CD200 in dentate gyrus improves depressive-like behaviors of mice through enhancing hippocampal neurogenesis via alleviation of microglia hyperactivation.

BACKGROUND: Neuroinflammation and microglia play critical roles in the development of depression. Cluster of differentiation 200 (CD200) is an anti-inflammatory glycoprotein that is mainly expressed in neurons, and its receptor CD200R1 is primarily in microglia. Although the CD200-CD200R1 pathway is necessary for microglial activation, its role in the pathophysiology of depression remains unknown. METHODS: The chronic social defeat stress (CSDS) with behavioral tests were performed to investigate the effect of CD200 on the depressive-like behaviors. Viral vectors were used to overexpress or knockdown of CD200. The levels of CD200 and inflammatory cytokines were tested with molecular biological techniques. The status of microglia, the expression of BDNF and neurogenesis were detected with immunofluorescence imaging. RESULTS: We found that the expression of CD200 was decreased in the dentate gyrus (DG) region of mice experienced CSDS. Overexpression of CD200 alleviated the depressive-like behaviors of stressed mice and inhibition of CD200 facilitated the susceptibility to stress. When CD200R1 receptors on microglia were knocked down, CD200 was unable to exert its role in alleviating depressive-like behavior. Microglia in the DG brain region were morphologically activated after exposure to CSDS. In contrast, exogenous administration of CD200 inhibited microglia hyperactivation, alleviated neuroinflammatory response in hippocampus, and increased the expression of BDNF, which in turn ameliorated adult hippocampal neurogenesis impairment in the DG induced by CSDS. CONCLUSIONS: Taken together, these results suggest that CD200-mediated alleviation of microglia hyperactivation contributes to the antidepressant effect of neurogenesis in dentate gyrus in mice.

Chronic Resistance Exercise Improves Functioning and Reduces Toll-Like Receptor Signaling in Elderly Patients With Postoperative Deconditioning.

OBJECTIVE: Elderly patients continue to experience low levels of mobility during and following postoperative hospitalization that lead to persistent physical decline. Therefore, here we compared chronic resistance (CR) exercise against chronic aerobic (CA) exercise in ameliorating postoperative functioning and reducing proinflammatory muscular Toll-like receptor (TLR)-associated signaling in elderly postoperative patients. METHODS: We conducted a prospective, randomized trial comparing the effects of 3 exercise programs (CR, CA, and CR + CA) in 66 elderly patients recovering from recent hip, femur, or pelvic fracture repair surgery. The primary outcomes were changes in anatomic/physical performance parameters (ie, maximal oxygen intake, endurance, quadriceps cross-sectional area, and maximum knee-extensor force). The secondary outcomes were changes in TLR/nuclear factor kappa beta signaling pathway marker expression. RESULTS: Three of the 4 anatomic/physical performance parameters significantly improved for the CR and CR + CA cohorts. Muscular expression of myeloid differentiation primary response gene 88, transforming growth factor beta-activated kinase 1 (TLR signaling pathway markers), p50, p65, tumor necrosis factor α, and interleukin 6 (nuclear factor kappa beta signaling pathway markers) all showed significant reductions after CR and CR + CA. Serum expression of 2 key TLR4 ligands, heat shock protein 70 and serum amyloid A, also showed significant reductions after CR and CR + CA. CONCLUSIONS: Three months of CR or CR + CA improves maximal oxygen consumption, quadriceps cross-sectional area, and maximum knee-extensor force while lowering muscular proinflammatory signaling markers in elderly adults with postoperative deconditioning.

Cellular plasticity and fate determination in gastric carcinogenesis.

Cellular plasticity serves as a crucial biological phenomenon in humans, integral to tissue repair and maintenance of dynamic environmental homeostasis post-injury. However, dysregulated activation of this beneficial mechanism can pave the way for tumorigenesis and cancer progression. In this review, we synthesize recent advancements concerning the properties and roles of gastric epithelial cells, with a special emphasis on cellular plasticity and fate specification during the progress of gastric tumorigenesis. Notably, the attribute of stemness is not exclusive to gastric stem cells but also extends to differentiated cells in gastric units. We delve into the extent of plasticity and changes in cellular fate that contribute to malignant transformation in both stem and mature cells within the stomach. Moreover, we explore matrix-epithelial interactions, immunological modulation, and epigenomic alterations throughout the course of gastric tumorigenesis. A comprehensive understanding of the underlying cellular mechanisms governing plasticity and fate decisions could catalyze the development of innovative approaches for cancer prevention and antineoplastic therapies.

Gastric intestinal metaplasia: progress and remaining challenges.

