GRIM19 deficiency aggravates metabolic disorder and ovarian dysfunction in PCOS.

CONTEXT: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. Retinoid-interferon-induced mortality 19 (GRIM19) is a functional component of mitochondrial complex I that plays a role in cellular energy metabolism. However, the role of GRIM19 in the pathogenesis of PCOS is still unclear. OBJECTIVE: To investigate the role of GRIM19 in the pathogenesis of PCOS. DESIGN: We first measured the expression of GRIM19 in human granulosa cells (hGCs) from patients with and without PCOS (n = 16 per group), and then established a PCOS mouse model with WT and Grim19+/- mice for in vivo experiments. Glucose uptake-related genes RAC1 and GLUT4 and energy metabolism levels in KGN cells were examined in vitro by knocking down GRIM19 in the cell lines. Additionally, ovulation-related genes such as p-ERK1/2, HAS2, and PTX3 were also studied to determine their expression levels. RESULTS: GRIM19 expression was reduced in hGCs of PCOS patients, which was negatively correlated with BMI and serum testosterone level. Grim19+/- mice with PCOS exhibited a markedly anovulatory phenotype and disturbed glycolipid metabolism. In vitro experiments, GRIM19 deficiency inhibited the RAC1/GLUT4 pathway, reducing insulin-stimulated glucose uptake in KGN cells. Moreover, GRIM19 deficiency induced mitochondrial dysfunction, defective glucose metabolism, and apoptosis. In addition, GRIM19 deficiency suppressed the expression of ovulation-related genes in KGN cells, which was regulated by dihydrotestosterone mediated androgen receptor. CONCLUSIONS: GRIM19 deficiency may mediate ovulation and glucose metabolism disorders in PCOS patients. Our results suggest that GRIM19 may be a new target for diagnosis and treatment.

N-acetylcysteine alleviated tris(2-chloroisopropyl) phosphate-induced sperm motility decline and functional dysfunction in mice through reversing oxidative stress and DNA damage.

The decline in male fertility caused by environmental pollutants has attracted worldwide attention nowadays. Tris(2-chloroisopropyl) phosphate (TCPP) is a chlorine-containing organophosphorus flame retardant applied in many consumer products and has multiple side effects on health. However, whether TCPP impairs spermatogenesis remains unclear. In this study, we found that TCPP reduced the sperm motility and blastocyst formation, inhibited proliferation and induced apoptosis in mice testes and spermatocyte cell line GC-2. Moreover, TCPP induced imbalance of oxidant and anti-oxidant, DNA damage and mitochondrial dysfunction, thus induced abnormal spermatogenesis. In this process, p53 signaling pathway was activated and N-acetylcysteine treatment partially alleviated the side effects of TCPP, including decrease of sperm motility, activation of p53 signaling pathway and DNA damage. Finally, our study verified that TCPP elevated reactive oxygen species (ROS), decreased mitochondrial membrane potential and induced apoptosis in human semen samples. Overall, ROS mediated TCPP-induced germ cell proliferation inhibition and apoptosis, which finally led to the decline of sperm motility.

Cresyl Diphenyl Phosphate exposure induces reproductive functional defects in men and male mice.

Cresyl Diphenyl Phosphate (CDP), as a novel organophosphate esters (OPEs), achieves widely used and exposed in multiple industries. However, its male reproductive toxicity and underlying mechanism remains unclear. In vivo, male mice were gavaged with CDP (0, 4, 20, or 100 mg/kg/d) for 8 weeks. And we treated TM3, TM4 and GC-2 cells with 0, 10, 25, and 50 µM CDP for 24 h to detect its reproductive toxicity effect in vitro. In our study, we revealed that CDP inhibited proliferation and induced apoptosis in mice testis and GC-2 cells, thereby leading to the decreased sperm quality. In mechanism, CDP trigger the oxidative stress and ROS production, thus partially causing DNA damage and cell apoptosis. Moreover, CDP exposure causes injury to Ledyig cells and Sertoli cells, thus disturbing the testicular microenvironment and inhibiting spermatogonia proliferation. In conclusion, this research reveals multiple adverse impacts of CDP on the male reproductive system and calls for further study of the toxicological effects of CDP on human health.

GRIM-19 deficiency promotes macrophage polarization to the M1 phenotype partly through glycolysis in unexplained recurrent spontaneous abortion†.

