Arginine methylation of ALKBH5 by PRMT6 promotes breast tumorigenesis via LDHA-mediated glycolysis.

ALKBH5 is a master regulator of N6-methyladenosine (m6A) modification, which plays a crucial role in many biological processes. Here, we show that ALKBH5 is required for breast tumor growth. Interestingly, PRMT6 directly methylates ALKBH5 at R283, which subsequently promotes breast tumor growth. Furthermore, arginine methylation of ALKBH5 by PRMT6 increases LDHA RNA stability via m6A demethylation, leading to increased aerobic glycolysis. Moreover, PRMT6-mediated ALKBH5 arginine methylation is confirmed in PRMT6-knockout mice. Collectively, these findings identify a PRMT6-ALKBH5-LDHA signaling axis as a novel target for the treatment of breast cancer.

Effect and mechanism of acupuncture on airway smooth muscle relaxation during acute asthma attack in rats. / é’ˆåˆºæ¾å¼›å“®å–˜æ€¥æ€§å‘ä½œå¤§é¼ æ°”é“å¹³æ»‘è‚Œçš„ä½œç”¨æœºåˆ¶.

OBJECTIVES: To explore the effect and mechanism of acupuncture at "Feishu" (BL 13) and "Dingchuan" (EX-B 1), and "Kongzui" (LU 6) and "Yuji" (LU 10) for relaxing the airway smooth muscle in the rats during acute asthma attack and compare the effect among the two pairs of acupoints and the acupoints combination. METHODS: Forty SD male rats with SPF grade were randomly divided into a blank group, a model group, a pair-point A group (acupuncture at "Feishu" [BL 13] and "Dingchuan" [EX-B 1]), a pair-point B group (acupuncture at "Kongzui" [LU 6] and "Yuji" [LU 10]) and a point combination group (acupuncture at "Feishu" [BL 13] , "Dingchuan" [EX-B 1], "Kongzui" [LU 6] and "Yuji" [LU 10]), with 8 rats in each group. Except the rats in the blank group, the model of acute asthma attack was induced by ovalbumin (OVA) combined with aluminum hydroxide gel in the rest groups. Started on the 15th day of modeling, except in the blank group and the model group, acupuncture was delivered in the other groups, 30 min in each intervention, once daily, for 14 days. In each group, the latent period of asthma inducing was measured; the lung resistance (LR) and dynamic lung compliance (Cdyn) were determined using lung function detector; the levels of endothelin-1 (ET-1), tumor necrosis factor-α (TNF-α), cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in serum and bronchoalveolar lavage fluid (BALF) were measured by ELISA; with Masson staining and electron microscopy adopted, the morphology and ultrastructure of airway smooth muscle of the rats were observed; the mRNA and protein expressions of ET-1 and beta-2 adrenergic receptor (ß2-AR) were detected by quantitative real-time fluorescence and Western blot, respectively. RESULTS: Compared with the blank group, the latent period of asthma inducing was shortened (P<0.05), RL increased and Cdyn decreased (P<0.05) with the different concentrations of methacholine (0.025 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg) in the model group. In the pair-point A group, the pair-point B group and the point combination group, the latent period of asthma inducing was prolonged (P<0.05), RL decreased and Cdyn increased (P<0.05) with different concentrations of methacholine when compared with those in the model group; and the latent period of asthma inducing in the point combination group was longer than that in the pair-point A group (P<0.05). Compared with the blank group, the levels of ET-1, TNF-α and cGMP in the serum and BALF were elevated (P<0.05), and those of cAMP reduced (P<0.05) in the model group. The levels of ET-1, TNF-α and cGMP in the serum and BALF were reduced (P<0.05), and those of cAMP elevated (P<0.05) in the pair-point A group, the pair-point B group and the point combination group when compared with those in the model group. In the blank group, the lung tissue was normal structurally. In the model group, the collagen fibers were proliferated increasingly, the smooth muscle was thickened, the mitochondria were swollen, and their cristae disrupted and reduced massively. In the pair-point B group, the collagen fibers were proliferated, the smooth muscle was thicker compared with that in the blank group, the mitochondria were mildly swollen and their cristae disrupted partially. In the pair-point A group and the point combination group, the lung tissue changes were obviously alleviated in comparison with the model group, the mitochondria were slightly swollen and their cristae disrupted occasionally. Compared with the blank group, the mRNA and protein expression of ET-1 increased and that of ß2-AR decreased in the lung tissue of the model group (P<0.05). In the pair-point A group, the pair-point B group and the point combination group, the mRNA and protein expression of ET-1 was reduced and that of ß2-AR elevated in the lung tissue when compared with those in the model group (P<0.05). In comparison with the pair-point A group, the mRNA expression of ß2-AR was elevated in the point combination group (P<0.05). When compared with the pair-point B group, the mRNA expression of ß2-AR increased, the protein expression of ET-1 decreased (P<0.05) in the point combination group. CONCLUSIONS: Acupuncture at "Feishu" (BL 13) and "Dingchuan" (EX-B 1), "Kongzui" (LU 6) and "Yuji" (LU 10), two pairs of acupoints relieves the airway smooth muscle spasm in the rats during acute asthma attack, which may be related to inhibiting the mRNA and protein expression of ET-1 to reduce the excretion of ET-1 and TNF-α; while enhancing the mRNA and protein expression of ß2-AR to balance the levels of cAMP and cGMP. The effect is optimal when acupuncture is delivered at two pairs of acupoints simultaneously.

