The immune microenvironment plays a pivotal role in maintaining ovarian homeostasis. Polycystic ovary syndrome (PCOS), a common endocrine and metabolic disorder, is closely associated with immune microenvironment imbalance. This review systematically describes the dysregulation of innate immune cells (e.g., macrophages, natural killer cells and dendritic cells) and adaptive immune cells (e.g., Th1, Th2, Treg and Th17) in PCOS, highlighting their impacts on ovarian function, insulin resistance, and hyperandrogenemia. These findings underscore the central role of immune microenvironment disturbances in PCOS pathogenesis. Additionally, the association between gut microbiota dysbiosis and PCOS is explored, emphasizing how gut microbiota influences metabolic byproducts and hormonal levels to contribute to PCOS development. Furthermore, therapeutic strategies targeting immune microenvironment imbalance such as modulating macrophage polarization, restoring Th1/Th2 and Th17/Treg balance, and ameliorating gut microbiota dysbiosis are discussed, offering novel insights for PCOS immunotherapy. In conclusion, this review comprehensively analyzes the pathogenesis of PCOS from the perspective of the immune microenvironment, aiming to provide a theoretical foundation and reference for future research and clinical practice.

The immune microenvironment plays a pivotal role in maintaining ovarian homeostasis. Polycystic ovary syndrome (PCOS), a common endocrine and metabolic disorder, is closely associated with immune microenvironment imbalance. This review systematically describes the dysregulation of innate immune cells (e.g., macrophages, natural killer cells and dendritic cells) and adaptive immune cells (e.g., Th1, Th2, Treg and Th17) in PCOS, highlighting their impacts on ovarian function, insulin resistance, and hyperandrogenemia. These findings underscore the central role of immune microenvironment disturbances in PCOS pathogenesis. Additionally, the association between gut microbiota dysbiosis and PCOS is explored, emphasizing how gut microbiota influences metabolic byproducts and hormonal levels to contribute to PCOS development. Furthermore, therapeutic strategies targeting immune microenvironment imbalance such as modulating macrophage polarization, restoring Th1/Th2 and Th17/Treg balance, and ameliorating gut microbiota dysbiosis are discussed, offering novel insights for PCOS immunotherapy. In conclusion, this review comprehensively analyzes the pathogenesis of PCOS from the perspective of the immune microenvironment, aiming to provide a theoretical foundation and reference for future research and clinical practice.

ObjectiveTo observe the clinical efficacy of the stasis-dispelling and detoxifying therapy in endometriosis （EMs） patients with the syndrome of kidney deficiency and blood stasis and the effects of this therapy on the expression levels of proteins related to the c-Jun N-terminal kinase （JNK） signaling pathway. MethodsA total of 72 patients with EMs due to kidney deficiency and blood stasis who met the criteria at the Integrated Traditional Chinese and Western Medicine Center for Reproduction and Genetics of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine from March 2024 to February 2025 were selected and randomized into a treatment group and a control group， with 36 patients in each group. Another 36 patients undergoing in vitro fertilization-embryo transfer （IVF-ET） due to male factors alone were selected as the blank group. The treatment group took the Zishen Quyu Jiedu formula orally， while the control group and the blank group took placebos. The treatment course encompassed the cycle before ovarian stimulation and the oocyte retrieval cycle. The TCM syndrome score of kidney deficiency and blood stasis， as well as the serum level of cancer antigen 125 （CA125）， were evaluated at the time of enrollment （before treatment） and on the trigger day （after treatment）. Serum levels of sex hormones were measured on day 2 of the menstrual cycle. On the trigger day， the duration and dosage of gonadotropin （Gn） administration and the serum levels of hormones on the day of human chorionic gonadotropin （HCG） injection were assessed. Embryo outcomes were evaluated 3 days after oocyte retrieval， and clinical pregnancy rates were assessed 28 days after embryo transfer. The baseline data of three groups were observed. The TCM syndrome scores and serum CA125 levels before and after treatment were compared between the treatment and control groups. The baseline endocrine levels， Gn days， Gn dosage， hormone levels on the day of HCG administration， number of oocytes retrieved， number of 2 pronucleus （2PN） fertilizations， number of available embryos， high-quality embryo rate， and clinical pregnancy rate were also assessed in all three groups. Six patients from each group were selected for determination of the protein levels of JNK， c-Jun， and nuclear receptor subfamily 4 group A member 2 （NR4A2） in ovarian granulosa cells （GCs） on the day of oocyte retrieval by Western blot. Results（1） There were no statistically significant differences in the baseline data among three groups， indicating comparability. （2） Compared with the baseline within the same group， the treatment group showed a decrease in the syndrome score of kidney deficiency and blood stasis after treatment. After treatment， serum CA125 levels decreased in both groups （P<0.05）， with a more substantial reduction in the treatment group， resulting in a difference between the two groups （P<0.05）. （3） There were no significant differences among three groups in terms of baseline serum levels of follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， estradiol （E₂）， and progesterone （P）， as well as the duration and dosage of Gn administration and the serum levels of LH， E₂， and P on the day of HCG administration. （4） For embryo outcomes， the number of oocytes retrieved， 2PN fertilizations， available embryos， and high-quality embryo rates in the treatment group and the blank group were higher than those in the control group （P<0.05）， and the treatment group and the blank group had similar 2PN fertilizations. （5） There were differences in clinical pregnancy rate among three groups （P<0.05）， and the treatment group had higher pregnancy rate than the control and blank groups. （6） The protein levels of JNK， c-Jun， and NR4A2 in the GCs of the treatment group were lower than those in the control group （P<0.01） and close to those in the blank group （P<0.01）. （7） No obvious adverse reactions were observed in any of the subjects during the clinical observation process. ConclusionZishen Quyu Jiedu formula can ameliorate the clinical symptoms of patients with EMs due to kidney deficiency and blood stasis， reduce the serum CA125 level， increase the number of oocytes retrieved， 2PN fertilizations， available embryos， and high-quality embryo rate， and improve pregnancy outcomes. The mechanism may involve downregulating the levels of JNK， c-Jun， and NR4A2 to reduce the apoptosis of ovarian GCs and improve the ovarian function in the patients.

