miRNAs in treatment-resistant depression: a systematic review.

BACKGROUND: Treatment-resistant depression (TRD) is a condition in a subset of depressed patients characterized by resistance to antidepressant medications. The global prevalence of TRD has been steadily increasing, yet significant advancements in its diagnosis and treatment remain elusive despite extensive research efforts. The precise underlying pathogenic mechanisms are still not fully understood. Epigenetic mechanisms play a vital role in a wide range of diseases. In recent years, investigators have increasingly focused on the regulatory roles of miRNAs in the onset and progression of TRD. miRNAs are a class of noncoding RNA molecules that regulate the translation and degradation of their target mRNAs via interaction, making the exploration of their functions in TRD essential for elucidating their pathogenic mechanisms. METHODS AND RESULTS: A systematic search was conducted in four databases, namely PubMed, Web of Science, Cochrane Library, and Embase, focusing on studies related to treatment-resistant depression and miRNAs. The search was performed using terms individually or in combination, such as "treatment-resistant depression," "medication-resistant depression," and "miRNAs." The selected articles were reviewed and collated, covering the time period from the inception of each database to the end of February 2024. We found that miRNAs play a crucial role in the pathophysiology of TRD through three main aspects: 1) involvement in miRNA-mediated inflammatory responses (including miR-155, miR-345-5p, miR-146a, and miR-146a-5p); 2) influence on 5-HT transport processes (including miR-674,miR-708, and miR-133a); and 3) regulation of synaptic plasticity (including has-miR-335-5p,has-miR- 1292-3p, let-7b, and let-7c). Investigating the differential expression and interactions of these miRNAs could contribute to a deeper understanding of the molecular mechanisms underlying TRD. CONCLUSIONS: miRNAs might play a pivotal role in the pathogenesis of TRD. Gaining a deeper understanding of the roles and interrelations of miRNAs in TRD will contribute to elucidating disease pathogenesis and potentially provide avenues for the development of novel diagnostic and therapeutic strategies.

The association between 5-HT1A binding and temporal lobe epilepsy: A meta-analysis of molecular imaging studies.

BACKGROUND: Studies have shown conflicting results in the correlation between serotonin-1A (5-HT1A) receptor binding levels in the brain and temporal lobe epilepsy (TLE). There is a need to systematically evaluate the correlation between the 5-HT1A binding level and TLE from the perspective of the brain using molecular imaging. METHODS: Chinese and English databases, such as the China National Knowledge Infrastructure (CNKI), the China Science and Technology Journal Database (VIP), WanFang, the Chinese Biomedical Literature Service System (SinoMed), PubMed and Web of Science, were searched. RESULTS: Two evaluators independently screened the literature, extracted data, and evaluated the risk of bias in the included studies according to the inclusion and exclusion criteria. RevMan 5.4.1 was used to analyze the data. A total of 196 participants were included; of these, 95 had TLE and 131 were healthy controls who had never had a seizure before participating in the study. Meta-analysis results suggested that 1) decreased 5-HT1A binding was found on the affected side of patients with TLE (standard mean difference (SMD) = -1.45, 95% confidence interval (CI) [-2.27, -0.64], Z = 3.48, P = 0.0005); 2) decreased 5-HT1A binding was found in the ipsilateral hippocampus of patients with TLE (SMD = -1.76, 95% CI [-2.51, -1.00], Z = 4.57, P＜0.00001); 3) decreased 5-HT1A binding was found in the ipsilateral temporal lobe cortex of patients with TLE (SMD = -0.46, 95% CI [-0.80, -0.12], Z = 2.66, P = 0.008); 4) decreased 5-HT1A binding was found in the ipsilateral amygdala in patients with TLE (SMD = -1.36, 95% CI [-2.48, -0.23], Z = 2.37, P = 0.02); and 5) decreased 5-HT1A binding was found in the frontal lobe of patients with TLE(SMD = -0.75, 95% CI [-1.29, -0.20], Z = 2.67, P = 0.008). CONCLUSION: A reduction in 5-HT1A binding in the hippocampus, temporal cortex, amygdala, and frontal lobe was observed on the affected side of patients with TLE. The decrease in 5-HT1A binding can be considered related to TLE. Potentially relevant factors should be considered in future molecular imaging studies.