Case report: The first account of undifferentiated sarcoma with epithelioid features originating in the pleura.

Undifferentiated epithelioid sarcoma (USEF) is a rare subtype of undifferentiated soft tissue sarcoma that presents unique challenges in clinical diagnosis and treatment. Here, we report a case of USEF occurring in the pleura of a 51-year-old man for the first time. Thoracoscopic examination revealed widespread nodular changes, and pathological analysis confirmed the presence of numerous epithelioid atypical cells. Immunohistochemical (IHC) analysis demonstrated an undifferentiated phenotype with distinct characteristics: epithelial membrane antigen (foci +), vimentin (+), Ki-67 (+70% +), TTF-1 (+), P53 (mutant type +90%), INI-1 (+), and CK5/6 (small foci +). Immunohistochemical examination of the tumor showed that the tumor was an undifferentiated epithelioid sarcoma. High-throughput DNA sequencing revealed pivotal mutations, including a nonsense mutation in the NF1 gene (c.641A > G(p.H214R)). and critical TP53 missense mutation (c.641A > G(p.H214R)). This TP53 mutation, with a tumor mutation burden of 16.5 Muts/Mb, signifies a high level of genomic instability, likely contributing to the rapid progression and aggressiveness of the disease. Detection of the TP53 mutation provides essential insights, indicating the disease's rapid progression and highlighting the potential for targeted therapies. Although the patient's disease progressed extremely rapidly and he tragically died within a week, we discussed the results of IHC and DNA sequencing in detail and discussed his possible treatment options. Insights gained from this case will be critical in shaping future diagnostic and therapeutic paradigms for USEF, particularly in the context of TP53 mutations.

A natural substitution of a conserved amino acid in eIF4E confers resistance against multiple potyviruses.

Eukaryotic translation initiation factor 4E (eIF4E), which plays a pivotal role in initiating translation in eukaryotic organisms, is often hijacked by the viral genome-linked protein to facilitate the infection of potyviruses. In this study, we found that the naturally occurring amino acid substitution D71G in eIF4E is widely present in potyvirus-resistant watermelon accessions and disrupts the interaction between watermelon eIF4E and viral genome-linked protein of papaya ringspot virus-watermelon strain, zucchini yellow mosaic virus or watermelon mosaic virus. Multiple sequence alignment and protein modelling showed that the amino acid residue D71 located in the cap-binding pocket of eIF4E is strictly conserved in many plant species. The mutation D71G in watermelon eIF4E conferred resistance against papaya ringspot virus-watermelon strain and zucchini yellow mosaic virus, and the equivalent mutation D55G in tobacco eIF4E conferred resistance to potato virus Y. Therefore, our finding provides a potential precise target for breeding plants resistant to multiple potyviruses.

Crescent calculator: A webtool enabling objective decision-making for assessment of IgA nephropathy immune activity throughout the disease course.

