Effectiveness of inactivated influenza vaccine against laboratory-confirmed influenza among Chinese elderly: a test-negative design.

BACKGROUND: Evidence on the effectiveness of influenza vaccination in the elderly is limited, and results are controversial. There are also few reports from China. METHODS: We conducted a test-negative case-control study design to estimate influenza vaccine effectiveness (VE) against laboratory-confirmed influenza-associated visits among elderly (aged ≥ 60 years) across four influenza seasons in Ningbo, China, from 2018 to 19 to 2021-22. Influenza-positive cases and negative controls were randomly matched in a 1:1 ratio according to age, sex, hospital, and date of influenza testing. We used logistic regression models to compare vaccination odds ratios (ORs) in cases to controls. We calculated the VE as [100% × (1-adjusted OR)] and calculated the 95% confidence interval (CI) around the estimate. RESULTS: A total of 30,630 elderly patients tested for influenza with virus nucleic acid or antigen during the study period. After exclusions, we included 1 825 influenza-positive cases and 1 825 influenza-negative controls. Overall, the adjusted VE for influenza-related visits was 63.5% (95% CI, 56.3-69.5%), but varied by season. Influenza VE was 59.8% (95% CI, 51.5-66.7%) for influenza A and 89.6% (95% CI, 77.1-95.3%) for influenza B. The VE for ages 60-69 and 70-79 was 65.2% (95% CI, 55.4-72.9%) and 69.8% (95% CI, 58.7-77.9%), respectively, but only 45.4% (95% CI, 6.2-68.2%) for ages 80 and over. CONCLUSIONS: Standard-dose inactivated influenza vaccine has shown good protection in the elderly in China. However, protection may not be satisfactory in people aged 80 years and older.

Galectin-3 impairs calcium transients and ß-cell function.

In diabetes, macrophages and inflammation are increased in the islets, along with ß-cell dysfunction. Here, we demonstrate that galectin-3 (Gal3), mainly produced and secreted by macrophages, is elevated in islets from both high-fat diet (HFD)-fed and diabetic db/db mice. Gal3 acutely reduces glucose-stimulated insulin secretion (GSIS) in ß-cell lines and primary islets in mice and humans. Importantly, Gal3 binds to calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and inhibits calcium influx via the cytomembrane and subsequent GSIS. ß-Cell CACNG1 deficiency phenocopies Gal3 treatment. Inhibition of Gal3 through either genetic or pharmacologic loss of function improves GSIS and glucose homeostasis in both HFD-fed and db/db mice. All animal findings are applicable to male mice. Here we show a role of Gal3 in pancreatic ß-cell dysfunction, and Gal3 could be a therapeutic target for the treatment of type 2 diabetes.

Incidence, risk factors, and outcomes of acute liver injury in hospitalized adults with acute kidney injury: a large multicenter study.

BACKGROUND: Acute kidney injury (AKI) and acute liver injury (ALI) were associated with poor outcomes during hospitalization, respectively. However, the clinical outcome of AKI combined with ALI (AKI-ALI) remains unknown. The current study aimed to describe AKI-ALI's incidences, risk factors, and outcomes. METHODS: The study population included patients aged 18-99 years with enough serum creatinine and liver testing hospitalized at 19 medical centers throughout China between 2000 and 2021. AKI was defined by Kidney Disease Improving Global Outcomes and ALI was defined by the change of liver enzymes based on Asia Pacific Association of Study of Liver consensus guidelines. Cox proportional hazard model was used to identify risk factors for AKI-ALI, and a time-dependent Cox proportional hazard regression model was used to estimate the association between AKI-ALI and in-hospital mortality. RESULTS: Among the 18,461 patients with AKI, 1689 (9.1%) combined with ALI. Male patients or those who have used nonsteroidal anti-inflammatory drugs or vasopressors, and who have heart failure or shock, with higher AST or GGT values, were associated with an increased risk of AKI-ALI. Compared with AKI-nonALI, patients with AKI-ALI were at higher risk of in-hospitalized mortality (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.54, 2.00). In addition, a stronger association between AKI-ALI and in-hospital mortality was found in those with lower AKI grades (p for interaction = 0.037). CONCLUSIONS: ALI was not uncommon among patients with AKI, especially in patients who used vasopressors and had shock. This study highlights the association between AKI-ALI and a significantly increased risk of mortality. It suggests that dynamic monitoring of liver function is essential, particularly in patients with AST and GGT exceeding the normal upper limit, to improve the in-hospital prognosis of AKI patients.