Risk of allergic rhinitis in patients with inflammatory bowel disease: A systematic review and meta-analysis.

BACKGROUND: Numerous parallels exist between inflammatory bowel disease (IBD) and allergic rhinitis (AR), which include risk factors (such as environmental and genetic factors), pathogenesis (immune disorders, epithelial cell barriers, etc.), and treatment (immunosuppressants and immunomodulators, such as cyclosporine and steroids). However, the risk of AR in IBD patients is unknown. OBJECTIVE: In this systematic review and meta-analysis, patients with IBD are examined for their risk of AR. METHODS: Several databases are accessible in both Chinese and English, including PubMed, BioRXiv, WanFang, the China National Knowledge Infrastructure (CNKI), Web of Science, METSTR, and MedRxiv. Findings presented at allergy, rhinology, thoracic, and gastrointestinal conferences were analyzed. Based on the inclusion and exclusion criteria, two evaluators independently retrieved data, read the literature, and evaluated bias risk. The data analysis was conducted using RevMan 5.4. Case-control and cohort studies were eligible study designs for this research. RESULTS: There were 10 case-control studies and 1 cohort study included in the meta-analysis. The experimental group consisted of 65,687 IBD patients, of whom 5838 had AR. A total of 345,176 participants without IBD were included in the control group, of whom 24,625 developed AR. The outcomes demonstrated that IBD patients had a higher risk of developing AR (odds ratio [OR] = 1.48, 95% confidence interval [CI] [1.12, 1.95], Z = 2.78, P = 0.005) than those without IBD. CONCLUSION: The risk of AR is higher in IBD patients. Further investigation is required to determine the mechanism behind the association between AR and IBD.

Development and validation of a novel model to predict liver-related mortality in patients with idiosyncratic drug-induced liver injury.

BACKGROUND: Early identification of patients with high mortality risk is critical for optimizing the clinical management of drug-induced liver injury (DILI). We aimed to develop and validate a new prognostic model to predict death within 6 months in DILI patients. METHODS: This multicenter study retrospectively reviewed the medical records of DILI patients admitted to three hospitals. A DILI mortality predictive score was developed using multivariate logistic regression and was validated with area under the receiver operating characteristic curve (AUC). A high-mortality-risk subgroup was identified according to the score. RESULTS: Three independent DILI cohorts, including one derivation cohort (n = 741) and two validation cohorts (n = 650, n = 617) were recruited. The DILI mortality predictive (DMP) score was calculated using parameters at disease onset as follows: 1.913 × international normalized ratio + 0.060 × total bilirubin (mg/dL) + 0.439 × aspartate aminotransferase/alanine aminotransferase - 1.579 × albumin (g/dL) - 0.006 × platelet count (109/L) + 9.662. The predictive performance for 6-month mortality of DMP score was desirable, with an AUC of 0.941 (95% CI: 0.922-0.957), 0.931 (0.908-0.949) and 0.960 (0.942-0.974) in the derivation, validation cohorts 1 and 2, respectively. DILI patients with a DMP score ≥ 8.5 were stratified into high-risk group, whose mortality rates were 23-, 36-, and 45-fold higher than those of other patients in the three cohorts. CONCLUSIONS: The novel model based on common laboratory findings can accurately predict mortality within 6 months in DILI patients, which should serve as an effective guidance for management of DILI in clinical practice.

Advances in Rodent Experimental Models of Sepsis.

In the development of therapeutic strategies for human diseases, preclinical experimental models have a key role. However, the preclinical immunomodulatory therapies developed using rodent sepsis were not successful in human clinical trials. Sepsis is characterized by a dysregulated inflammation and redox imbalance triggered by infection. Human sepsis is simulated in experimental models using methods that trigger inflammation or infection in the host animals, most often mice or rats. It remains unknown whether the characteristics of the host species, the methods used to induce sepsis, or the molecular processes focused upon need to be revisited in the development of treatment methods that will succeed in human clinical trials. Our goal in this review is to provide a survey of existing experimental models of sepsis, including the use of humanized mice and dirty mice, and to show how these models reflect the clinical course of sepsis. We will discuss the strengths and limitations of these models and present recent advances in this subject area. We maintain that rodent models continue to have an irreplaceable role in studies toward discovering treatment methods for human sepsis.

Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a major cause of blindness. Recent studies have reported impaired glycolysis in AMD patients with a high lactate/pyruvate ratio. Elevated homocysteine (Hcy) (Hyperhomocysteinemia, HHcy) was observed in several clinical studies, reporting an association between HHcy and AMD. We established the effect of HHcy on barrier function, retinal pigment epithelium (RPE) structure, and induced choroidal neovascularization (CNV) in mice. We hypothesize that HHcy contributes to AMD by inducing a metabolic switch in the mitochondria, in which cells predominantly produce energy by the high rate of glycolysis, or "Warburg", effect. Increased glycolysis results in an increased production of lactate, cellular acidity, activation of angiogenesis, RPE barrier dysfunction, and CNV. Evaluation of cellular energy production under HHcy was assessed by seahorse analysis, immunofluorescence, and western blot experiments. The seahorse analysis evaluated the extracellular acidification rate (ECAR) as indicative of glycolysis. HHcy showed a significant increase in ECAR both in vivo using (Cystathionine ß-synthase) cbs+/- and cbs-/- mice retinas and in vitro (Hcy-treated ARPE-19) compared to wild-type mice and RPE cells. Moreover, HHcy up-regulated glycolytic enzyme (Glucose transporter-1 (GlUT-1), lactate dehydrogenase (LDH), and hexokinase 1 (HK1)) in Hcy-treated ARPE-19 and primary RPE cells isolated from cbs+/+, cbs+/-, and cbs-/- mice retinas. Inhibition of GLUT-1 or blocking of N-methyl-D-aspartate receptors (NMDAR) reduced glycolysis in Hcy-treated RPE and improved albumin leakage and CNV induction in Hcy-injected mice eyes. The current study suggests that HHcy causes a metabolic switch in the RPE cells from mitochondrial respiration to glycolysis during AMD and confirms the involvement of NMDAR in this process. Therefore, targeting Glycolysis or NMDAR could be a novel therapeutic target for AMD.

The analgesic effect of tramadol combined with butorphanol on uterine cramping pain after repeat caesarean section: a randomized, controlled, double-blind study.

PURPOSE: This study aimed to explore the effect of patient-controlled intravenous analgesia (PCIA) using tramadol combined with butorphanol on uterine cramping pain in women undergoing repeat caesarean section. METHODS: A total of 126 patients, who were scheduled to undergo repeat caesarean section under spinal anesthesia, were included. PCIA using tramadol combined with butorphanol or sufentanil was randomly performed for postoperative pain control. Postoperative uterine cramping pain and wound pain within 48 h after surgery were evaluated. Postoperative analgesic consumption, early activity time, and length of hospital stay were also recorded and analyzed. RESULTS: Uterine cramping pain intensity in women undergoing repeat caesarean section was significantly higher compared with their wound pain (P < 0.05). The mean visual analog scale (VAS) score for uterine cramping pain in the tramadol-butorphanol group was significantly lower than that in the sufentanil group at rest, and at 6 h and 12 h after surgery. VAS scores for uterine cramping pain during movement at 6 h, 12 h, and 24 h after surgery in the tramadol-butorphanol group were also significantly lower than that in sufentanil group (P < 0.05). There was no significant difference in VAS score for wound pain at the different time points between the tramadol-butorphanol and sufentanil groups (P > 0.05). Patient-controlled intravenous analgesia with tramadol accelerated early rehabilitation and decreased the length of hospital stay (P < 0.05). CONCLUSION: PCIA using tramadol combined with butorphanol provided a better analgesic effect and accelerated postoperative rehabilitation compared with sufentanil, and may be an optimal analgesic strategy for women undergoing repeat caesarean section. CLINICAL TRIAL REGISTRATION: The trial was registered at Chinese Clinical Trial Registry ( www.chictr.org.cn ) with ID: ChiCTR-1800014986.

AMPKα2 knockout enhances tumour inflammation through exacerbated liver injury and energy deprivation-associated AMPKα1 activation.