IgA nephropathy (IgAN) is an immune-mediated glomerulonephritis, posing a challenge for the long-term management. It is crucial to monitor the disease's activity over the disease course. Crescent lesions have been known as an active lesion associated with immune activity. We aimed to develop the Crescent Calculator to aid clinicians in making timely and well-informed decisions throughout the long-term disease course, such as renal biopsies and immunosuppressive therapy. 1,761 patients with biopsy-proven IgAN were recruited from four medical centers in Zhejiang Province, China. 16.9% presented crescent lesions. UPCR, URBC, eGFR and C4 were independently associated with the crescent lesions. By incorporating these variables, the Crescent Calculator was constructed to estimate the likelihood of crescent lesions. The predictor achieved AUC values of over 0.82 in two independent testing datasets. In addition, to fulfill varied clinical needs, multiple classification modes were established. The Crescent Calculator was developed to estimate the risk of crescent lesions for patients with IgAN, assisting clinicians in making timely, objective, and well-informed decisions regarding the need for renal biopsies and more appropriate use of immunosuppressive therapy in patients with IgAN.

PFKFB3 promotes endometriosis cell proliferation via enhancing the protein stability of ß-catenin.

Endometriosis is a common inflammatory disease in women of reproductive age and is highly associated with infertility. However, the molecular mechanism of endometriosis remains unclear. 6-Phosphofructose-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a key enzyme in glycolysis and plays an important regulatory role in the development of cancer. Here we found that PFKFB3 is highly expressed in endometriotic tissues. PFKFB3 promotes the proliferation and growth of endometriosis cells. Meanwhile, PFKFB3 promotes glycolysis in endometriosis cells. Furthermore, PFKFB3 promotes migration and invasion of endometriosis cells. On this basis, we found that PFKFB3 promotes epithelial-mesenchymal transition (EMT) in endometriosis cells. PFKFB3 interacts with the essential factor of EMT, ß-catenin, and promotes the protein stability of ß-catenin. In addition, the PFKFB3 inhibitor PFK-015 inhibites the growth of endometriosis cells and the development of endometrial tissue. In conclusion, our study shows that PFKFB3 plays an important role in the development of endometriosis and provides new ideas for the clinical diagnosis or treatment of endometriosis.

[Effects of acupuncture on pulmonary function and airway smooth muscle spasm in asthma rats].

OBJECTIVE: To observe the effects of acupuncture at "Kongzui" (LU 6) and "Yuji" (LU 10) on the latent period of inducing asthma, pulmonary function and the expression of endothelin-1 (ET-1) and metallothionein-2 (MT-2) in asthma rats, and to explore the possible mechanism of acupuncture in alleviating airway smooth muscle spasm and improving the acute attack of asthma. METHODS: A total of 40 male SD rats of SPF-grade were randomly divided into a normal group, a model group, a medication group and an acupuncture group, 10 rats in each group. Except for the normal group, ovalbumin sensitization method was used to establish the asthma model in the other 3 groups. Salbutamol nebulization was adopted in the medication group, while acupuncture was applied at bilateral "Kongzui" (LU 6) and "Yuji" (LU 10) in the acupuncture group. The intervention was given once a day for 14 days in the two groups. The latent period of inducing asthma and pulmonary function were observed, the levels of ET-1 and tumor necrosis factor (TNF)-α in serum and bronchoalveolar lavage fluid (BALF) were detected by ELISA method, the morphology of the airway was observed by Masson staining, the ultrastructure of the airway smooth muscle was observed by transmission electron microscopy, the mRNA and protein expression of ET-1 and MT-2 in lung tissue was detected by real-time PCR and Western blot methods. RESULTS: Compared with the normal group, in the model group, the latent period of inducing asthma was shortened (P<0.01); the airway resistance (RL) was increased while the dynamic compliance (Cdyn) was decreased (P<0.01, P<0.05); the levels of ET-1 and TNF-α in serum and BALF were increased (P<0.01); collagen fibers and collagen depositions were found around the bronchi, airway smooth muscle was thickened, the cell damage was severe and mitochondria were swollen; the mRNA and protein expression of ET-1 was increased while the mRNA and protein expression of MT-2 was decreased (P<0.01). Compared with the model group, in the acupuncture group, the latent period of inducing asthma was prolonged (P<0.05), the RL was decreased while the Cdyn was increased (P<0.01, P<0.05). Compared with the model group, in the medication group and the acupuncture group, the levels of ET-1 and TNF-α in serum and BALF were decreased (P<0.01, P<0.05); collagen fibers and collagen depositions around the bronchi were reduced, the thickened airway smooth muscle was lightened, the cell damage was improved; the mRNA and protein expression of ET-1 was decreased while the mRNA and protein expression of MT-2 was increased (P<0.01). Compared with the medication group, the mRNA expression of MT-2 was increased in the acupuncture group (P<0.05). CONCLUSION: Acupuncture at "Kongzui" (LU 6) and "Yuji" (LU 10) can improve the pulmonary function and alleviate the airway smooth muscle spasm in rats with asthma. Its mechanism may be related to the down-regulation of ET-1 expression and up-regulation of MT-2 expression.