The study of female college students' consumer psychology mechanism toward male celebrity endorsed products: Tempted or coerced?

The trend of male celebrities endorsing female products is increasing. However, research is lacking on whether this influence is due to the positive emotions generated by the male celebrity's attractiveness or the peer pressure due to mass purchases by the celebrity's fans, and how these effects differ across products with different attributes. This study aims to fill the gap in the existing literature by investigating the influence of male endorsers on female consumers purchase intention, and to deepen the understanding of the mechanisms by which attractiveness and conformity jointly influence purchase decisions. This study used a mixed-design text experiment to investigate the impact of male endorsers' attractiveness and conformity on female college students' positive product attitude and purchase intention for gender-neutral product, female skincare product, and female intimate product, based on the Theory of Planned Behaviour (TPB). The data collected from 456 female college students were analyzed using bootstrap analysis. The study found that both male endorsers' attractiveness and conformity can enhance female college students' positive product attitude and promote their purchase intention for gender-neutral product. However, for female skincare product, male endorsers' attractiveness affects their positive product attitude and purchase intention. Nevertheless, when conformity was present, attractiveness no longer had an effect. Furthermore, for individuals with high levels of loneliness, attractiveness had a detrimental effect on their positive product attitude. On the other hand, conformity had a positive effect by promoting positive product attitude and increasing purchase intention. For female's intimate product, attractiveness did not affect positive product attitude and purchase intention, but the positive effect of conformity remained significant, and both relationships were not moderated by loneliness. It enhances our comprehension of the intricate dynamics underlying the influence of male celebrity endorsements on consumer purchasing decisions, and also offers theoretical justification for the selection of male endorsers for diverse female product.

Repeated vaccination does not appear to significantly weaken the protective effect of influenza vaccine in the elderly: A test-negative case-control study in China.

BACKGROUND: The impact of repeated influenza vaccination on vaccine effectiveness has been a topic of debate. Conducting more multinational, multicenter studies in different influenza seasons is crucial for a better understanding of this issue. There is a lack of comprehensive related research reports in China. METHODS: Using the Regional Health Information Platform, we conducted a test-negative case-control study to evaluate the impact of repeated vaccination on the prevention of laboratory-confirmed influenza in individuals aged 60 and above in Ningbo during four influenza seasons from 2018-19 to 2021-22. Influenza-positive cases and negative controls were matched in a 1:1 ratio based on the visiting hospital and the date of influenza testing. Propensity score adjustment and multivariable logistic regression were used to estimate risk and address confounding effects. RESULTS: During the study period, a total of 30,630 elderly patients underwent influenza virus nucleic acid or antigen testing. After exclusions, we included 1976 cases of influenza-positive and 1976 cases of influenza-negative controls. Multivariable logistic regression analysis revealed that individuals receiving the vaccine in two consecutive seasons did not exhibit a significantly increased risk of influenza illness compared to those receiving the vaccine only in the current season (adjusted odds ratio: 1.22, 95% confidence interval: 0.94-1.58). However, the risk of influenza illness was found to be elevated in individuals who received the vaccine only in the previous season (adjusted odds ratio: 1.56, 95% confidence interval: 1.15-2.10) and even further elevated in those who had not received the vaccine in either of the consecutive two seasons (adjusted odds ratio: 3.39, 95% confidence interval: 2.80-4.09). CONCLUSIONS: Regardless of the vaccination history in the previous season, receiving the current season influenza vaccine is the best choice for the elderly population. Our study supports the initiative to vaccinate elderly individuals against influenza annually.

Identification of naphthalimide-derivatives as novel PBD-targeted polo-like kinase 1 inhibitors with efficacy in drug-resistant lung cancer cells.