ObjectiveTo observe the clinical efficacy of the stasis-dispelling and detoxifying therapy in endometriosis （EMs） patients with the syndrome of kidney deficiency and blood stasis and the effects of this therapy on the expression levels of proteins related to the c-Jun N-terminal kinase （JNK） signaling pathway. MethodsA total of 72 patients with EMs due to kidney deficiency and blood stasis who met the criteria at the Integrated Traditional Chinese and Western Medicine Center for Reproduction and Genetics of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine from March 2024 to February 2025 were selected and randomized into a treatment group and a control group， with 36 patients in each group. Another 36 patients undergoing in vitro fertilization-embryo transfer （IVF-ET） due to male factors alone were selected as the blank group. The treatment group took the Zishen Quyu Jiedu formula orally， while the control group and the blank group took placebos. The treatment course encompassed the cycle before ovarian stimulation and the oocyte retrieval cycle. The TCM syndrome score of kidney deficiency and blood stasis， as well as the serum level of cancer antigen 125 （CA125）， were evaluated at the time of enrollment （before treatment） and on the trigger day （after treatment）. Serum levels of sex hormones were measured on day 2 of the menstrual cycle. On the trigger day， the duration and dosage of gonadotropin （Gn） administration and the serum levels of hormones on the day of human chorionic gonadotropin （HCG） injection were assessed. Embryo outcomes were evaluated 3 days after oocyte retrieval， and clinical pregnancy rates were assessed 28 days after embryo transfer. The baseline data of three groups were observed. The TCM syndrome scores and serum CA125 levels before and after treatment were compared between the treatment and control groups. The baseline endocrine levels， Gn days， Gn dosage， hormone levels on the day of HCG administration， number of oocytes retrieved， number of 2 pronucleus （2PN） fertilizations， number of available embryos， high-quality embryo rate， and clinical pregnancy rate were also assessed in all three groups. Six patients from each group were selected for determination of the protein levels of JNK， c-Jun， and nuclear receptor subfamily 4 group A member 2 （NR4A2） in ovarian granulosa cells （GCs） on the day of oocyte retrieval by Western blot. Results（1） There were no statistically significant differences in the baseline data among three groups， indicating comparability. （2） Compared with the baseline within the same group， the treatment group showed a decrease in the syndrome score of kidney deficiency and blood stasis after treatment. After treatment， serum CA125 levels decreased in both groups （P<0.05）， with a more substantial reduction in the treatment group， resulting in a difference between the two groups （P<0.05）. （3） There were no significant differences among three groups in terms of baseline serum levels of follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， estradiol （E₂）， and progesterone （P）， as well as the duration and dosage of Gn administration and the serum levels of LH， E₂， and P on the day of HCG administration. （4） For embryo outcomes， the number of oocytes retrieved， 2PN fertilizations， available embryos， and high-quality embryo rates in the treatment group and the blank group were higher than those in the control group （P<0.05）， and the treatment group and the blank group had similar 2PN fertilizations. （5） There were differences in clinical pregnancy rate among three groups （P<0.05）， and the treatment group had higher pregnancy rate than the control and blank groups. （6） The protein levels of JNK， c-Jun， and NR4A2 in the GCs of the treatment group were lower than those in the control group （P<0.01） and close to those in the blank group （P<0.01）. （7） No obvious adverse reactions were observed in any of the subjects during the clinical observation process. ConclusionZishen Quyu Jiedu formula can ameliorate the clinical symptoms of patients with EMs due to kidney deficiency and blood stasis， reduce the serum CA125 level， increase the number of oocytes retrieved， 2PN fertilizations， available embryos， and high-quality embryo rate， and improve pregnancy outcomes. The mechanism may involve downregulating the levels of JNK， c-Jun， and NR4A2 to reduce the apoptosis of ovarian GCs and improve the ovarian function in the patients.