The occurrence of unexplained recurrent spontaneous abortion (URSA) is closely related to immune system disorders, however, the underlying mechanisms remain unclear. The purpose of this study was to investigate the expression of GRIM-19 in URSA and the possible pathogenesis of URSA according to macrophage polarization. Here, we showed that GRIM-19 was downregulated in the uterine decidual macrophages of patients with URSA and that GRIM-19 downregulation was accompanied by increased M1 macrophage polarization. Furthermore, the expression levels of glycolytic enzymes were substantially enhanced in the uterine decidual macrophages of URSA patients, and glycolysis in THP-1-derived macrophages was further enhanced by the downregulation of GRIM-19. Additionally, the increase of M1 macrophages resulting from the loss of GRIM-19 was significantly reversed in cells treated with 2-deoxy-D-glucose (2-DG, an inhibitor of glycolysis). To provide more direct evidence, GRIM-19 deficiency was shown to promote macrophage polarization to the M1 phenotype in GRIM-19+/- mouse uteri. Overall, our study provides evidence that GRIM-19 deficiency may play a role in regulating macrophage polarization in URSA, and that glycolysis may participate in this process.

Identification and validation of senescence-related genes in polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is an exceedingly intractable issue affecting female endocrine and reproductive health. However, the etiology and intricate pathological mechanisms of PCOS remain unclear. Nowadays, aging was found to share multiple common pathological mechanisms with PCOS, which causes probing into the pathogenesis of PCOS from senescence. However, no bioinformatics analyses have specifically focused on connection between PCOS and ovarian aging. METHODS: Differentially expressed aging-related genes in PCOS were identified and then analyzed using function enrichment method. Hub genes were determined based on multiple algorithms, and expression validation of hub genes was performed in both datasets and experiments (human granulosa-like tumor cell line, KGN; human Granulosa Cell, hGCs). Finally, a transcription factor-miRNA-gene network of hub genes was constructed. RESULTS: Here, we identified 73 aging-related differential expression genes (ARDEGs) by intersecting DEGs in PCOS and senescence-related gene set. Furthermore, we performed biological functions and potential pathways of ARDEGs and potential hub genes were also screened by multiple algorithms. From the perspective of immune dysfunction, we analyzed the correlation between PCOS and immune cells. Finally, TF-miRNA-gene networks were constructed. Finally, TF-miRNA-gene networks were constructed. CONCLUSIONS: Our work aimed to elucidate the relation between PCOS and cellular senescence based on bioinformatics strategy, deepening the understanding of mechanisms and to seek for novel therapy strategies for improving reproductive lifespan and female health. Exploring the potential molecular mechanism of cell aging in PCOS is expected to bring a new breakthrough for PCOS diagnosis and therapy strategies. And this, might deepen our understanding about intricate mechanisms of ovarian aging.

Colorectal motility patterns and psychiatric traits in functional constipation and constipation-predominant irritable bowel syndrome: A study from China.

BACKGROUND: Functional constipation (FC) and constipation-predominant irritable bowel syndrome (IBS-C) represent a spectrum of constipation disorders. However, the majority of previous clinical investigations have focused on Western populations, with limited data originating from China. AIM: To determine and compare the colorectal motility and psychiatric features of FC and IBS-C in an Eastern Chinese population. METHODS: Consecutive chronic constipation patients referred to our motility clinic from December 2019 to February 2023 were enrolled. FC and IBS-C diagnoses were established using ROME IV criteria, and patients underwent high-resolution anorectal manometry (ARM) and a colonic transmit test using the Sitz marker study. Constipation-related symptoms were obtained through questionnaires. Anxiety and depression were assessed by the Hamilton anxiety rating scale and the Hamilton Depression Rating Scale-21. The clinical characteristics and colorectal motility patterns of FC and IBS-C patients were compared. RESULTS: No significant differences in sex, age or abdominal discomfort symptoms were observed between IBS-C and FC patients (all P > 0.05). The proportion of IBS-C patients with delayed colonic transit was higher than that of patients with FC (36.63% vs 15.91%, P < 0.05), while rectosigmoid accumulation of radiopaque markers was more common in the FC group than in the IBS-C group (50% vs 26.73%, P < 0.05). Diverse proportions of these dyssynergic patterns were noted within both the FC and IBS-C groups by ARM. IBS-C patients were found to have a higher prevalence of depression than FC patients (66.30% vs 42.42%, P < 0.05). The scores for feelings of guilt, suicide, psychomotor agitation, diurnal variation, obsessive/compulsive disorder, hopelessness, self-abasedment and gastrointestinal symptoms were significantly higher in IBS-C patients than that in FC patients (P < 0.05). For IBS-C (χ2 = 5.438, P < 0.05) but not FC, patients with normal colon transit time were significantly more likely to have anxiety than those with slow colon transit time. For IBS-C patients but not FC patients, the threshold of first constant sensation, desire to defecate and sustained urgency were all weakly correlated with the degree of anxiety (r = 0.414, r = 0.404, and r = 0.418, respectively, P < 0.05). The proportion of patients with a low threshold of desire to defecate among IBS-C patients with depression was lower than that in those without depression (69.6% vs 41.9%, χ2 = 4.054, P < 0.05). CONCLUSION: Our findings highlight both overlapping and distinctive patterns of colon transit, dyssynergic patterns, anorectal sensation, psychological distress, and associations of psychiatric and colorectal motility characteristics in FC and IBS-C patients in an Eastern Chinese population, providing valuable insights into the pathophysiological underpinnings of these disorders.