Targeting polo-box domain (PBD) small molecule for polo-like kinase 1 (PLK1) inhibition is a viable alternative to target kinase domain (KD), which could avoid pan-selectivity and dose-limiting toxicity of ATP-competitive inhibitors. However, their efficacy in these settings is still low and inaccessible to clinical requirement. Herein, we utilized a structure-based high-throughput virtual screen to find novel chemical scaffold capable of inhibiting PLK1 via targeting PBD and identified an initial hit molecule compound 1a. Based on the lead compound 1a, a structural optimization approach was carried out and several series of derivatives with naphthalimide structural motif were synthesized. Compound 4Bb was identified as a new potent PLK1 inhibitor with a KD value of 0.29 µM. 4Bb could target PLK1 PBD to inhibit PLK1 activity and subsequently suppress the interaction of PLK1 with protein regulator of cytokinesis 1 (PRC1), finally leading to mitotic catastrophe in drug-resistant lung cancer cells. Furthermore, 4Bb could undergo nucleophilic substitution with the thiol group of glutathione (GSH) to disturb the redox homeostasis through exhausting GSH. By regulating cell cycle machinery and increasing cellular oxidative stress, 4Bb exhibited potent cytotoxicity to multiple cancer cells and drug-resistant cancer cells. Subcutaneous and oral administration of 4Bb could effectively inhibit the growth of drug-resistant tumors in vivo, doubling the survival time of tumor bearing mice without side effects in normal tissues. Thus, our study offers an orally-available, structurally-novel PLK1 inhibitor for drug-resistant lung cancer therapy.

The Effect of Steroid Intervention before Vitrectomy for Rhegmatogenous Retinal Detachment Associated with Choroidal Detachment: A Meta-Analysis and Systematic Review.

PURPOSE: This meta-analysis discusses the effectiveness of steroid intervention before vitrectomy in patients with rhegmatogenous retinal detachment associated with choroidal detachment. METHODS: We searched PubMed, MEDLINE, EMBASE, and the Cochrane Library for randomized controlled trials and observational studies published until August 2023. We included studies involving: patients with rhegmatogenous retinal detachment associated with choroidal detachment with proliferative vitreoretinopathy; an experimental group that was not administered steroids and a control group that was administered steroids; and assessment of visual acuity, retinal reattachment rate, and complications. The heterogeneity, publication bias, and sensitivity analysis were performed to ensure the statistical power and reliability of the analysis. RESULTS: Two randomized controlled trials and four case-control studies involving 490 eyes were included in the meta-analysis. There were no significant differences in the primary and final retinal reattachment rates after surgery between the steroid and non-steroid groups (primary retinal reattachment rate: odds ratio = 1.01, 95% confidence interval = 0.63-1.63, p = .41; final retinal reattachment rate: odds ratio = 0.82, 95% confidence interval = 0.43-1.59, p = .33). There was no statistically significant difference in postoperative visual acuity improvement between the two groups (odds ratio = 1.19, confidence interval = 0.63-2.25, p = .69). In addition, subgroup analyses of different types of steroids showed that systemic and local administration of steroids had similar results for retinal reattachment rate and visual acuity improvement. CONCLUSION: Patients with rhegmatogenous retinal detachment associated with choroidal detachment who did not receive preoperative steroids achieved the same effect as patients with rhegmatogenous retinal detachment associated with choroidal detachment who did receive preoperative steroids in terms of retinal reattachment rate and visual acuity. It is recommended that patients with rhegmatogenous retinal detachment associated with choroidal detachment undergo surgery as promptly as possible.

Smart Energy Storage: W18O49 NW/Ti3C2Tx Composite-Enabled All Solid State Flexible Electrochromic Supercapacitors.