Tissue damage and its associated-inflammation act as tumour initiators or propagators. AMP-activated protein kinase (AMPK) is activated by environmental or nutritional stress factors, such as hypoxia, glucose deprivation, and other cell injury factors, to regulate cell energy balance and differentiation. We previously have reported that AMPKα2 deficiency resulted in the energy deprivation in tumour-bearing liver and the enhanced-hepatocyte death. In this study, AMPKα2 knockout mice and the liver metastasis model of colon cancer cells were used to address the role of AMPKα isoforms in tumour inflammation. First, we found that the AMPKα2 deficiency exacerbated the liver injury and recruitment of macrophages. Meanwhile, although compensatory expression of AMPKα1 was not significant after AMPKα2 knockout, AMPKα1 phosphorylation was elevated in remnant liver in AMPKα2 knockout mice, which was positively associated with the enhanced energy deprivation in the AMPKα2 deficient mice. Furthermore, the activated AMPKα1 in macrophage contributed to its polarizing to tumour-associated phenotype. Thus, the enhanced tumour-associated inflammation and activation of AMPKα1 in the AMPKα2 deficient mice may exacerbate the tumour development by affecting the tumour inflammatory microenvironment. Our study suggests that the two isoforms of AMPKα, AMPKα1 and AMPKα2 play different roles in controlling tumour development.

A longitudinal analysis of the association between the living arrangements and psychological well-being of older Chinese adults: the role of income sources.

BACKGROUND: Understanding how living arrangements may affect psychological well-being (PWB) is critical in China, a society with the largest older population in the world. However, few studies have examined the moderating effect of income sources on the relationship between living arrangements and PWB. Our aim was to examine whether living arrangements are associated with PWB and whether income sources moderate this association. METHODS: The data were drawn from the third (2002) to sixth (2011/2012) waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Six questions reflecting older adults' well-being were used to measure PWB. Living arrangements were classified as follows: living alone, living with family and living in an institution. Income sources were categorized into financially independent, supported by children, and governmental support. We performed random-effects ordinal probit models to examine the association of living arrangements with PWB and the moderating effect of income sources on this relationship. RESULTS: We included a total sample of 30,899 observations for 16,020 respondents aged 65 and over during 9-year follow-up. Older adults living with family (ß = .29, p < .001) and those living in an institution (ß = .34, p < .001) had stronger PWB than those living alone; moreover, support from children (ß= -.24, p < .001) or from the government (ß= -.08, p < .05) has a negative effect on PWB compared to the effect of financial self-support. Living in an institution with support from children (ß= -.22, p < .05) led to lower PWB than living alone with financial self-support. The opposite result was observed for older adults living with their family and supported by the government (ß = .16, p < .05). CONCLUSIONS: Our analysis provides a significant contribution to the existing literature on the relationship between living arrangements and PWB in China. We recognize that living with family or in an institution leads to better PWB than does living alone. In addition, financial support from the government can moderate this association.

Hypoxic postconditioning attenuates apoptosis via activation of adenosine A2a receptors on dermal microvascular endothelial cells of human flaps.

BACKGROUND: In recent years, many studies have demonstrated that endogenous adenosine induced by ischemia postconditioning reduces apoptosis in various models, but no study has clearly elucidated the effects of hypoxic postconditioning (HPC) in human dermal microvascular endothelial cells (HDMECs) of flaps, and the subtype of adenosine receptors involved remains unknown. In our study, we sought to identify the role of adenosine A2a receptor in the antiapoptotic effects of HPC. MATERIALS AND METHODS: The HDMECs were isolated from human upper eyelid tissue. After hypoxia for 6 h, the HDMECs were either abruptly reperfused with medium for 12 h (reoxygenation) or postconditioned by three cycles of 5 min of transitory reoxygenation and 5 min of rehypoxia followed by 11.5 h of reoxygenation. CGS-21680 was used as an adenosine A2a agonist. RESULTS: Adenosine A2a receptors were found in the cytoplasm of HDMECs. Hypoxia/reoxygenation (H/R) resulted in severe injury in HDMECs as evidenced by an increase in apoptosis percentage and an increase in expressions of apoptosis-related proteins (the ratio of Bax/Bcl-2 and caspase-3), which can be significantly attenuated by HPC treatment or exposure to CGS-21680, a selective adenosine A2a receptor agonist (all P values < 0.05). Meanwhile, HPC treatment or CGS-21680 significantly activated A2a receptors compared with the hypoxia/reoxygenation group (P < 0.05 versus P < 0.05, respectively). Statistical analysis showed that the increase of cell apoptosis closely correlated inversely with the increase of relative protein level of adenosine A2a receptors (r2 = 0.8177, P < 0.0001). CONCLUSIONS: HPC protects against apoptosis induced by reoxygenation via activation of adenosine A2a receptors on HDMECs.

