Methyl 3,4-Dihydroxybenzoate Enhances Resistance to Oxidative Stressors and Lifespan in C. elegans Partially via daf-2/daf-16.

Genetic studies have elucidated mechanisms that regulate aging; however, there has been little progress in identifying drugs that retard ageing. Caenorhabditis elegans is among the classical model organisms in ageing research. Methyl 3,4-dihydroxybenzoate (MDHB) can prolong the life-span of C. elegans, but the underlying molecular mechanisms are not yet fully understood. Here, we report that MDHB prolongs the life-span of C. elegans and delays age-associated declines of physiological processes. Besides, MDHB can lengthen the life-span of eat-2 (ad1113) mutations, revealing that MDHB does not work via caloric restriction (CR). Surprisingly, the life-span⁻extending activity of MDHB is completely abolished in daf-2 (e1370) mutations, which suggests that daf-2 is crucial for a MDHB-induced pro-longevity effect in C. elegans. Moreover, MDHB enhances the nuclear localization of daf-16/FoxO, and then modulates the expressions of genes that positively correlate with defenses against stress and longevity in C. elegans. Therefore, our results indicate that MDHB at least partially acts as a modulator of the daf-2/daf-16 pathway to extend the lifespan of C. elegans, and MDHB might be a promising therapeutic agent for age-related diseases.

Postoperative Pain in Patients Undergoing Cancer Surgery and Intravenous Patient-Controlled Analgesia Use: The First and Second 24 h Experiences.

INTRODUCTION: Postoperative cancer pain imposes severe physical and psychological problems. We aimed to investigate the pain experiences of patients with cancer after surgery, analyze the impact of infusion volume by patient-controlled analgesia (PCA), and explore the variations between day 1 and day 2. METHODS: Data were retrospectively extracted from a large health data platform. Descriptive statistics were presented for the demographic and clinical profiles of patients. Multiple logistic regression analyses were performed to evaluate associations between intensity of pain and PCA use after adjustment for risk factors. RESULTS: Among 11,383 patients with cancer, the incidence of pain (moderate to severe pain) was 93.3% (18.3%) at the first 24 h after operation, while the respect values decreased to 91.1% and 9.5% at the second 24 h. Further, female patients consistently experienced higher risk of pain over the whole 48 h postoperatively. Surgical sites were related to pain risk, with the highest risk among the respiratory system (OR 2.077, 95% CI 1.392-3.100). High doses of continuous volume (OR 2.453, 95% CI 1.742-3.456) and total volume (OR 2.830, 95% CI 2.037-3.934) of infusions were related to 1-3-fold elevated pain risk. Additionally, the observed associations were mostly repeated and could be up to over 10 times when pain was evaluated with number of PCA pump compressions instead of Numerical Rating Scale (NRS). CONCLUSIONS: High risk of postoperative cancer pain, particularly among the high PCA dose group, could possibly indicate inadequate pain control, and presence of modifiable risk factors warrants more aggressive pain management strategies perioperatively.

Pain Incidence and Associated Risk Factors among Cancer Patients within 72 Hours after Surgery: A Large Retrospective Analysis.

BACKGROUND: A fundamental principle of pain management is to determine the distribution and causes of pain. However, relevant data among postoperative cancer patients based on a large amount of data remain sparse. OBJECTIVE: We aimed to investigate the incidence of postoperative pain in cancer patients and to explore the associated risk factors. METHODS: We retrospectively collected information on postoperative pain-evaluation records of cancer patients who underwent surgery between 1 January 2014 and 31 December 2019. Descriptive statistics were presented, and multinominal logistic regression analysis was performed to explore the risk factors associated with postoperative pain. RESULTS: Among the 11,383 patients included in the study, the incidence of mild/moderate to severe pain at the 24th hour after surgery was 74.9% and 18.3%, respectively. At the 48th and 72nd hour after surgery, the incidence of mild pain increased slightly, while the incidence of moderate to severe pain continued to decrease. Female patients experienced a higher risk of pain (ORs: 1.37-1.58). Undergoing endoscopic surgery was associated with a higher risk of pain (ORs: 1.40-1.56). Patients with surgical sites located in the respiratory system had a higher risk of pain compared to in the digestive system (ORs: 1.35-2.13), and other patients had a relatively lower risk of pain (ORs: 0.11-0.61). CONCLUSION: The majority of cancer patients experienced varying degrees of postoperative pain but may not receive adequate attention and timely treatment. Female, young age and endoscopic surgery were associated with increased pain risk, and effective identification of these high-risk groups had positive implications for enhanced postoperative pain management.

Gallic Acid Induces Neural Stem Cell Differentiation into Neurons and Proliferation through the MAPK/ERK Pathway.

Neural stem cell (NSC) differentiation and proliferation are important biological processes in the cerebral neural network. However, these two abilities of NSCs are limited. Thus, the induction of differentiation and/or proliferation through the administration of plant-derived small-molecule compounds could be used to repair damaged neural networks. The present study reported that gallic acid (GA), an important phenolic acid found in tea, selectively caused NSCs to differentiate into immature neurons and promoted NSC proliferation by activating the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) pathway. In addition, it was found that 3,4-dihydroxybenzoic acid was the main active structure exhibiting neurotrophic activity. The substitution of the carboxyl group on the benzene ring with the ester group may promote differentiation based on the structure of 3,4-dihydroxybenzoic acid. Furthermore, the introduction of the 5-hydroxyl group may promote proliferation. The present study identified that GA can promote the differentiation and proliferation of NSCs in vitro and exert pharmacological activity on NSCs.