Developing a highly efficient electrochromic energy storage device with sufficient color fluctuation and significant electrochemical performance is highly desirable for practical energy-saving applications. Here, to achieve a highly stable material with a large electrochemical storage capacity, a W18O49 NW/Ti3C2Tx composite has been fabricated and deposited on a pre-assembled Ag and W18O49 NW conductive network by Langmuir-Blodgett technique. The resulting hybrid electrode composed of 15 layers of W18O49 NW/Ti3C2Tx composite exhibits an areal capacitance of 125 mF cm-2, with a fast and reversible switching response. An optical modulation of 98.2% can be maintained at a current density of 5 mA cm-2. Using this electrode, a bifunctional symmetric electrochromic supercapacitor device having an energy density of 10.26 µWh cm-2 and a power density of 0.605 mW cm-2 is fabricated, with high capacity retention and full columbic efficiency over 4000 charge-discharge cycles. Meanwhile, the device displays remarkable electrochromic characteristics, including fast switching time (5 s for coloring and 7 s for bleaching), and a significant coloration efficiency of 116 cm2 C-1 with good optical modulation stability. In addition, the device exhibits significant mechanical flexibility and fast switching while being stable over 100 bending cycles, which is promising for real-world applications.

The GPR40 novel agonist SZZ15-11 improves non-alcoholic fatty liver disease by activating the AMPK pathway and restores metabolic homeostasis in diet-induced obese mice.

AIM: Non-alcoholic fatty liver is the most common cause of chronic liver disease. GPR40 is a potential therapeutic target for energy metabolic disorders. GPR40 is a potential therapeutic target for energy metabolic disorders. SZZ15-11 is a newly synthesized GPR40 agonist. In this study, we estimate the potency of SZZ15-11 in fatty liver treatment. METHODS: In vivo, diet-induced obese (DIO) mice received SZZ15-11 (50 mg/kg) and TAK875 (50 mg/kg) for 6 weeks. Blood glucose and lipid, hepatocyte lipid and liver morphology were analysed. In vitro, HepG2 cells and GPR40-knockdown HepG2 cells induced with 0.3 mM oleic acid were treated with SZZ15-11. Triglyceride and total cholesterol of cells were measured. At the same time, the AMPK pathway regulating triglycerides and cholesterol esters synthesis was investigated via western blot and quantitative polymerase chain reaction in both liver tissue and HepG2 cells. RESULTS: SZZ15-11 was found to not only attenuate hyperglycaemia and hyperlipidaemia but also ameliorate fatty liver disease in DIO mice. At the same time, SZZ15-11 decreased triglyceride and total cholesterol content in HepG2 cells. Whether examined in the liver of DIO mice or in HepG2 cells, SZZ15-11 upregulated AMPKα phosphorylation and then downregulated the expression of the cholesterogenic key enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibited acetyl-CoA carboxylase activity. Furthermore, SZZ15-11 promotes AMPK activity via [cAMP]i accumulation. CONCLUSION: This study confirmed that SZZ15-11, a novel GPR40 agonist, improves hyperlipidaemia and fatty liver, partially via Gs signalling and the AMPK pathway in hepatocytes.

Lotus Leaf Extract Alleviates Lipopolysaccharide-Induced Intestinal Injury in Mice by Regulating Oxidative Stress and Inflammation.

Inflammatory bowel disease, a disease featured by intestinal epithelial barrier destruction and dysfunction, has been a constant threat to animal health. The primary objective of this research was to assess the impact of the extract derived from lotus leaves (LLE) on lipopolysaccharide (LPS) induced damage to the intestines in mice, as well as to investigate the fundamental mechanism involved. The LLE was prepared using ultrasonic extraction in this experiment, and the LLE total flavonoid content was 117.02 ± 10.73 mg/g. The LLE had strong antioxidant activity in vitro, as assessed by 2, 2-diphenyl-1-picrylhydrazyl, ferric reducing antioxidant power, and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) methods. In the vivo experiment, different doses of LLE (50, 100, and 200 mg/kg) were administered for 2 weeks before LPS treatment in mice. The results revealed that LLE alleviates intestinal tissue damage in LPS-induced mice. In the jejunum tissue, LLE significantly upregulated mRNA and protein expression levels of tight junction proteins, such as ZO-1, occludin, and claudin-1, and decreased the contents of the inflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α. Furthermore, the malondialdehyde and lactate dehydrogenase contents increased by LPS in the liver were significantly reduced after administration of LLE, and the total antioxidant capacity, superoxide dismutase, and reduced glutathione decreased by LPS were remarkably increased by LLE. It was found that LLE could relieve LPS-induced oxidative stress by upregulating mRNA and protein expression of Nrf2 and HO-1 in jejunum tissue. In conclusion, LLE alleviates LPS-induced intestinal damage through regulation of the Nrf2/HO-1 signal pathway to alleviate oxidative stress, reducing inflammatory factors and increasing the expression of tight junction proteins in mice.