Most gastric cancers arise in the setting of chronic inflammation which alters gland organization, such that acid-pumping parietal cells are lost, and remaining cells undergo metaplastic change in differentiation patterns. From a basic science perspective, recent progress has been made in understanding how atrophy and initial pyloric metaplasia occur. However, pathologists and cancer biologists have long been focused on the development of intestinal metaplasia patterns in this setting. Arguably, much less progress has been made in understanding the mechanisms that lead to the intestinalization seen in chronic atrophic gastritis and pyloric metaplasia. One plausible explanation for this disparity lies in the notable absence of reliable and reproducible small animal models within the field, which would facilitate the investigation of the mechanisms underlying the development of gastric intestinal metaplasia (GIM). This review offers an in-depth exploration of the current state of research in GIM, shedding light on its pivotal role in tumorigenesis. We delve into the histological subtypes of GIM and explore their respective associations with tumor formation. We present the current repertoire of biomarkers utilized to delineate the origins and progression of GIM and provide a comprehensive survey of the available, albeit limited, mouse lines employed for modeling GIM and engage in a discussion regarding potential cell lineages that serve as the origins of GIM. Finally, we expound upon the myriad signaling pathways recognized for their activity in GIM and posit on their potential overlap and interactions that contribute to the ultimate manifestation of the disease phenotype. Through our exhaustive review of the progression from gastric disease to GIM, we aim to establish the groundwork for future research endeavors dedicated to elucidating the etiology of GIM and developing strategies for its prevention and treatment, considering its potential precancerous nature.

Metaplastic regeneration in the mouse stomach requires a reactive oxygen species pathway.

In pyloric metaplasia, mature gastric chief cells reprogram via an evolutionarily conserved process termed paligenosis to re-enter the cell cycle and become spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Here, we use single-cell RNA sequencing (scRNA-seq) following injury to the murine stomach to analyze mechanisms governing paligenosis at high resolution. Injury causes induced reactive oxygen species (ROS) with coordinated changes in mitochondrial activity and cellular metabolism, requiring the transcriptional mitochondrial regulator Ppargc1a (Pgc1α) and ROS regulator Nf2el2 (Nrf2). Loss of the ROS and mitochondrial control in Ppargc1a-/- mice causes the death of paligenotic cells through ferroptosis. Blocking the cystine transporter SLC7A11(xCT), which is critical in lipid radical detoxification through glutathione peroxidase 4 (GPX4), also increases ferroptosis. Finally, we show that PGC1α-mediated ROS and mitochondrial changes also underlie the paligenosis of pancreatic acinar cells. Altogether, the results detail how metabolic and mitochondrial changes are necessary for injury response, regeneration, and metaplasia in the stomach.

Prophylactic cranial irradiation for extensive stage small cell lung cancer: a meta-analysis of randomized controlled trials.

Background: Previous studies have demonstrated that prophylactic cranial irradiation (PCI) could reduce the risk of brain metastases and prolong the overall survival (OS) of patients with small cell lung cancer (SCLC). However, it remains controversial whether the efficacy and safety of PCI would be subjected to the different characteristics of patients with extensive stage of SCLC. This meta-analysis aims to evaluate the efficacy and safety of PCI in patients with extensive stage SCLC. Methods: PubMed, Embase, and the Cochrane Library were searched for relevant studies from inception to May, 2021. Hazard ratios (HRs) were used to measure the OS and progression-free survival (PFS), and relative risks (RRs) were employed to calculate the incidence of brain metastases, survival rate, and adverse events. Summary results were pooled using random-effect models. Results: There were 1215 articles identified, and 15 trials were included, with a total of 1,623 participants. Patients who received PCI did not result in significantly improved OS [HR=0.87, 95%CI (0.70, 1.08) p=0.417] and PFS [HR=0.81, 95%CI (0.69, 0.95) p=0.001], compared with those who did not receive PCI, while patients who received PCI had a significantly decreased incidence of brain metastases [RR=0.57, 95%CI (0.45, 0.74), p<0.001]. PCI group showed no improvements in 2-year (RR=1.03, p=0.154), 3-year (RR=0.97, p=0.072), 4-year (RR=0.71, p=0.101) and 5-year survival rates (RR=0.32, p=0.307), compared with non-PCI group, whereas the overall RR indicated that PCI was associated with a higher 1-year survival rate [RR=1.46, 95%CI (1.08, 1.97), p=0.013]. In addition, PCI treatment was shown to be associated with increased incidence of adverse events, including fatigue, dermatitis, anorexia, nausea, vomiting, malaise, and cognitive impairment. Conclusion: This meta-analysis suggests that PCI can reduce the incidence of brain metastases in extensive stage SCLC. Although PCI has no significant effect on the OS, it improves 1-year survival in patients with extensive stage SCLC. However, PCI does not significantly affect 2,3,4,5-year survival and may result in a significantly increased risk of adverse events.