The Immune System Drives Synapse Loss During Lipopolysaccharide-Induced Learning and Memory Impairment in Mice.

Although lipopolysaccharides (LPS) have been used to establish animal models of memory loss akin to what is observed in Alzheimer's disease (AD), the exact mechanisms involved have not been substantiated. In this study, we established an animal model of learning and memory impairment induced by LPS and explored the biological processes and pathways involved. Mice were continuously intraperitoneally injected with LPS for 7 days. Learning- and memory-related behavioral performance and the pathological processes involved were assessed using the Morris water maze test and immunostaining, respectively. We detected comprehensive expression of C1q, C3, microglia, and their regulatory cytokines in the hippocampus. After 7 days of LPS administration, we were able to observe LPS-induced learning and memory impairment in the mice, which was attributed to neural impairment and synapse loss in the hippocampus. We elucidated that the immune system was activated, with the classical complement pathway and microglial phagocytosis being involved in the synapse loss. This study demonstrates that an LPS-injected mouse can serve as an early memory impairment model for studies on anti-AD drugs.

Gene Expression Analysis Reveals Novel Gene Signatures Between Young and Old Adults in Human Prefrontal Cortex.

Human neurons function over an entire lifetime, yet the molecular mechanisms which perform their functions and protecting against neurodegenerative disease during aging are still elusive. Here, we conducted a systematic study on the human brain aging by using the weighted gene correlation network analysis (WGCNA) method to identify meaningful modules or representative biomarkers for human brain aging. Significantly, 19 distinct gene modules were detected based on the dataset GSE53890; among them, six modules related to the feature of brain aging were highly preserved in diverse independent datasets. Interestingly, network feature analysis confirmed that the blue modules demonstrated a remarkably correlation with human brain aging progress. Besides, the top hub genes including PPP3CB, CAMSAP1, ACTR3B, and GNG3 were identified and characterized by high connectivity, module membership, or gene significance in the blue module. Furthermore, these genes were validated in mice of different ages. Mechanically, the potential regulators of blue module were investigated. These findings highlight an important role of the blue module and its affiliated genes in the control of normal brain aging, which may lead to potential therapeutic interventions for brain aging by targeting the hub genes.

Norisoboldine, a natural AhR agonist, promotes Treg differentiation and attenuates colitis via targeting glycolysis and subsequent NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway.

Norisoboldine (NOR), a natural aryl hydrocarbon receptor (AhR) agonist, has been demonstrated to attenuate ulcerative colitis (UC) and induce the generation of Treg cells. Under UC condition, hypoxia widely exists in colonic mucosa, and secondary changes of microRNAs (miRs) expressions and glycolysis contribute to Treg differentiation. At present, we worked for exploring the deep mechanisms for NOR-promoted Treg differentiation in hypoxia and its subsequent anti-UC action from the angle of AhR/miR or AhR/glycolysis axis. Results showed that NOR promoted Treg differentiation in hypoxia and the effect was stronger relative to normoxia. It activated AhR in CD4+ T cells under hypoxic microenvironment; CH223191 (a specific AhR antagonist) and siAhR-3 abolished NOR-promoted Treg differentiation. Furthermore, the progress of glycolysis, levels of Glut1 and HK2, and expression of miR-31 rather than miR-219 and miR-490 in CD4+ T cells were downregulated by NOR treatment under hypoxic microenvironment. However, HK2 plasmid but not miR-31 mimic significantly interfered NOR-enhanced Treg polarization. In addition, NOR reduced NAD+ and SIRT1 levels, facilitated the ubiquitin-proteasomal degradation of SUV39H1 protein, and inhibited the enrichment of H3K9me3 at -1, 201 to -1,500 region of Foxp3 promoter in CD4+ T cells under hypoxic microenvironment, which was weakened by HK2 plasmid, CH223191, and siAhR-3. Finally, the correlation between NOR-mediated activation of AhR, repression of glycolysis, regulation of NAD+/SIRT1/SUV39H1/H3K9me3 signals, induction of Treg cells, and remission of colitis was confirmed in mice with DSS-induced colitis by using CH223191 and HK2 plasmid. In conclusion, NOR promoted Treg differentiation and then alleviated the development of colitis by regulating AhR/glycolysis axis and subsequent NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway.

Methyl 3,4-Dihydroxybenzoate Induces Neural Stem Cells to Differentiate Into Cholinergic Neurons in vitro.

Neural stem cells (NSCs) have been shown as a potential source for replacing degenerated neurons in neurodegenerative diseases. However, the therapeutic potential of these cells is limited by the lack of effective methodologies for controlling their differentiation. Inducing endogenous pools of NSCs by small molecule can be considered as a potential approach of generating the desired cell types in large numbers. Here, we reported the characterization of a small molecule (Methyl 3,4-dihydroxybenzoate; MDHB) that selectively induces hippocampal NSCs to differentiate into cholinergic motor neurons which expressed synapsin 1 (SYN1) and postsynaptic density protein 95 (PSD-95). Studies on the mechanisms revealed that MDHB induced the hippocampal NSCs differentiation into cholinergic motor neurons by inhibiting AKT phosphorylation and activating autophosphorylation of GSK3ß at tyrosine 216. Furthermore, we found that MDHB enhanced ß-catenin degradation and abolished its entering into the nucleus. Collectively, this report provides the strong evidence that MDHB promotes NSCs differentiation into cholinergic motor neurons by enhancing gene Isl1 expression and inhibiting cell cycle progression. It may provide a basis for pharmacological effects of MDHB directed on NSCs.