Trimethylamine N-oxide impairs ß-cell function and glucose tolerance.

ß-Cell dysfunction and ß-cell loss are hallmarks of type 2 diabetes (T2D). Here, we found that trimethylamine N-oxide (TMAO) at a similar concentration to that found in diabetes could directly decrease glucose-stimulated insulin secretion (GSIS) in MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels impairs GSIS, ß-cell proportion, and glucose tolerance in male C57BL/6 J mice. TMAO inhibits calcium transients through NLRP3 inflammasome-related cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on ß-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes ß-cell ER stress, dedifferentiation, and apoptosis and inhibits ß-cell transcriptional identity. Inhibition of TMAO production improves ß-cell GSIS, ß-cell proportion, and glucose tolerance in both male db/db and choline diet-fed mice. These observations identify a role for TMAO in ß-cell dysfunction and maintenance, and inhibition of TMAO could be an approach for the treatment of T2D.

The relationship between maternal exposure to ambient air pollutants and premature rupture of membranes: A systematic review and meta-analysis.

Air pollution is an environmental stimulus that may predispose pregnant women to preterm rapture of membrane (PROM). However, the relationship of maternal exposure to air pollutants and PROM is still unclear. To investigate the relationship between the long-term and short-term maternal exposure to air pollution and PROM. We searched all studies published in PubMed, Embase and Web of Science up to February 2024. The studies provided quantitative effect estimates with 95% confidence intervals, for the impact of short-term (<30 days) or long-term (≥30 days) maternal exposure to air pollutants on PROM, preterm PROM (PPROM) or term PROM (TPROM). The odds ratio (OR), risk ratio (RR), or hazard ratio (HR), with 95% confidence intervals was extracted, and RR or HR were deemed as OR because of the low prevalence of PROM. Fixed- or random-effects meta-analyses performed. In total, 17 relevant studies were included. Maternal exposure to PM2.5 in the second trimester increases the risk of PROM (pooled OR = 1.15, 95%CI: 1.05-1.26). Maternal exposure to PM10, NO2, NO, CO and SO2 during pregnancy and short-term maternal exposure to PM2.5, NO2, SO2 and O3 also associate with PROM occurrence. The results of the study show that both long-term maternal exposure in the second or third trimester and short-term maternal exposure to ambient air pollution can increase the risk of PROM.

Sonic hedgehog-heat shock protein 90ß axis promotes the development of nonalcoholic steatohepatitis in mice.

Sonic hedgehog (SHH) and heat shock protein 90ß (HSP90ß) have been implicated in nonalcoholic steatohepatitis (NASH) but their molecular mechanisms of action remain elusive. We find that HSP90ß is a key SHH downstream molecule for promoting NASH process. In hepatocytes, SHH reduces HSP90ß ubiquitylation through deubiquitylase USP31, thus preventing HSP90ß degradation and promoting hepatic lipid synthesis. HSP90ß significantly increases in NASH mouse model, leading to secretion of exosomes enriched with miR-28-5p. miR-28-5p directly targetes and decreases Rap1b levels, which in turn promotes NF-κB transcriptional activity in macrophages and stimulates the expression of inflammatory factors. Genetic deletion, pharmacological inhibition of the SHH-HSP90ß axis, or delivery of miR-28-5p to macrophages in the male mice liver, impairs NASH symptomatic development. Importantly, there is a markedly higher abundance of miR-28-5p in NASH patient sera. Taken together, the SHH-HSP90ß-miR-28-5p axis offers promising therapeutic targets against NASH, and serum miR-28-5p may serve as a NASH diagnostic biomarker.

Modulation of Acute Intestinal Inflammation by Dandelion Polysaccharides: An In-Depth Analysis of Antioxidative, Anti-Inflammatory Effects and Gut Microbiota Regulation.