True intratracheal oxygen concentration delivered by SentriO Oxy™ masks under various respiratory conditions: a bench study.

SentriO Oxy™ is a newly available, Food and Drug Administration-approved oxygenation mask system that provides high oxygenation, even on low-flow (5-10 L/min) oxygen. This study aimed to accurately measure the intratracheal fraction of inspired oxygen (FiO2) using SentriO Oxy™ masks under relatively low oxygen flow rates. A manikin-ventilator-test lung simulation system was used. We measured FiO2 at the level of the carina, 5 minutes after applying 45 different respiratory parameter combinations using SentriO Oxy™ masks. Tidal volume (TV) was set to 300, 500, and 700 mL; respiratory rate (RR) was set to 8, 12, 16, 20, and 24 breaths per minute; and oxygen flow rate was set to 6, 8, and 10 L/min. Our hypothesis was that FiO2 would be proportional to the difference between oxygen flow rate and minute ventilation. FiO2 measured by smaller TV, lower RR, or higher oxygen flows revealed a significantly higher value, confirming our hypothesis. In addition, using linear regression analysis, we found that TV, RR, and oxygen flow were all significant factors influencing the measured FiO2. Our experiment proposed two prediction equations considering the oxygen flow rate, TV, and RR. The results of our study may provide information and prediction of FiO2 for clinicians to use SentriO Oxy™ masks during sedative anesthetic procedures under low oxygen flow rates.

Factors affecting do-not-attempt-resuscitation (DNAR) decisions among adult patients in the emergency department of a general tertiary teaching hospital in China: a retrospective observational study.

OBJECTIVE: Do-not-attempt-resuscitation (DNAR) orders are designed to allow patients to opt out of receiving cardiopulmonary resuscitation in the event of a cardiac arrest. While DNAR has become a standard component of medical care, there is limited research available specifically focusing on DNAR orders in the context of emergency departments in China. This study aimed to fill that gap by examining the factors related to DNAR orders among patients in the emergency department of a general tertiary teaching hospital in China. DESIGN: Retrospective observational study. SETTING: Emergency department. PARTICIPANTS: This study and analysis on adult patients with DNAR or no DNAR data between 1 January 2022 and 1 January 2023 in the emergency department of a large academic comprehensive tertiary teaching hospital. A total of 689 were included in our study. PRIMARY OUTCOME MEASURES: Whether the patient received DNAR was our dependent variable. RESULTS: Among the total patients, 365 individuals (53.0%) had DNAR orders. The following variables, including age, sex, age-adjusted Charlson comorbidity index (ACCI), primary diagnosis of cardiogenic or cancer related, history of neurological dysfunction or cancer, were independently associated with the difference between the DNAR group and the no DNAR group. Furthermore, there were significant statistical differences observed in the choice of DNAR among patients with different stages of cancer. CONCLUSIONS: In comparison to the no DNAR group, patients with DNAR were characterised by being older, having a higher proportion of female patients, higher ACCI scores, a lower number of patients with a primary diagnosis of cardiogenic and a higher number of patients with a primary diagnosis of cancer related, history of neurological dysfunction or cancer.

HIF-1α is positively associated with endometrial receptivity by regulating PKM2.