Complement 5a Enhances Hepatic Metastases of Colon Cancer via Monocyte Chemoattractant Protein-1-mediated Inflammatory Cell Infiltration.

Complement 5a (C5a), a potent immune mediator generated by complement activation, promotes tumor growth; however, its role in tumor metastasis remains unclear. We demonstrate that C5a contributes to tumor metastases by modulating tumor inflammation in hepatic metastases of colon cancer. Colon cancer cell lines generate C5a under serum-free conditions, and C5a levels increase over time in a murine syngeneic colon cancer hepatic metastasis model. Furthermore, in the absence of C5a receptor or upon pharmacological inhibition of C5a production with an anti-C5 monoclonal antibody, tumor metastasis is severely impaired. A lack of C5a receptor in colon cancer metastatic foci reduces the infiltration of macrophages, neutrophils, and dendritic cells, and the role for C5a receptor on these cells were further verified by bone marrow transplantation experiments. Moreover, C5a signaling increases the expression of the chemokine monocyte chemoattractant protein-1 and the anti-inflammatory molecules arginase-1, interleukin 10, and transforming growth factor ß, but is inversely correlated with the expression of pro-inflammatory molecules, which suggests a mechanism for the role of C5a in the inflammatory microenvironment required for tumor metastasis. Our results indicate a new and potentially promising therapeutic application of complement C5a inhibitor for the treatment of malignant tumors.

Adiponectin induces CXCL1 secretion from cancer cells and promotes tumor angiogenesis by inducing stromal fibroblast senescence.

Adiponectin is an adipocyte-specific adipocytokine with proliferative and pro-angiogenic effects that regulates many biological processes, including immunity, insulin resistance, and inflammation. The oncogenic role of adiponectin has been implicated in several cancer types. Stromal cells within tumor contribute tumor growth and angiogenesis; however, it is not clear that how adiponectin regulates stromal cell-mediated tumorigenesis. In this study, using the tumor xenograft models, we demonstrated that tumor development was severely impaired in mouse subcutaneous cancer tissue and metastasis tumor tissue in adiponectin knockout mice. Our results indicated adiponectin deficiency resulted in decrease of blood vessel and stromal senescent fibroblasts in subcutaneous and metastasis tumor tissue. These observations were confirmed in vitro, in which co-cultured tumor cells and fibroblasts treated with adiponectin promoted ECs tube formation. A secretion of CXCL1 by adiponectin-treated tumor cells was observed during the process of inducing stromal fibroblast senescence. Furthermore, stromal cells senescence was through p53 and p16 pathways. Taken together, our results indicate that adiponectin promotes stromal cell senescence within invasive colon cancer contributing to angiogenesis and tumor growth in part through the production of CXCL1 and may serve as a therapeutic target for tumor patients. © 2015 Wiley Periodicals, Inc.

Association between omentin-1 expression in human epicardial adipose tissue and coronary atherosclerosis.