SOV sensitizes gastric cancer cells to radiation by suppressing radiation-induced autophagy in vitro and in vivo.

Vanadium is a transition metal that naturally occurs in the environment and has a variety of biological and physiological impacts on humans. Sodium orthovanadate (SOV), a well-known chemical compound of vanadium, has shown notable anti-cancer activity in various types of human malignancies. However, the effect of SOV on stomach cancer is yet undetermined. Furthermore, only a few studies have investigated the association of SOV and radiosensitivity with stomach cancer. Our study has investigated the ability of SOV to increase the sensitivity of gastric cancer cells to radiation. To detect autophagy triggered by ionizing radiation and the influence of SOV on cell radiosensitivity, the Cell Counting Kit-8 (CCK8) test, EDU staining experiment, colony formation assay, and immunofluorescence were performed. The possible synergistic effects of SOV and irradiation were examined in vivo using a xenograft mouse model of stomach cancer cells. Both in vitro and in vivo studies showed that SOV markedly reduced the growth of stomach cancer cells and improved their radiosensitivity. Our results showed that SOV increased gastric cancer cells' radiosensitivity, thereby blocking the radiation-induced autophagy-related protein, ATG10. Thus, SOV can be considered a potential agent for radiosensitizing gastric cancer.

FDX1 enhances endometriosis cell cuproptosis via G6PD-mediated redox homeostasis.

Cuproptosis is a new form of programmed cell death, which is associated with the mitochondrial TCA (tricarboxylic acid) cycle. But the functions of cuproptosis in endometriosis progression are still unknown. Here, we find that cuproptosis suppresses the growth of endometriosis cells and the growth of ectopic endometrial tissues in a mouse model. FDX1 as a key regulator in cuproptosis pathway could promote cuproptosis in endometriosis cells. Interestingly, FDX1 interacts with G6PD, and reduces its protein stability, which predominantly affects the cellular redox-regulating systems. Then, the reduced G6PD activity enhances cuproptosis via down-regulating NADPH and GSH levels. Collectively, our study demonstrates that FDX1 mediates cuproptosis in endometriosis via G6PD pathway, resulting in repression of endometriosis cell proliferation and metastasis.

Adenosine and P1 receptors: Key targets in the regulation of sleep, torpor, and hibernation.

Sleep, torpor, and hibernation are three distinct hypometabolic states. However, they have some similar physiological features, such as decreased core body temperature and slowing heart rate. In addition, the accumulation of adenosine seems to be a common feature before entry into these three states, suggesting that adenosine and its receptors, also known as P1 receptors, may mediate the initiation and maintenance of these states. This review, therefore, summarizes the current research on the roles and possible neurobiological mechanisms of adenosine and P1 receptors in sleep, torpor, and hibernation. Understanding these aspects will give us better prospects in sleep disorders, therapeutic hypothermia, and aerospace medicine.

Erratum: CHL1 suppresses tumor growth and metastasis in nasopharyngeal carcinoma by repressing PI3K/AKT signaling pathway via interaction with Integrin ß1 and Merlin: Erratum.

[This corrects the article DOI: 10.7150/ijbs.34785.].

Emerging hallmarks of endometriosis metabolism: A promising target for the treatment of endometriosis.

Endometriosis, characterized by ectopic endometrium growth in the extrauterine environment, is one of the most notable diseases of the female reproductive system. Worldwide, endometriosis affects nearly 10 % of women in their reproductive years and causes a significant decline in quality of life. Despite extensive investigations of endometriosis over the past years, the mechanisms of endometriosis pathogenesis remain unclear. In recent years, metabolic factors have increasingly been considered factors in endometriosis. There is compelling evidence regarding the progress of endometriosis in the context of severe metabolic dysfunction. Hence, the curative strategies and ongoing attempts to conquer endometriosis might start with metabolic pathways. This review focuses on metabolic mechanisms and summarizes current research progress. These findings provide valuable information for the non-intrusive diagnosis of the disease and may contribute to the understanding of the pathogenesis of endometriosis.