PURPOSE: Numerous advancements have been introduced into the field of assisted reproductive technology (ART) in the past four decades. Nonetheless, implantation failure is still a key limiting step for a successful pregnancy. Building of endometrial receptivity (ER) is essential for successful implantation. However, the fundamental biological processes and mechanisms of ER remain elusive. Our study investigates the function of hypoxia inducible factor-1α (HIF-1α) during ER establishment and shed lights on the novel molecular mechanism by which HIF-1α regulates ER-related gene expression network. METHODS: Levels of HIF-1α, homeobox A10 (HOXA10), insulin-like growth factor-binding protein 1 (IGFBP1), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA) in endometrial tissues were measured via real-time PCR, immunoblotting and immunohistochemistry. The correlation between HIF-1α and HOXA10, IGFBP1, PKM2, LDHA were analyzed separately. Ishikawa cells were treated with vector HIF-1α, HIF-1α-siRNA, and PKM2-siRNA. After transfection, the levels of HOXA10, IGFBP1, LDHA, and PKM2 were measured via real-time PCR and immunoblotting, and the lactate concentrations and cell migration of Ishikawa cells were measured. RESULTS: Levels of HIF-1α, IGFBP1, HOXA10, LDHA, and PKM2 were significantly decreased in recurrent implantation failure (RIF) patients and levels of HOXA10, IGFBP1, PKM2, and LDHA were correlated with HIF-1α in endometrium. Then in a cellular model established by HIF-1α vector and HIF-1α-siRNA, the expression of HOXA10, IGFBP1, LDHA, PKM2, and lactate concentrations were dramatically upregulated and downregulated. And the expression of HOXA10, and IGFBP1 were dramatically decreased by PKM2-siRNA. CONCLUSIONS: HIF-1α plays a crucial role in the building of ER through regulating glycolysis.

Effects of Nintedanib associated with Shenfu Injection on paraquat-induced lung injury in rats / 中华劳动卫生职业病杂志

Objective: To study the effects of Nintedanib associated with Shenfu Injection on lung injury induced by paraquat (PQ) intoxication. Methods: In September 2021, a total of 90 SD rats were divided into 5 groups in random, namely control group, PQ poisoning group, Shenfu Injection group, Nintedanib group and associated group, 18 rats in each group. Normal saline was given by gavage route to rats of control group, 20% PQ (80 mg/kg) was administered by gavage route to rats of other four groups. 6 hours after PQ gavage, Shenfu Injection group (12 ml/kg Shenfu Injection), Nintedanib group (60 mg/kg Nintedanib) and associated group (12 ml/kg Shenfu Injection and 60 mg/kg Nintedanib) were administered with medicine once a day. The levels of serum transforming growth factor beta1 (TGF-β1), interleukin-1 beta (IL-1β) were determined at 1, 3 and 7 d, respectively. The pathological changes of lung tissue, the ratio of wet weight and dry weight (W/D) of lung tissue, the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in lung tissue were observed and determined after 7 d. Western blot was used to analyse the expression levels of fibroblast growth factor receptor 1 (FGFR1), platelet derivation growth factor receptor alpha (PDGFRα), vascular endothelial growth factor receptor 2 (VEGFR2) in lung tissue after 7 d. Results: The levels of TGF-β1, IL-1β in all poisoning groups went up first and then went down. The levels of TGF-β1, IL-1β in associated group at 1, 3, 7 d were lower than that of PQ poisoning group, Shenfu Injection group and Nintedanib group at the same point (P<0.05). Pathological changes of lung tissue under the light microscopes showed that the degrees of hemorrhage, effusion and infiltration of inflammatory cells inside the alveolar space of Shenfu Injection group, Nintedanib group and associated group were milder than that of PQ poisoning group, and the midest in associated group. Compared with control group, the W/D of lung tissue was higher, the level of MDA in lung tissue was higher, while the level of SOD was lower, the expressions of FGFR1, PDGFRα and VEGFR2 in lung tissue were higher in PQ poisoning group (P<0.05). Compared with PQ poisoning group, Shenfu Injection group and Nintedanib group, the W/D of lung tissue was lower, the level of MDA in lung tissue was lower, while the level of SOD was higher, the expressions of FGFR1, PDGFRα and VEGFR2 in lung tissue were lower in associated group (P<0.05) . Conclusion: Nintedanib associated with Shenfu Injection can relieve lung injury of rats induced by PQ, which may be related to Nintedanib associated with Shenfu Injection can inhibit the activation of TGF-β1 and the expressions of FGFR1, PDGFRα, VEGFR2 in lung tissue of rats.