BACKGROUND: Omentin-1, a novel adipocytokine mainly expressed in visceral adipose tissue, has been found to inhibit the inflammatory response and improve insulin resistance as well as other obesity-related disorders. This study investigated the association between omentin-1 expression in human epicardial adipose tissue (EAT) and coronary atherosclerosis. METHODS: Serum samples, and paired biopsies from EAT and subcutaneous adipose tissue (SAT), were obtained from patients with and without coronary artery disease (CAD, n = 28 and NCAD, n = 12, respectively) during elective cardiac surgery. Coronary angiography was performed to identify CAD presence. Serum omentin-1 and adiponectin levels were measured by ELISA. mRNA expression of omentin-1 and adiponectin was detected in adipose tissue by quantitative real-time PCR, and omentin-1 protein expression was evaluated by immunohistochemistry. Correlation and multivariate linear regression analyses were performed to determine the association between omentin-1 expression and clinical risk factors. RESULTS: mRNA and protein expression of omentin-1 were higher in EAT than paired SAT in patients with CAD and NCAD. Compared with NCAD patients, CAD patients had lower omentin-1 and adiponectin mRNA levels in EAT and serum levels as well as lower omentin-1 protein levels. Among patients with CAD, omentin-1 expression was lower in EAT surrounding coronary segments with stenosis than those without stenosis, in terms of mRNA and protein, whereas adiponectin mRNA level in EAT did not seem to differ between stenotic and non-stenotic coronary segments in CAD patients. In multivariate linear regression analysis, CAD was an independent predictor of EAT omentin-1 mRNA expression (beta = -0.57, 95 % CI -0.89 to -0.24; P = 0.001) and serum omentin-1 levels (beta = -0.35, 95 % CI -0.67 to -0.03; P = 0.036). CONCLUSIONS: Circulating and EAT-derived omentin-1 levels were reduced in patients with CAD. Omentin-1 expression in patients with CAD was lower in EAT adjacent to coronary stenotic segments than non-stenotic segments.

Activation of brain indoleamine 2,3-dioxygenase contributes to epilepsy-associated depressive-like behavior in rats with chronic temporal lobe epilepsy.

BACKGROUND: Depression has most often been diagnosed in patients with temporal lobe epilepsy (TLE), but the mechanism underlying this association remains unclear. In this study, we report that indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting enzyme in tryptophan metabolism, plays a key role in epilepsy-associated depressive-like behavior. METHODS: Rats which develop chronic epilepsy following pilocarpine status epilepticus exhibited a set of interictal disorders consistent with depressive-like behavior. Changes of depressive behavior were examined by taste preference test and forced swim test; brain IL-1ß, IL-6 and IDO1 expression were quantified using real-time reverse transcriptase PCR; brain kynurenine/tryptophan and serotonin/tryptophan ratios were analyzed by liquid chromatography-mass spectrometry. Oral gavage of minocycline or subcutaneous injection of 1-methyltryptophan (1-MT) were used to inhibite IDO1 expression. RESULTS: We observed the induction of IL-1ß and IL-6 expression in rats with chronic TLE, which further induced the upregulation of IDO1 expression in the hippocampus. The upregulation of IDO1 subsequently increased the kynurenine/tryptophan ratio and decreased the serotonin/tryptophan ratio in the hippocampus, which contributed to epilepsy-associated depressive-like behavior. The blockade of IDO1 activation prevented the development of depressive-like behavior but failed to influence spontaneous seizures. This effect was achieved either indirectly, through the anti-inflammatory tetracycline derivative minocycline, or directly, through the IDO antagonist 1-MT, which normalizes kynurenine/tryptophan and serotonin/tryptophan ratios. CONCLUSION: Brain IDO1 activity plays a key role in epileptic rats with epilepsy-associated depressive-like behavior.

High-efficiency inverted polymer solar cells controlled by the thickness of polyethylenimine ethoxylated (PEIE) interfacial layers.

In this work, we investigate the effect of the thickness of the polyethylenimine ethoxylated (PEIE) interface layer on the performance of two types of polymer solar cells based on inverted poly(3-hexylthiophene) (P3HT):phenyl C61-butryric acid methyl ester (PCBM) and thieno[3,4-b]thiophene/benzodithiophene (PTB7):[6,6]-phenyl C71-butyric acid methyl ester (PC71BM). Maximum power conversion efficiencies of 4.18% and 7.40% were achieved at a 5.02 nm thick PEIE interface layer, for the above-mentioned solar cell types, respectively. The optimized PEIE layer provides a strong enough dipole for the best charge collection while maintaining charge tunneling ability. Optical transmittance and atomic force microscopy measurements indicate that all PEIE films have the same high transmittance and smooth surface morphology, ruling out the influence of the PEIE layer on these two parameters. The measured external quantum efficiencies for the devices with thick PEIE layers are quite similar to those of the optimized devices, indicating the poor charge collection ability of thick PEIE layers. The relatively low performance of devices with a PEIE layer of thickness less than 5 nm is the result of a weak dipole and partial coverage of the PEIE layer on ITO.

Exogenous spermine pretreatment confers tolerance to combined high-temperature and drought stress in vitro in trifoliate orange seedlings via modulation of antioxidative capacity and expression of stress-related genes.