RNA Demethylase ALKBH5 Prevents Lung Cancer Progression by Regulating EMT and Stemness via Regulating p53.

Background: Although N6-methyladenosine (m6A) RNA methylation is the most abundant reversible methylation of mRNA, which plays a critical role in regulating cancer processing, few studies have examined the role of m6A in nonsmall-cell lung cancer-derived cancer stem-like cells (CSCs). Methods: CSCs were enriched by culturing NSCLC cells in a serum-free medium, and stem factors, including CD24, CD44, ALDH1, Nanog, Oct4, and Sox2 were detected by Western blot. ALKBH5 expression was measured by employing a tissue array. Global m6A methylation was measured after ALKBH5 knockdown. Malignances of CSCs were detected by performing CCK-8 assay, invasion assay, cell cycle analysis, and tumor formation in vitro and in vivo. Results: m6A demethylase ALKBH5 is highly expressed in CSCs derived from NSCLC. Knockdown of ALKBH5 increased global m6A level, and also increased E-cadherin, decreased stem hallmarkers, Nanog and Oct4, and inhibited stemness of CSCs. In lung carcinoma, ALKBH5 is found to be positively correlated with p53 by using Gene Expression Profiling Interactive Analysis (GEPIA) online tool. P53 transcriptionally regulates ALKBH5 and subsequently regulates the global m6A methylation level. Knockdown of p53 or inhibition of p53's transcriptional activity by addition of its specific inhibitor PFT-α decreased expression of ALKBH5 and CSCs' malignancies, including proliferation, invasion, and tumor formation ability, indicating that p53 may partially regulate CSC's malignancies via ALKBH5. Furthermore, we also found p53 transcriptionally regulates PRRX1, which is consistent with our previous report. Conclusion: Collectively, our findings indicate the pivotal role of ALKBH5 in CSCs derived from NSCLC and highlight the regulatory function of the p53/ALKBH5 axis in modulating CSC progression, which could be a promising therapeutic target for NSCLC.

The Emerging Roles of Rad51 in Cancer and Its Potential as a Therapeutic Target.

Defects in DNA repair pathways are emerging hallmarks of cancer. Accurate DNA repairs and replications are essential for genomic stability. Cancer cells require residual DNA repair capabilities to repair the damage from replication stress and genotoxic anti-tumor agents. Defective DNA repair also promotes the accumulation of genomic changes that eventually lead to tumorigenesis, tumor progression, and therapeutic resistance to DNA-damaging anti-tumor agents. Rad51 recombinase is a critical effector of homologous recombination, which is an essential DNA repair mechanism for double-strand breaks. Rad51 has been found to be upregulated in many malignant solid tumors, and is correlated with poor prognosis. In multiple tumor types, Rad51 is critical for tumor metabolism, metastasis and drug resistance. Herein, we initially introduced the structure, expression pattern of Rad51 and key Rad51 mediators involved in homologous recombination. Additionally, we primarily discussed the role of Rad51 in tumor metabolism, metastasis, resistance to chemotherapeutic agents and poly-ADP ribose polymerase inhibitors.

Combination of microsized mineral particles and rosin as a basis for converting cellulosic fibers into "sticky" superhydrophobic paper.

The unique features of cellulosic paper including flexibility, biodegradability, and low cost enables it as a versatile, sustainable biomaterial for promising applications. In the paper industry, microsized mineral particles are widely used in the production of printing/writing paper grades, while rosin derived from trees is the earliest internal sizing agent for paper hydrophobication. On the basis of existing commercial practices associated with the use of mineral particles and rosin in paper production, we present a process concept of converting cellulosic fibers (paper-grade pulp) into "sticky" superhydrophobic paper involving the use of microsized mineral particles and rosin (a tree-derived natural product, mainly a mixture of resin acids, especially abietic acid with chemical formula of C19H29COOH). Internal filling of cellulosic networks with mineral particles was basically used to hold out the mineral particles added at the surface, and the delicate integration of wet-end/surface applications of mineral particles with paper surface engineering with rosin/alum led to the development of "sticky" superhydrophobicity, i.e., ultrahigh water-repellency and strong adhesion to water. This proposed concept may provide valuable implications for expanding the use of paper-based products to unconventional applications, e.g., ultrahigh-performance ink jet printing paper for mitigating the "coffee-ring effect" and paper-based microfluidic devices for biomedical testing.