Study on the efficacy and influencing factors of pyrotinib in treatment of patients with human epidermal growth factor receptor 2-positive metastatic breast cancer / 肿瘤研究与临床

Objective:To evaluate the efficacy of oral pyrotinib in treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer in the real world, and to explore its influencing factors.Methods:The clinical data of 148 patients with HER2-positive metastatic breast cancer treated with oral pyrrolitinib in Shanxi Cancer Hospital from September 2018 to December 2020 were retrospectively analyzed. The efficacy was evaluated according to the efficacy evaluation criteria for solid tumors, version 1.1, and the adverse effects were graded according to the National Cancer Institute common terminology criteria of adverse effects, version 4.0. The Kaplan-Meier method was used to draw progression-free survival (PFS) curves, the patients were stratified by different clinical characteristics, and log-rank test was used for univariate analysis of PFS; the multivariate analysis of PFS was performed using Cox proportional hazards model.Results:The objective response rate (ORR) of 148 patients was 71.6% (106/148), and the disease control rate (DCR) was 89.2% (132/148). The overall median PFS time was 11.0 months (95% CI 10.1-11.9 months), and the median PFS of 19 patients with brain metastases was 10.0 months (95% CI 7.4-12.6 months). The differences in PFS between patients stratified by disease-free interval (DFI), the number of metastatic site and Eastern Cooperative Oncology Group (ECOG) score were statistically significant (all P < 0.05), but the difference in PFS between patients with negative and positive hormone receptor was not statistically significant ( P > 0.05). Multivariate Cox regression analysis showed that DFI (>1 year vs. ≤1 year: HR = 5.254, 95% CI 0.728-37.933, P = 0.046) and ECOG score (≥2 points vs. 0-1 point: HR = 2.454, 95% CI 1.261-4.788, P = 0.008) were independent influencing factors of PFS. The most common ≥grade 3 adverse effects were diarrhea (31 cases, 20.9%) and hand-foot syndrome (38 cases, 25.8%). Conclusions:The pyrotinib has definite efficacy and good safety in the treatment of HER2-positive metastatic breast cancer in the real world, especially for patients with DFI > 1 year and ECOG score 0-1 point, the efficacy and safety are particularly good.

Prognostic value of hemoglobin-to-red cell distribution width ratio in patients with cardiopulmonary resuscitation after out-of-hospital cardiac arrest / 中华危重病急救医学

OBJECTIVE@#To investigate the prognostic value of hemoglobin-to-red cell distribution width ratio (HRR) in patients with cardiopulmonary resuscitation (CPR) after out-of-hospital cardiac arrest (OHCA).@*METHODS@#A retrospective study was conducted. Patients aged ≥ 18 years with OHCA who were transferred to intensive care unit (ICU) after successful CPR from the emergency room of the First Affiliated Hospital of Zhengzhou University from August 2016 to February 2022 were enrolled. General clinical data, initial vital signs, acute physiology and chronic health evaluation II (APACHE II), Glasgow coma scale (GCS), first laboratory indicators after admission to ICU [including white blood cell count (WBC), red blood cell count (RBC), hemoglobin (Hb), pH value, lactic acid (Lac), 6-hour lactic acid clearance (LCR), red cell distribution width (RDW), HRR], length of ICU stay were collected. According to whether the patients died in hospital, the patients were divided into survival group and death group. Binary Logistic regression was used to analyze the independent factors influencing the prognosis of patients after CPR. Receiver operator characteristic curve (ROC curve) was drawn to analyze the predictive value of independent influencing factors for the prognosis of patients after CPR.@*RESULTS@#A total of 122 patients were enrolled after OHCA CPR, of which 88 died in hospital, the in-hospital mortality was 72.13%. There were no significant differences in age, past medical history, initial vital signs and WBC in ICU between the two groups. Compared with the death group, the survival group had higher GCS score, RBC, Hb, pH value, 6-hour LCR, HRR, lower APACHE II score, Lac, RDW level, and longer length of ICU stay. Multivariate Logistic regression analysis showed that APACHE II score, GCS score, 6-hour LCR, HRR, length of ICU stay were independent factors influencing the prognosis of patients after CPR [APACHE II score: odds ratio (OR) = 0.784, 95% confidence interval (95%CI) was 0.683-0.901, P = 0.001; GCS score: OR = 1.390, 95%CI was 1.059-1.823, P = 0.018; 6-hour LCR: OR = 1.039, 95%CI was 1.015-1.064, P = 0.001; HRR: OR = 2.047, 95%CI was 1.383-3.029, P < 0.001; length of ICU stay: OR = 1.128, 95%CI was 1.046-1.216, P = 0.002]. ROC curve analysis showed that HRR, 6-hour LCR and APACHE II score could predict the prognosis of patients after CPR. The sensitivity was 85.3% and the specificity was 54.5% when the area under the ROC curve (AUC) of HRR was 0.731, and the cut-off value was 8.555. The sensitivity was 88.2% and the specificity was 46.6%, when the AUC of 6-hour LCR was 0.701, and the cut-off value was 28.947%. The sensitivity was 73.9% and the specificity was 79.4% when the AUC of APACHE II score was 0.848, the cut-off value was 22.000. The predictive value of the combination of HRR and 6-hour LCR was higher than that of a single index. The sensitivity was 79.3% and the specificity was 76.1%, when the AUC was 0.796, the cut-off value was 0.296.@*CONCLUSIONS@#HRR, 6-hour LCR and APACHE II score have high prognostic value in patients with OHCA after CPR. HRR < 8.555, 6-hour LCR < 28.947% and APACHE II score > 22.000 indicated poor prognosis.

