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Bile acids are recognized as important signaling molecules that enable fine-tuned inter-communication from the liver, through the intestine, to virtually any organ, thus encouraging their pleiotropic physiological effects. Aging is a complex natural process defined as a progressive decline in cellular and organismal functions. A causal link between bile acids and the aging process is emerging. However, there are gaps in our understanding of the molecular mechanisms and precise targets responsible for the alteration of bile acid profiles and their role in the aging process. Intestinal barrier dysfunction leads to endotoxemia, systemic inflammation, insulin resistance, diabetes, lipid accumulation, obesity and fatty liver diseases, and health decline and death. In fact, intestinal barrier dysfunction is suggested to be an evolutionarily conserved hallmark of aging. Bile acids may modulate the aging process by regulating intestinal barrier integrity.

Cuscuta chinensis Lam. is a traditional medicinal herb used to treat female sterility and male reproductive system disorders. However, the anti-lung cancer properties of Cuscuta chinensis Lam. and possible molecular mechanisms have yet to be explored. Thus, the study's main purpose was to evaluate in vitro and in vivo anti-lung cancer properties of C. chinensis water extract (CLW) in human lung adenocarcinomas and the underlying molecular mechanism involved. Our results demonstrated that CLW caused a significant inhibition of cell viability and induced G1 cycle arrest in lung cancer cells. Furthermore, RNA-seq transcriptome analysis revealed 602 common genes with a significant expression in A549 and H1650 cells under CLW treatment. Functional enrichment analysis suggested that these common genes regulated by CLW mainly involve lung cancer cell proliferation, metastases and apoptosis processes. In addition, forty-six common genes (> 2-fold change) regulated by CLW in A549 and H1650 cells were selected for further validation. In vitro quantitative real-time PCR results confirmed that twelve genes were up-regulated, and four genes were down-regulated in A549 and H1650 cells. The in vivo experiment demonstrated CLW could significantly decrease tumour volume and tumour weight of mice compared with the control group. Moreover, in vivo quantitative real-time PCR results revealed that C11orf96, FGFBP1, FOSB and NPTX1 genes were up-regulated and EGR1, GBP4 and MAP2K6 genes were down-regulated in tumour tissues compared with the control group. These data strongly suggest that CLW could be developed as an efficacious drug for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Background. Adenosine, derived from the degradation of ATP via ectonucleotidases CD39 and CD73, is a critical immunosuppressive metabolite in the hypoxic microenvironment of tumor tissue. Adenosine signaling via A2aR can inhibit the antitumor immune response of CD8+ T cells. CD39 and CD73 high-expressing Tregs play a critical role in tumor immune evasion of gastric cancer (GC). The present study investigated the underlying mechanism by which Tregs suppress antitumor immune responses in GC. Materials and Methods. Fifty-two GC samples were collected, and the frequency of FoxP3+ Tregs and CD8+ T cells and density ratios of A2aR+/CD8+ T cells, CD39+/FoxP3+ Tregs, and CD73+/FoxP3+ Tregs in GC were assessed with multiplex immunofluorescence. The expression of FoxP3 and A2aR in GC tissues was also detected by the immunoblotting assay. We next investigated the relationship between density of FoxP3+ Tregs, ratio of A2aR+/CD8+ T cells, and clinicopathological parameters. At the same time, Tregs and CD8+ T cells were isolated from peripheral blood of five GC patients, and the antagonists of CD39 and CD73 were used to assess the ability of Tregs to decompose ATP into adenosine. In addition, we cocultured CD8+ T cells and Tregs with antagonists of A2aR and A2bR in order to examine the alterations in immune function of CD8+ T cells. Results. The density of both FoxP3+ Tregs and A2aR+/CD8+ T cells was higher in GC tissue compared to peritumoral normal tissue and significantly correlated with the TNM stage, lymph node metastasis, and distant metastasis of GC. The process of Treg hydrolysis of ATP into adenosine was blocked by the antagonists of CD39 and CD73. In addition, Tregs could induce apoptosis and inhibit proliferation of CD8+ T cells, while this effect could be obviously reduced by applying the antagonist of A2aR or A2aR+A2bR. Moreover, IFN-γ, TNF-α, and perforin generated by CD8+ T cells could also be inhibited through the adenosine A2aR pathway. Conclusions. The FoxP3+ Tregs and A2aR+/CD8+ T cells were excessively infiltrated in GC tissue. Tregs from GC can decompose ATP to adenosine and in turn induce apoptosis and inhibit the proliferation of CD8+ T cells through the A2aR pathway, further leading to immune escape of GC. [ABSTRACT FROM AUTHOR]