Acute colitis is a complex disease that can lead to dysregulation of the gut flora, inducing more complex parenteral diseases. Dandelion polysaccharides (DPSs) may have potential preventive and therapeutic effects on enteritis. In this study, LPS was used to induce enteritis and VC was used as a positive drug control to explore the preventive and therapeutic effects of DPS on enteritis. The results showed that DPS could repair the intestinal barrier, down-regulate the expression of TNF-α, IL-6, IL-1ß, and other pro-inflammatory factors, up-regulate the expression of IL-22 anti-inflammatory factor, improve the antioxidant capacity of the body, and improve the structure of intestinal flora. It is proved that DPS can effectively prevent and treat LPS-induced acute enteritis and play a positive role in promoting intestinal health.

Clock knockout in inhibitory neurons reduces predisposition to epilepsy and influences anxiety-like behaviors in mice.

Epilepsy is a brain disorder affecting up to 1 in 26 individuals. Despite its clinical importance, the molecular mechanisms of epileptogenesis are still far from clarified. Our previous study showed that disruption of Clock in excitatory neurons alters cortical circuits and leads to generation of focal epilepsy. In this study, a GAD-Cre;Clockflox/flox mouse line with conditional Clock gene knockout in inhibitory neurons was established. We observed that seizure latency was prolonged, the severity and mortality of pilocarpine-induced seizure were significantly reduced, and memory was improved in GAD-Cre;Clockflox/flox mice. We hypothesize that mice with CLOCK knockout in inhibitory neurons have increased threshold for seizure, opposite from mice with CLOCK knockout in excitatory neurons. Further investigation showed Clock knockout in inhibitory neurons upregulated the basal protein level of ARC, a synaptic plasticity-associated immediate-early gene product, likely through the BDNF-ERK pathway. Altered basal levels of ARC may play an important role in epileptogenesis after Clock deletion in inhibitory neurons. Although sEPSCs and intrinsic properties of layer 5 pyramidal neurons in the somatosensory cortex exhibit no changes, the spine density increased in apical dendrite of pyramidal neurons in CLOCK knockout group. Our results suggest an underlying mechanism by which the circadian protein CLOCK in inhibitory neurons participates in neuronal activity and regulates the predisposition to epilepsy.

Dl-3-n-Butylphthalide Alleviates Secondary Brain Damage and Improves Working Memory After Stroke in Cynomolgus Monkeys.

BACKGROUND: Remote secondary neurodegeneration is associated with poststroke cognitive impairment (PSCI). Dl-3-n-butylphthalide (NBP) improves PSCI clinically. However, whether it ameliorates PSCI by alleviating secondary neurodegeneration remains uncertain. Nonhuman primates provide more relevant models than rodents for human stroke and PSCI. This study investigated the effects of NBP on PSCI and secondary neurodegeneration in cynomolgus monkeys after permanent left middle cerebral artery occlusion (MCAO). METHODS: Thirteen adult male cynomolgus monkeys were randomly assigned to sham (n=4), MCAO+placebo (n=5), and MCAO+NBP groups (n=4). The MCAO+placebo and MCAO+NBP groups received saline and NBP injections intravenously, respectively, starting at 6-hour postsurgery for 2 weeks, followed by soybean oil and NBP orally, respectively, for 10 weeks after MCAO. Infarct size was assessed at week 4 by magnetic resonance imaging. Working memory and executive function were evaluated dynamically using the delayed response task and object retrieval detour task, respectively. Neuron loss, glia proliferation, and neuroinflammation in the ipsilateral dorsal lateral prefrontal cortex, thalamus, and hippocampus were analyzed by immunostaining 12 weeks after MCAO. RESULTS: Infarcts were located in the left middle cerebral artery region, apart from the ipsilateral dorsal lateral prefrontal cortex, thalamus, or hippocampus, with no significant difference between the MCAO+placebo and MCAO+NBP group. Higher success in delayed response task was achieved at weeks 4, 8, and 12 after NBP compared with placebo treatments (P<0.05), but not in the object retrieval detour task (all P>0.05). More neurons and less microglia, astrocytes, CD68-positive microglia, tumor necrosis factor-α, and inducible NO synthase were observed in the ipsilateral dorsal lateral prefrontal cortex and thalamus after 12 weeks of NBP treatment (P<0.05), but not in the hippocampus (P>0.05). CONCLUSIONS: Our findings indicate that NBP improves working memory by alleviating remote secondary neurodegeneration and neuroinflammation in the ipsilateral dorsal lateral prefrontal cortex and thalamus after MCAO in cynomolgus monkeys.