Granulocytic MDSC with Deficient CCR5 Alleviates Lipogenesis and Inflammation in Nonalcoholic Fatty Liver Disease.

C-C chemokine receptor type 5 (CCR5) positively contributes to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a common metabolic liver disease associated with chronic inflammation. CCR5 signaling also facilitates the immunosuppressive activity of a group of immature myeloid cells known as granulocytic myeloid-derived suppressor cells (g-MDSCs). While both hepatocyte and g-MDSC express CCR5, how CCR5 coordinates these two distinct cell types in the hepatic microenvironment remains largely unknown. Here, we used in vivo and ex vivo approaches to define the molecular details of how CCR5 mediates the crosstalk between hepatocytes and g-MDSCs in a mouse model of NAFLD. Global CCR5-deficient mice exhibited more severe steatosis, increased hepatic gene expression of lipogenesis, and exacerbated liver damage in diet-induced obesity. Either NAFLD or CCR5-deficiency per se is causative for the increase of g-MDSCs. Purified g-MDSCs have a higher survival rate in the fatty liver microenvironment, and blockade of CCR5 significantly decreases g-MDSCs' expression of anti-inflammatory factors. On the other hand, the null of CCR5 signaling increases hepatocytes' expression of lipogenic genes in the NAFLD microenvironment. Most importantly, inhibiting g-MDSCs' CCR5 signaling in the fatty liver microenvironment dramatically reduces STAT3 signaling, lipogenic, and pro-inflammatory gene expression in primary hepatocytes. Adoptive cell transfer experiments further demonstrate that CCR5-deficient g-MDSCs mitigate hepatic lipogenic gene expression without facilitating pro-inflammatory cytokine production and liver damage in NAFLD mice. These results suggest that targeting g-MDSCs' CCR5 signaling might serve as a potential therapeutic strategy for NAFLD.

Grim-19 deficiency promotes decidual macrophage autophagy in recurrent spontaneous abortion.

Dysregulation of decidual macrophages leads to the occurrence of recurrent spontaneous abortion (RSA). However, the role of macrophages in RSA occurrence remains unclear. In this study, we found that the expression of Grim-19 was decreased, and the expression of autophagy related proteins Beclin1, LC3B II/I and BNIP3 was markedly upregulated in decidual macrophages of RSA patients compared with the normal pregnancy group. Furthermore, we demonstrated that downregulation of GRIM-19 increased the expression of autophagy related proteins Beclin1, LC3B II/I, BNIP3 and the proinflammatory cytokines IL1B, IL6 and TNFa in uterine mononuclear cells of GRIM-19+/- mice. The proportion of CD45+CD11b+F4/80+LC3B+ cells in GRIM-19+/- mouse uteri was significantly higher than that in WT mouse uteri. In addition, we confirmed that inhibition of Grim-19 by siRNA enhanced the expression of autophagy related proteins in RAW264.7 cells and THP-1 cells. More importantly, downregulation of Grim-19 in RAW264.7 cells promoted the release of proinflammatory cytokines and promoted phagocytic activity, which could be reversed by autophagy blockade. For THP-1-derived macrophages, the results of RNA-seq suggested that Grim-19 mainly modulates immune and inflammatory-related pathways, leading to cytokine production, and thus contributing to inflammation. Therefore, our data reveal that Grim-19 deficiency influences macrophage function, characterized by enhanced proinflammatory cytokines and phagocytic activity, and this might be regulated by autophagy. This may represent a novel mechanism for the occurrence of RSA.