Background and Aims: Although the benefits of vertical sleeve gastrectomy (VSG) surgery are well known, the molecular mechanisms by which VSG alleviates obesity and its complications remain unclear. We aim to determine the role of CYP8B1 (cytochrome P450, family 8, subfamily B, polypeptide 1) in mediating the metabolic benefits of VSG., Approach and Results: We found that expression of CYP8B1, a key enzyme in controlling the 12α-hydroxylated (12α-OH) bile acid (BA) to non-12α-OH BA ratio, was strongly downregulated after VSG. Using genetic mouse models of CYP8B1 overexpression, knockdown, and knockout, we demonstrated that overexpression of CYP8B1 dampened the metabolic improvements associated with VSG. In contrast, short hairpin RNA-mediated CYP8B1 knockdown improved metabolism similar to those observed after VSG. Cyp8b1 deficiency diminished the metabolic effects of VSG. Further, VSG-induced alterations to the 12α-OH/non-12α-OH BA ratio in the BA pool depended on CYP8B1 expression level. Consequently, intestinal lipid absorption was restricted, and the gut microbiota (GM) profile was altered. Fecal microbiota transplantation from wild type-VSG mice (vs. fecal microbiota transplantation from wild-type-sham mice) improved metabolism in recipient mice, while there were no differences between mice that received fecal microbiota transplantation from knockout-sham and knockout-VSG mice., Conclusions: CYP8B1 is a critical downstream target of VSG. Modulation of BA composition and gut microbiota profile by targeting CYP8B1 may provide novel insight into the development of therapies that noninvasively mimic bariatric surgery to treat obesity and its complications., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Adenosine, derived from the degradation of ATP via ectonucleotidases CD39 and CD73, is a critical immunosuppressive metabolite in the hypoxic microenvironment of tumor tissue. Adenosine signaling via A2aR can inhibit the antitumor immune response of CD8 + T cells. CD39 and CD73 high-expressing Tregs play a critical role in tumor immune evasion of gastric cancer (GC). The present study investigated the underlying mechanism by which Tregs suppress antitumor immune responses in GC., Materials and Methods: Fifty-two GC samples were collected, and the frequency of FoxP3 + Tregs and CD8 + T cells and density ratios of A2aR + /CD8 + T cells, CD39 + /FoxP3 + Tregs, and CD73 + /FoxP3 + Tregs in GC were assessed with multiplex immunofluorescence. The expression of FoxP3 and A2aR in GC tissues was also detected by the immunoblotting assay. We next investigated the relationship between density of FoxP3 + Tregs, ratio of A2aR + /CD8 + T cells, and clinicopathological parameters. At the same time, Tregs and CD8 + T cells were isolated from peripheral blood of five GC patients, and the antagonists of CD39 and CD73 were used to assess the ability of Tregs to decompose ATP into adenosine. In addition, we cocultured CD8 + T cells and Tregs with antagonists of A 2a R and A 2b R in order to examine the alterations in immune function of CD8 + T cells., Results: The density of both FoxP3 + Tregs and A2aR + /CD8 + T cells was higher in GC tissue compared to peritumoral normal tissue and significantly correlated with the TNM stage, lymph node metastasis, and distant metastasis of GC. The process of Treg hydrolysis of ATP into adenosine was blocked by the antagonists of CD39 and CD73. In addition, Tregs could induce apoptosis and inhibit proliferation of CD8 + T cells, while this effect could be obviously reduced by applying the antagonist of A 2a R or A 2a R + A 2b R. Moreover, IFN- γ , TNF- α , and perforin generated by CD8 + T cells could also be inhibited through the adenosine A2aR pathway., Conclusions: The FoxP3 + Tregs and A2aR + /CD8 + T cells were excessively infiltrated in GC tissue. Tregs from GC can decompose ATP to adenosine and in turn induce apoptosis and inhibit the proliferation of CD8 + T cells through the A2aR pathway, further leading to immune escape of GC., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2019 Linsen Shi et al.)

NADPH oxidase 4 (NOX4) is one of the main sources of reactive oxygen species, and plays a crucial role in the occurrence and development of tumors. However, there is currently little evidence demonstrating that NOX4 expression is associated with gastric cancer. To establish whether NOX4 plays a role in gastric cancer progression and prognosis, we performed immunohistochemistry on gastric cancer tissues and paired adjacent normal tissues from 90 gastric cancer patients to detect and compare NOX4 expression. Next, we analyzed the association between NOX4 expression and clinicopathological characteristics. Survival analysis was performed to explore the association between NOX4 expression and the prognosis of gastric cancer patients. Furtherly, we investigated the effect of NOX4-knockdown using siRNA on gastric cancer progression in vitro and in vivo . Our results revealed that NOX4 expression in gastric cancer tissues is higher than in paired adjacent normal tissues ( P = 0.0009). NOX4 expression is significantly correlated with tumor size ( P = 0.0321), lymphatic metastasis ( P = 0.0125) and vascular invasion ( P = 0.0017) and a poor prognosis ( P = 0.0000) in gastric cancer patients. NOX4 depletion could significantly inhibit the invasion, proliferation, EMT and MMP7 expression of gastric cancer cells and suppress the progression of gastric cancer in vivo . In conclusion, NOX4 is related to gastric cancer development and predicts a poor prognosis. NOX4 may play an essential role in the progression of gastric cancer, and is a promising target for the prevention and treatment of gastric cancer., Competing Interests: None.