Lifestyle-related risk factors correlated with mental health problems: A longitudinal observational study among 686 male college students in Chongqing, China.

Aim: Public concerns over the mental health problems of college students are rising. Previous research show that female tend to suffer more from mental health problems than males, with few studies focusing on males. This study sought to explore the association of lifestyle-related risk factors with the prevalence of mental health problems among male college students in China. Methods: The lifestyle information and mental health status of 686 male college students from Chongqing, China, were assessed in 2014, and 582 of them were followed up a year later. Participants completed a questionnaire assessing demographic and lifestyle factors which include sleep quality, computer usage, sedentariness, physical activity, smoking, current alcohol, coke, coffee, and milk tea drinking, and current tea/fried food/baked food consumption. Mental health problems were measured using the Depression Anxiety Stress Scale-21 (DASS-21). Results: Univariate analyses indicated that age, sleep latency, sleep duration, computer usage time, milk tea drinking, and fried food consumption were potential risk factors for mental health problems (p's < 0.05). Multivariate analysis further revealed that, either at baseline or during follow-up, participants with (i) more computer usage time were at a higher risk of having depression symptoms (p's < 0.05) and (ii) a higher frequency of fried food consumption were associated with a higher risk of having depression, anxiety, and stress symptoms (p's < 0.05). Additionally, the cross-lagged analysis showed that (i) computer usage time in 2014 is positively correlated with depression status (ß = 0.106, p < 0.05) but not anxiety (ß = 0.047, p > 0.05) and stress (ß = 0.019, p > 0.05) status a year later and (ii) fried food consumption in 2014 is positively correlated with depression (ß = 0.129, p < 0.01), anxiety (ß = 0.168, p < 0.001), and stress (ß = 0.113, p < 0.01) status a year later. Conclusions: Computer usage time and fried food consumption were lifestyle-related risk factors for mental health problems in male college students in Chongqing, China. These results might emphasize further preventive strategies for mental health problems, especially in male college students.

Ovarian tumorB1-mediated heat shock transcription factor 1 deubiquitination is critical for glycolysis and development of endometriosis.

Endometriosis is a common chronic condition characterized by abnormal growth of the endometrium outside the uterus. Heat shock transcription factor 1 (HSF1) is a significant regulator of the proteotoxic stress response and plays an essential role in developing endometriosis. However, the mechanisms regulating HSF1 protein stability in endometriosis remain unclear. Here, we demonstrate that OTUB1 interacts with HSF1 and promotes HSF1 protein stability through deubiquitination. In addition, OTUB1 enhances glycolysis and epithelial-mesenchymal transition of endometriosis cells, leading to promote proliferation, migration, and invasion of endometriosis cells. The progression of endometriosis is inhibited in an OTUB1-knockout mouse model. In summary, OTUB1 promotes the development of endometriosis by up-regulating HSF1. OTUB1/HSF1 axis may become a new therapeutic target for endometriosis.

Clostridium septicum brain abscess.

We present a previously well woman in her 70s who was admitted for 2 weeks of progressively worsening abdominal pain, high fever and drowsiness. She was eventually diagnosed with Clostridium septicum brain abscess, meningoencephalitis and ventriculitis. The diagnosis was challenging as cerebrospinal fluid cultures were negative and a microbiological diagnosis was only obtained on brain biopsy. Despite early initiation of antibiotics that would have been effective against C. septicum, her central nervous system (CNS) infection progressed, and she eventually succumbed to the infection. Infections with C. septicum are typically fulminant and associated with high mortality. In a patient with a CNS infection and concomitant abdominal manifestations, infection with C. septicum should be considered.

Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis.