Spermine (Spm) is thought to play an important role in drought or high-temperature (HT) tolerance. However, it is not clear whether Spm confers similar resistance in the presence of both drought and HT, which often occur simultaneously. In the present study, the trifoliate orange (Poncirus trifoliata (L.) Raf.) seedlings were pretreated with 1 mmol L-1 Spm to evaluate their tolerance to combined drought and HT (45 ºC) stress. Spm-pretreated seedlings showed less leaf wilting, less water loss and less electrolyte leakage than control leaves not treated with Spm within 180 min of treatment. Histochemical staining with diaminobenzidine and nitro blue tetrazolium showed that Spm-pretreated seedlings accumulated less hydrogen peroxide and superoxide than those of control plants 60, 120 and 180 min after treatment when exposed to both drought and HT (45 ºC). However, superoxide dismutase, peroxidase and catalase were significantly more active in Spm-pretreated seedlings than in control seedlings. In addition, Spm-pretreated seedlings showed significantly higher expression of heat shock proteins, abscisic acid (ABA)-responsive element binding factor and 9-cis-epoxycarotenoid dioxygenase 3 than controls either before (0 min) or after (60, 120 and 180 min) combined drought and HT treatment. All of these data suggest that exogenous Spm pretreatment confers tolerance to simultaneously occurring drought and HT stresses. Spm may influence this by activating antioxidant enzymes, increasing the effectiveness of scavenging of reactive oxygen species. It may also increase the expression levels of stress-related genes that protect trifoliate orange seedlings from stress damage.

Interactions of Cellular Energetic Gene Clusters in the Alzheimer's Mouse Brain.

Alzheimer's disease (AD) is the most common cause of dementia in the aging population. The pathological characteristics include extracellular senile plaques and intracellular neurofibrillary tangles. In addition, mitochondrial dysfunction, oxidative stress, and neuroinflammation contribute to AD pathogenesis. In this study, we sought to determine the crosstalk between different pathways in the brain of 5XFAD mice, a mouse model for amyloid pathology, by RNA-seq analysis. We observed significant changes in the expression of genes (1288 genes; adj p value < 0.05; log2-fold > 1 and < 1) related to pathways including oxidation-reduction, oxidative phosphorylation, innate immune response, ribosomal protein synthesis, and ubiquitin proteosome system. The most striking feature was the downregulation of genes related to oxidation-reduction process with changes in the expression of a large number of mitochondrial genes. We also observed an upregulation of several immune response genes. Gene interaction network of oxidation-reduction related genes further confirmed a tight cluster of mitochondrial genes. Furthermore, gene interaction analysis of all the 1288 genes showed at least three distinct interaction clusters, with the predominant one relating to cellular energetics. In summary, we identified 1288 genes distinctly different in the 5XFAD brain compared to the WT brain and found cellular energetics to be the most distinct gene cluster in the AD mouse brain.

A meta-analysis of the changes in the Gut microbiota in patients with intractable epilepsy compared to healthy controls.

OBJECTIVE: To explore gut microbiota changes in intractable epilepsy patients compared to healthy control individuals through meta-analysis. METHODS: PubMed, Web of Science, CNKI, Wanfang, medRxiv, bioRxiv, ilae.org, clinical trial databases, and papers from the International Epilepsy Congress (IEC) were searched, and the literature on the correlation between intractable epilepsy and the gut microbiota reported from database establishment to June 2023 was included. Literature meeting the inclusion criteria was screened, and meta-analysis of the included literature was performed using RevMan5.4 software. RESULTS: Ten case-control studies were included in the meta-analysis. There were 183 patients with intractable epilepsy and 283 healthy control subjects. The analysis results indicated that Bacteroidetes (MD = -0.64, 95 %-CI = -1.21 to -0.06) and Ruminococcaceae (MD = -1.44, 95 % CI = -1.96 to -0.92) were less abundant in the patients with intractable epilepsy than in the normal population. Proteobacteria (MD = 0.53, 95 % CI = 0.02 to 1.05) and Verrucomicrobia (MD = 0.26, 95 % CI = 0.06 to 0.45) were more abundant in the patients with intractable epilepsy than in the normal population. CONCLUSION: This meta-analysis indicated that the abundances of Bacteroidetes and Ruminococcaceae were reduced while those of Proteobacteria and Verrucomicrobia were significantly increased in patients with intractable epilepsy. The above changes in these four taxa of the gut microbiota may have been induced by intractable epilepsy, which may increase the risk of seizures. Their roles in the pathogenesis of intractable epilepsy need to be further explored, and related factors that influence microbiota changes should be considered in future studies.