Diabetic cardiomyopathy is a distinct form of cardiomyopathy that can lead to heart failure, arrhythmias, cardiogenic shock, and sudden death. It has become a major cause of mortality in diabetic patients. The pathogenesis of diabetic cardiomyopathy is complex, involving increased oxidative stress, activation of inflammatory responses, disturbances in glucose and lipid metabolism, accumulation of advanced glycation end products (AGEs), abnormal autophagy and apoptosis, insulin resistance, and impaired intracellular Ca²⁺ homeostasis. Recent studies have shown that adenosine monophosphate-activated protein kinase (AMPK) plays a crucial protective role by lowering blood glucose levels, promoting lipolysis, inhibiting lipid synthesis, and exerting antioxidant, anti-inflammatory, anti-apoptotic, and anti-ferroptotic effects. It also enhances autophagy, thereby alleviating myocardial injury under hyperglycemic conditions. Consequently, AMPK is considered a key protective factor in diabetic cardiomyopathy. As part of diabetes prevention and treatment strategies, both pharmacological and exercise interventions have been shown to mitigate diabetic cardiomyopathy by modulating the AMPK signaling pathway. However, the precise regulatory mechanisms, optimal intervention strategies, and clinical translation require further investigation. This review summarizes the role of AMPK in the prevention and treatment of diabetic cardiomyopathy through drug and/or exercise interventions, aiming to provide a reference for the development and application of AMPK-targeted therapies. First, several classical AMPK activators (e.g., AICAR, A-769662, O-304, and metformin) have been shown to enhance autophagy and glucose uptake while inhibiting oxidative stress and inflammatory responses by increasing the phosphorylation of AMPK and its downstream target, mammalian target of rapamycin (mTOR), and/or by upregulating the gene expression of glucose transporters GLUT1 and GLUT4. Second, many antidiabetic agents (e.g., teneligliptin, liraglutide, exenatide, semaglutide, canagliflozin, dapagliflozin, and empagliflozin) can promote autophagy, reverse excessive apoptosis and autophagy, and alleviate oxidative stress and inflammation by enhancing AMPK phosphorylation and its downstream targets, such as mTOR, or by increasing the expression of silent information regulator 1 (SIRT1) and peroxisome proliferator-activated receptor‑α (PPAR‑α). Third, certain anti-anginal (e.g., trimetazidine, nicorandil), anti-asthmatic (e.g., farrerol), antibacterial (e.g., sodium houttuyfonate), and antibiotic (e.g., minocycline) agents have been shown to promote autophagy/mitophagy, mitochondrial biogenesis, and inhibit oxidative stress and lipid accumulation via AMPK phosphorylation and its downstream targets such as protein kinase B (PKB/AKT) and/or PPAR‑α. Fourth, natural compounds (e.g., dihydromyricetin, quercetin, resveratrol, berberine, platycodin D, asiaticoside, cinnamaldehyde, and icariin) can upregulate AMPK phosphorylation and downstream targets such as AKT, mTOR, and/or the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), thereby exerting anti-inflammatory, anti-apoptotic, anti-pyroptotic, antioxidant, and pro-autophagic effects. Fifth, moderate exercise (e.g., continuous or intermittent aerobic exercise, aerobic combined with resistance training, or high-intensity interval training) can activate AMPK and its downstream targets (e.g., acetyl-CoA carboxylase (ACC), GLUT4, PPARγ coactivator-1α (PGC-1α), PPAR-α, and forkhead box protein O3 (FOXO3)) to promote fatty acid oxidation and glucose uptake, and to inhibit oxidative stress and excessive mitochondrial fission. Finally, the combination of liraglutide and aerobic interval training has been shown to activate the AMPK/FOXO1 pathway, thereby reducing excessive myocardial fatty acid uptake and oxidation. This combination therapy offers superior improvement in cardiac dysfunction, myocardial hypertrophy, and fibrosis in diabetic conditions compared to liraglutide or exercise alone.