Endometriosis (EM) is one of the vanquished wonted causes of chronic pelvic sting in women and is closely associated with infertility. The long-term, complex, systemic, and post-treatment recurrence of EM wreaks havoc on women's quality of life. Extensive metabolic reprogramming (aerobic glycolysis, glucose overweening intake, and high lactate production) and cancer-like changes have been found in EM, which bears striking similarities to tumorigenesis. The key glycolysis regulator PFKFB4 is overexpressed in EM. However, the mechanism of PFKFB4 in EM remains unknown. We found that PFKFB4 was upregulated and was closely related to the progression of EM. We identified focus PIM2 as a new pioneering adjoin protein of PFKFB4. Vigorous biochemical methods were used to confirm that PIM2 phosphorylated site Thr140 of PFKFB4. PIM2 also could enhance PFKFB4 protein expression through the ubiquitin-proteasome pathway. Moreover, PIM2 expression was really corresponding prevalent with PFKFB4 in endometriosis in vivo. Importantly, phosphorylation of PFKFB4 on Thr140 by PIM2 promoted EM glycolysis and cell growth. Our study demonstrates that PIM2 mediates PFKFB4 Thr140 phosphorylation thus regulating glycolysis and EM progression. We illustrated a new mechanism that PIM2 simulated a central upstream partnership in the regulation of PFKFB4, and reveal a novel means of PIM2-PFKFB4 setting EM growth. Our research provided new theoretical support for further clarifying the reprogramming of EM glucose metabolism, and provided new clues for exploring non-contraceptive treatments for EM.

Associations between isoflavone exposure and reproductive damage in adult males: evidence from human and model system studies†.

It is controversial whether exposure to isoflavones exerts male reproductive toxicity. The aim of this study was to investigate whether isoflavone exposure during adulthood could have deleterious impacts on male reproductive health by the cross-sectional study, animal experiments, and in vitro tests. In the cross-sectional study, we observed that urinary isoflavones were not significantly associated with semen quality including sperm concentrations, sperm count, progressive motility, and total motility, respectively. However, negative associations were found between plasma testosterone and urinary Σisoflavones, genistein, glycitein, and dihydrodaidzein. In the animal experiments, serum and intratesticular testosterone levels were decreased in mice exposed to several dosages of genistein. Genistein administration caused upregulation of estrogen receptor alpha and downregulation of cytochrome P45017A1 protein levels in testes of mice. In vitro tests showed that genistein caused a concentration-dependent inhibition of testosterone production by TM3 Leydig cells. Elevated protein expression of estrogen receptor alpha and decreased messenger RNA/protein level of cytochrome P45017A1 were also observed in genistein-treated cells. Protein level of cytochrome P45017A1 and testosterone concentration were significantly restored in the estrogen receptor alpha small interferring RNA-transfected cells, compared to cells that treated with genistein alone. The results demonstrate that exposure to isoflavones during adulthood may be associated with alterations of reproductive hormones. Particularly, genistein, which inhibits testosterone biosynthesis through upregulation of estrogen receptor alpha in Leydig cells of mice, might induce the disruption of testosterone production in human. The present study provides novel perspective into potential targets for male reproductive compromise induced by isoflavone exposure.

Natural History of Anal Papillomavirus Infection in HIV-Negative Men Who Have Sex With Men Based on a Markov Model: A 5-Year Prospective Cohort Study.

Objective: Men who have sex with men (MSM) are at increased risk for Human papillomavirus (HPV) infection compared to women and heterosexual men. We aimed to assess the incidence, clearance and duration of anal human papillomavirus (HPV) infection in HIV-negative MSM and the influencing factors in a 5-year prospective cohort study. Methods: From April 2016 to April 2021, HIV-negative MSM were recruited and followed every 6 months in Urumqi, Xinjiang, China. Questionnaires and anal swabs were collected at baseline and every 6 months. We detected 37 anal HPV genotypes using the HPV Geno Array Diagnostic Kit Test. Incidence and clearance rates of anal HPV infection and the influencing factors were estimated using a two-state Markov model. Results: A total of 585 MSM were included with a median age of 37 years [interquartile range (IQR): 31-43 years] and were followed for a median 2.8 years (IQR: 1.8-3.6 years). Incidence rates for any HPV and high-risk HPV (Hr-HPV) were 53.4 [95% confidence interval (CI): 49.1-58.0] and 39.0 (95% CI: 35.7-42.5)/1,000 person-months. Median duration of infection was 9.67 (95% CI: 8.67-10.86) and 8.51 (95% CI: 7.57-9.50) months, respectively. Clearance rates for any HPV and Hr-HPV were 50.9 (95% CI: 46.7-55.3) and 62.1 (95% CI: 56.8-66.7)/1,000 person-months, respectively. HPV16 and HPV6 had the highest incidence, lowest clearance rate and longest duration of infection among Hr-HPV and low-risk HPV (Lr-HPV) types, respectively. Receptive anal sex is a risk factor for any HPV [hazard ratio (HR) = 1.66, 95% CI: 1.16-2.38] and Hr-HPV infection (HR = 1.99, 95% CI:1.39-2.85). Recent anal sex without condom use was significantly associated with any HPV (HR = 1.80, 95% CI: 1.10-2.94) and Hr-HPV infection (HR = 2.60, 95% CI: 1.42-4.77). Age ≥35 years was significantly associated with Lr-HPV HPV infection only (HR = 1.40, 95% CI: 1.02-1.93). Both inserted and receptive anal sex (HR = 0.60, 95% CI: 0.40-0.89) and anal sex ≥2 times per week (HR = 0.61, 95% CI: 0.43-0.87) were associated with reduced Hr-HPV clearance. Six of the nine-valent vaccine types (HPV6, 11, 16, 18, 52 and 58) occurred most frequently, which indicates the need for high vaccination coverage in MSM. Conclusions: In this cohort study, high incidence and low clearance of any HPV, Hr-HPV and individual HPV infections emphasize the importance of MSM vaccination. Modifiable behavioral factors such as condoms and drug use should be incorporated into HPV prevention strategies.