Linalyl Acetate Ameliorates Mechanical Hyperalgesia Through Suppressing Inflammation by TSLP/IL-33 Signaling.

Neuropathic pain is a debilitating chronic disorder, significantly causing personal and social burdens, in which activated neuroinflammation is one major contributor. Thymic stromal lymphopoietin (TSLP) and interleukin (IL)-33 is important for chronic inflammation. Linalyl acetate (LA) is main component of lavender oil with an anti-inflammatory property through TSLP signaling. The aim of the study is to investigate how LA regulates mechanical hyperalgesia after sciatic nerve injury (SNI). Adult Sprague-Dawley male rats were separated into 3 groups: control group, SNI group and SNI with LA group. LA was administrated intraperitoneally one day before SNI. Pain behavior test was evaluated through calibration forceps testing. Ipsilateral sciatic nerves (SNs), dorsal root ganglions (DRGs) and spinal cord were collected for immunofluorescence staining and Western blotting analyses. SNI rats were more sensitive to hyperalgesia response to mechanical stimulus since operation, which was accompanied by spinal cord glial cells reactions and DRG neuro-glial interaction. LA could relieve the pain sensation, proinflammatory cytokines and decrease the expression of TSLP/TSLPR complex. Also, LA could reduce inflammation through reducing IL-33 signaling. This study is the first to indicate that LA can modulate pain through TSLP/TSLPR and IL-33 signaling after nerve injury.

Impact of seborrheic dermatitis on osteoporosis risk: A population-based cohort study.

Osteoporosis is a systemic bone-resorbing disease that easily causes subsequent risk of fracture. Hence, the substantial physical burden of osteoporosis makes it an important public health issue. Seborrheic dermatitis (SD) is a chronic, recurrent, inflammatory skin disease. Despite the advances in medication for treating osteoporosis, identifying undiagnosed osteoporosis patients is still challenging. Since osteoporosis and SD share a similar pathobiology, e.g. inflammation and hormonal imbalance, we aimed to investigate whether the existence of SD increases osteoporosis risk by using the Taiwan National Health Insurance Research Database. A total of 7831 patients aged 18-50 years with SD and a control group of 31 324 patients without SD matched by age, gender, Charlson Comorbidity Index, and index date at a ratio of 1:4 during 1996-2010 were recruited in the study. To measure the cumulative incidence and compare the hazard ratios of osteoporosis between each group, the Kaplan-Meier method and Cox proportional hazard regression models were utilized. It was found that 0.98% of SD patients had osteoporosis. Compared to the non-SD group, the SD group had a 5.95-fold higher osteoporosis risk after adjustment for variables. The impact of SD on osteoporosis risk was largest in the female and young age groups. In addition, the presence of hyperlipidemia, hyperthyroidism, and epilepsy synergistically increased osteoporosis incidence in the SD group. This first large cohort study demonstrated an association between SD and osteoporosis. Since the effect on bone health in SD patients with concomitant diseases is largest in early life, diet or lifestyle recommendations as well as regular bone examinations are advised during follow-up of SD.

Decreased expression of GRIM-19 induces autophagy through the AMPK/ULK1 signaling pathway during adenomyosis†.

The processes underlying adenomyosis are similar to those of tumor metastasis, and it is defined as progressive invasion by the endometrium and the subsequent creation of ectopic lesions. GRIM-19 regulates cell death via the mitochondrial respiratory chain. Stress following oxygen deprivation can induce tumor cell autophagy, leading to cell invasion and migration. Here, we revealed that GRIM-19 negatively regulates autophagy, and, at least in adenomyosis, decreased expression of GRIM-19 is accompanied by an increased level of autophagy and 5'-adenosine monophosphate-activated protein kinase-Unc-51 like autophagy activating kinase 1 (AMPK-ULK1) activation. Upregulation of GRIM-19 expression in human primary endometrial cells and ISHIKAWA cells inhibits autophagy via the AMPK-ULK1 pathway and helps control cell invasion and migration. In addition, we also identified increased expression of AMPK and ULK1, and higher levels of autophagy in the uterine tissues of GRIM-19+/- mice. Importantly, the function of the GRIM-19-AMPK-ULK1 axis in regulating autophagy in adenomyosis is similar to that of tumor tissues, which may help elucidate the regulation of adenomyosis tumor-like behavior, and is expected to help identify novel targets for the diagnosis and treatment of adenomyosis.

