritic cell (DC) fine-tunes inflammatory versus tolerogenic responses to protect from immune-pathology. However, the role of co-regulators in maintaining this balance is unexplored. NCoR1-mediated repression of DC immune-tolerance has been recently reported. Here we found that depletion of NCoR1 paralog SMRT (NCoR2) enhanced cDC1 activation and expression of IL-6, IL-12 and IL-23 while concomitantly decreasing IL-10 expression/secretion. Consequently, co-cultured CD4+ and CD8+ T-cells depicted enhanced Th1/Th17 frequency and cytotoxicity, respectively. Comparative genomic and transcriptomic analysis demonstrated differential regulation of IL-10 by SMRT and NCoR1. SMRT depletion represses mTOR-STAT3-IL10 signaling in cDC1 by down-regulating NR4A1. Besides, Nfkbia and Socs3 were down-regulated in Ncor2 (Smrt) depleted cDC1, supporting increased production of inflammatory cytokines. Moreover, studies in mice showed, adoptive transfer of SMRT depleted cDC1 in OVA-DTH induced footpad inflammation led to increased Th1/Th17 and reduced tumor burden after B16 melanoma injection by enhancing oncolytic CD8+ T-cell frequency, respectively. We also depicted decreased Ncor2 expression in Rheumatoid Arthritis, a Th1/Th17 disease.