M6 A demethylase fat mass and obesity-associated protein regulates cisplatin resistance of gastric cancer by modulating autophagy activation through ULK1.

Drug resistance is an important factor for treatment failure of gastric cancer. N6 -methyladenosine (m6 A) is the predominant mRNA internal modification in eukaryotes. The roles of m6 A modification in drug resistance of gastric cancer remains unclear. In the present study, the m6 A methylated RNA level was significantly decreased while the expression of m6 A demethylase fat mass and obesity-associated protein (FTO) was obviously elevated in cisplatin-resistant (SGC-7901/DDP) gastric cancer cells. Knockdown of FTO reversed cisplatin resistance of SGC-7901/DDP cells both in vitro and in vivo, which was attributed to the inhibition of Unc-51-like kinase 1 (ULK1)-mediated autophagy. Mechanistically, ULK1 expression was regulated in an FTO-m6 A-dependent and YTHDF2-mediated manner. Collectively, our findings indicate that the FTO/ULK1 axis exerts crucial roles in cisplatin resistance of gastric cancer.

Analysis by transcriptomics and metabolomics for the proliferation inhibition and dysfunction through redox imbalance-mediated DNA damage response and ferroptosis in male reproduction of mice and TM4 Sertoli cells exposed to PM2.5.

Sertoli cells play a pivotal role in the complex spermatogenesis process. This study aimed to investigate the effects of PM2.5 on Sertoli cells using the TM4 cell line and a real time whole-body PM2.5 exposure mouse model, and further explore the underlying mechanisms through the application of metabolomics and transcriptomics. The results in vivo and in vitro showed that PM2.5 reduced Sertoli cells number in seminiferous tubules and inhibited cell proliferation. PM2.5 exposure also induced Sertoli cell dysfunction by increasing androgen binding protein (ABP) concentration, reducing the blood-testis barrier (BTB)-related protein expression, and decreasing glycolysis capacity and lactate production. The results of transcriptomics, metabolomics, and integrative analysis of multi-omics in the TM4 Sertoli cells revealed the activation of xenobiotic metabolism, and the disturbance of glutathione and purine metabolism after PM2.5 exposure. Further tests verified the reduced GSH/GSSG ratio and the elevation of xanthine oxidase (XO) activity in the PM2.5-exposed TM4 cells, indicating that excessive reactive oxygen species (ROS) was generated via metabolic disorder caused by PM2.5. Moreover, the redox imbalance was proved by the increase in the mitochondrial ROS level, superoxide dismutase (SOD) and catalase (CAT) activity, as well as the activation of the Nrf2 antioxidative pathway. Further study found that the redox imbalance caused by PM2.5 induced DNA damage response and cell cycle arrest. Additionally, PM2.5 induced ferroptosis through iron overload and lipid peroxidation. Taken all together, our study provided new insights for understanding proliferation inhibition and dysfunction of TM4 Sertoli cells exposed to PM2.5 via metabolic disorder and redox imbalance-mediated DNA damage response and ferroptosis.