S100A9 and SOCS3 as diagnostic biomarkers of acute myocardial infarction and their association with immune infiltration.

Acute myocardial infarction (AMI) is one of the leading causes of death globally, with a mortality rate of over 20%. However, the diagnostic biomarkers frequently used in current clinical practice have limitations in both sensitivity and specificity, likely resulting in delayed diagnosis. This study aimed to identify potential diagnostic biomarkers for AMI and explored the possible mechanisms involved. Datasets were retrieved from the Gene Expression Omnibus. First, we identified differentially expressed genes (DEGs) and preserved modules, from which we identified candidate genes by LASSO (least absolute shrinkage and selection operator) regression and the SVM-RFE (support vector machine-recursive feature elimination) algorithm. Subsequently, we used ROC (receiver operating characteristic) analysis to evaluate the diagnostic accuracy of the candidate genes. Thereafter, functional enrichment analysis and an analysis of immune infiltration were implemented. Finally, we assessed the association between biomarkers and biological processes, infiltrated cells, clinical traits, tissues and time points. We identified nine preserved modules containing 1,016 DEGs and managed to construct a diagnostic model with high accuracy (GSE48060: AUC = 0.923; GSE66360: AUC = 0.973) incorporating two genes named S100A9 and SOCS3. Functional analysis revealed the pivotal role of inflammation; immune infiltration analysis indicated that eight cell types (monocytes, epithelial cells, neutrophils, CD8+ T cells, Th2 cells, NK cells, NKT cells and platelets) were likely involved in AMI. Furthermore, we observed that S100A9 and SOCS3 were correlated with inflammation, variably infiltrated cells, clinical traits of patients, sampling tissues and sampling time points. In conclusion, we suggested S100A9 and SOCS3 as diagnostic biomarkers of AMI and discovered their association with inflammation, infiltrated immune cells and other factors.

Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

Sepsis is a syndrome characterized by life-threatening organ dysfunction caused by the dysregulated host response to an infection. Sepsis, especially septic shock and multiple organ dysfunction is a medical emergency associated with high morbidity, high mortality, and prolonged after-effects. Over the past 20 years, regulatory T cells (Tregs) have been a key topic of focus in all stages of sepsis research. Tregs play a controversial role in sepsis based on their heterogeneous characteristics, complex organ/tissue-specific patterns in the host, the multi-dimensional heterogeneous syndrome of sepsis, the different types of pathogenic microbiology, and even different types of laboratory research models and clinical research methods. In the context of sepsis, Tregs may be considered both angels and demons. We propose that the symptoms and signs of sepsis can be attenuated by regulating Tregs. This review summarizes the controversial roles and Treg checkpoints in sepsis.

The effect and mechanism of Grim 19 on mouse sperm quality and testosterone synthesis.

Abnormal sperm parameters such as oligospermia, asthenospermia, and teratozoospermia result in male factor infertility. Previous studies have shown that mitochondria play an important role in human spermatozoa motility. But the related pathogenesis is far from elucidated. The aim of this study was to investigate the association between gene associated with retinoid-interferon-induced mortality 19 (GRIM19) and asthenospermia. In this study, Grim19 knockout model (Grim19+/- mouse) was created through genome engineering. We showed that compared with WT mice, the sperm count and motility of Grim19+/- mice were significantly reduced. Grim19 may contribute to sperm count and vitality by influencing the mitochondrial membrane potential, intracellular reactive oxygen species production, and increasing cell apoptosis. The spermatogenic cells of all levels in the lumen of the seminiferous tubules were sparsely arranged, and the intercellular space became larger in the testis tissue of Grim19+/- mice. The serum testosterone concentration is significantly reduced in Grim19+/- mice. The expression of steroid synthesis-related proteins STAR, CYP11A1, and HSD3B was decreased in Grim19+/- mice. To further confirm whether changes in testosterone biosynthesis were due to Grim19 downregulation, we validated this result using Leydig cells and TM3 cells. We also found that Notch signaling pathway was involved in Grim19-mediated testosterone synthesis to some extent. In conclusion, we revealed a mechanism underlying Grim19 mediated spermatozoa motility and suggested that Grim19 affected the synthesis of testosterone and steroid hormones in male mouse partly through regulating Notch signal pathways.