Interleukin-12p35 deletion promotes CD4 T-cell-dependent macrophage differentiation and enhances angiotensin II-Induced cardiac fibrosis.

OBJECTIVE: Interleukin-12 is essential for the differentiation of naïve T cells into interferon-γ-producing T cells, which regulate inflammatory responses. We investigated this process of regulating hypertension-induced cardiac fibrosis. METHODS AND RESULTS: Mice infused with angiotensin II showed a marked increase in interleukin-12p35 expression in cardiac macrophages. The degree of cardiac fibrosis was significantly enhanced in interleukin-12p35 knockout (p35-KO) mice compared with wild-type (WT) littermates in response to angiotensin II. Fibrotic hearts of p35-KO mice showed increased accumulation of alternatively activated (M2) macrophages and expression of M2 genes such as Arg-1 and Fizz1. Bone marrow-derived macrophages from WT or p35-KO mice did not differ in differentiation in response to angiotensin II treatment; however, in the presence of CD4(+) T cells, macrophages from p35-KO mice differentiated into M2 macrophages and showed elevated expression of transforming growth factor-ß. Moreover, CD4(+) T-cell-treated p35-KO macrophages could stimulate cardiac fibroblasts to differentiate into α-smooth muscle actin-positive and collagen I-positive myofibroblasts in 3-dimensional nanofiber gels. Neutralizing antibodies against transforming growth factor-ß inhibited myofibroblast formation induced by M2 macrophages. CONCLUSIONS: Deficiency in interleukin-12p35 regulates angiotensin II-induced cardiac fibrosis by promoting CD4(+) T-cell-dependent differentiation of M2 macrophages and production of transforming growth factor-ß.

[Study on inhibitory effect of combined administration of bear bile powder and cyclophosphamide on colorectal cancer liver metastasis by regulating tumor microenvironment].

OBJECTIVE: To explore the inhibitory effect of combined administration of bear bile powder (BBP) and cyclophosphamide (Cytoxan, CTX) on colorectal cancer liver metastasis by regulating tumor promotion inflammation microenvironment. METHOD: The CRC liver metastasis mode in mice was established through in situ spleenic injection of SL4 tumor cells into spleens. The mice were randomly divided into 5 groups: the model group, the CTX (80 mg x kg(-1)) treatment group, the CTX + BBP high dose (300 mg x kg(-1)) group, the CTX + BBP middle dose (150 mg x kg(-1)) group and the CTX + BBP low dose (75 mg x kg(-1)) group. Mice were orally administered with drugs for 12 days, and sacrificed on the 13'h day for weighing their spleens and lives, HE staining, and immunofluorescence analysis. Their peripheral blood, and metastatic tumor in spleens and lives were analyzed with flow cytometry. RESULT: Spleen and liver weights of the: CTX treatment group and other doses groups were significantly lower than that of the model group. HE staining and immunofluorescence analysis showed that lymphocyte infiltration was detected in normal tissues, and macrophages infiltration was observed around the tumor tissues. Flow cytometry analysis showed that the number of T-lymphocytes in peripheral blood of different doses groups were much higher than that of the CTX treatment group (P < 0.05), with the rise in the ratio of CD4/CD8; the total number of lymphocytes in spleen cell suspension increased in different doses groups, compared to the CTX treatment group, with notable increase in B cells (P < 0.05) and significant decrease in CD11b, F4/80 cells (P < 0.05). The combined treatment showed less monocyte macrophages in liver metastasis than that of the CTX treatment group. CONCLUSION: The combined treatment of bear bile powder and cyclophosphamide has the effect in not only protecting liver and increase immunity, but also in anti-inflammation and antitumor by regulating tumor microenvironment and reducing the collection of mononuclear macrophages. Particularly, the combined administration of low dose of bear bile powder and CTX shows the most significant effect in reducing inflammatory cell infiltration.