Targeting IL-17A enhances imatinib efficacy in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia.

Dysregulated hematopoietic niches remodeled by leukemia cells lead to imbalances in immunological mediators that support leukemogenesis and drug resistance. Targeting immune niches may ameliorate disease progression and tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive B-ALL (Ph+ B-ALL). Here, we show that T helper type 17 (Th17) cells and IL-17A expression are distinctively elevated in Ph+ B-ALL patients. IL-17A promotes the progression of Ph+ B-ALL. Mechanistically, IL-17A activates BCR-ABL, IL6/JAK/STAT3, and NF-kB signalling pathways in Ph+ B-ALL cells, resulting in robust cell proliferation and survival. In addition, IL-17A-activated Ph+ B-ALL cells secrete the chemokine CXCL16, which in turn promotes Th17 differentiation, attracts Th17 cells and forms a positive feedback loop supporting leukemia progression. These data demonstrate an involvement of Th17 cells in Ph+ B-ALL progression and suggest potential therapeutic options for Ph+ B-ALL with Th17-enriched niches.

Physiological-biochemical responses and transcriptomic analysis reveal the effects and mechanisms of sulfamethoxazole on the carbon fixation function of Chlorella pyrenoidosa.

The occurrence of sulfamethoxazole (SMX) is characterized by low concentration and pseudo-persistence. However, the toxic effects and mechanisms of SMX, especially for low concentration and long-term exposure, are still not clear. This study investigated the effects and mechanisms of SMX on carbon fixation-related biological processes of Chlorella pyrenoidosa at population, physiological-biochemical, and transcriptional levels. Results showed that 1-1000 µg/L SMX significantly inhibited the dry weight and carbon fixation rate of C. pyrenoidosa during 21 d. The upregulation of superoxide dismutase (SOD) and catalase (CAT) activities, as well as the accumulation of malondialdehyde (MDA) demonstrated that SMX posed oxidative damage to C. pyrenoidosa. SMX inhibited the activity of carbonic anhydrase (CA), and consequently stimulated the activity of Rubisco. Principal component analysis (PCA) revealed that SMX concentration was positively correlated with Rubisco and CAT while exposure time was negatively correlated with CA. Transcriptional analysis showed that the synthesis of chlorophyll-a was stabilized by regulating the diversion of protoporphyrin IX and the chlorophyll cycle. Meanwhile, multiple CO2 compensation mechanisms, including photorespiratory, C4-like CO2 compensation and purine metabolism pathways were triggered in response to the CO2 requirements of Rubisco. This study provides a scientific basis for the comprehensive assessment of the ecological risk of SMX.

S100A8/A9 promotes endometrial fibrosis via regulating RAGE/JAK2/STAT3 signaling pathway.

Intrauterine adhesion (IUA) is characterized by endometrial fibrosis. S100A8/A9 plays an important role in inflammation and fibroblast activation. However, the role of S100A8/A9 in IUA remains unclear. In this study, we collect normal and IUA endometrium to verify the expression of S100A8/A9. Human endometrial stromal cells (hEnSCs) are isolated to evaluate fibrosis progression after S100A8/A9 treatment. A porcine IUA model is established by electrocautery injury to confirm the therapeutic effect of menstrual blood-derived stromal cells (MenSCs) on IUA. Our study reveals increased S100A8/A9 expression in IUA endometrium. S100A8/A9 significantly enhances hEnSCs proliferation and upregulates fibrosis-related and inflammation-associated markers. Furthermore, S100A8/A9 induces hEnSCs fibrosis through the RAGE-JAK2-STAT3 pathway. Transplantation of MenSCs in a porcine IUA model notably enhances angiogenesis, mitigates endometrial fibrosis and downregulates S100A8/A9 expression. In summary, S100A8/A9 induces hEnSCs fibrosis via the RAGE-JAK2-STAT3 pathway, and MenSCs exhibit marked effects on endometrial restoration in the porcine IUA model.