Diminished ovarian reserve (DOR) refers to the decrease in the number of follicles and the quality of oocytes that appear prematurely before menopause. The pathogenesis of DOR is not yet fully understood, and clinical treatment lacks efficient methods, making it an urgent problem to be solved in the field of reproductive medicine. Acupuncture and moxibustion has been gradually popularized in the world for the treatment of gynecological diseases due to its advantages such as convenient operation, good curative effect and quick effect. With the rapid development of omics technology, molecular targets related to DOR pathogenesis (proteins, nucleic acids, receptors, etc.) are gradually recognized. In this review, we plan to make a summary from the perspective of the target of acupuncture and moxibustion treatment of DOR, in order to provide a reliable basis for the clinical treatment of DOR.

Diminished ovarian reserve (DOR) refers to the decrease in the number of follicles and the quality of oocytes that appear prematurely before menopause. The pathogenesis of DOR is not yet fully understood, and clinical treatment lacks efficient methods, making it an urgent problem to be solved in the field of reproductive medicine. Acupuncture and moxibustion has been gradually popularized in the world for the treatment of gynecological diseases due to its advantages such as convenient operation, good curative effect and quick effect. With the rapid development of omics technology, molecular targets related to DOR pathogenesis (proteins, nucleic acids, receptors, etc.) are gradually recognized. In this review, we plan to make a summary from the perspective of the target of acupuncture and moxibustion treatment of DOR, in order to provide a reliable basis for the clinical treatment of DOR.

Objective: Retrospective analysis of the efficacy and influencing factors of bladder preservation integrated therapy for unresectable invasive bladder cancer confined to the pelvis was done, also including the bladder function preservation and adverse effects analysis. Methods: Sixty-nine patients with unresectable locally invasive bladder cancer who received radiotherapy-based combination therapy from March 1999 to December 2021 at our hospital were selected. Among them, 42 patients received concurrent chemoradiotherapy, 32 underwent neoadjuvant chemotherapyand 43 with transurethral resection of bladder tumors (TURBT) prior to radiotherapy. The late adverse effect of radiotherapy, preservation of bladder function, replase and metastasis and survival were followed-up. Cox proportional hazards models were applied for the multifactorial analysis. Results: The median age was 69 years. There were 63 cases (91.3%) of uroepithelial carcinoma, 64 of stage Ⅲ and 4 of stage Ⅳ. The median duration of follow-up was 76 months. There were 7 grade 2 late genito urinary toxicities, 2 grade 2 gastrointestinal toxicities, no grade 3 or higher adverse events occurred. All patients maintained normal bladder function, except for 8 cases who lost bladder function due to uncontrolled tumor in the bladder. Seventeen cases recurred locally. There were 11 cases in the concurrent chemoradiotherapy group with a local recurrence rate of 26.2% (11/42) and 6 cases in the non-concurrent chemoradiotherapy group with a local recurrence rate of 22.2% (6/27), and the difference in local recurrence rate between the two groups was not statistically significant (P=0.709). There were 23 cases of distant metastasis (including 2 cases of local recurrence with distant metastasis), including 10 cases in the concurrent chemoradiotherapy group with a distant metastasis rate of 23.8% (10/42) and 13 cases in the non-concurrent chemoradiotherapy group with a distant metastasis rate of 48.1% (13/27), and the distant metastasis rate in the non-concurrent chemoradiotherapy group was higher than that in the concurrent chemoradiotherapy group (P=0.036). The median 5-year overall survival (OS) time was 59 months and the OS rate was 47.8%. The 5-year progression-free survival (PFS) time was 20 months and the PFS rate was 34.4%. The 5-year OS rates of concurrent and non-concurrent chemoradiotherapy group were 62.9% and 27.6% (P<0.001), and 5-year PFS rates were 45.4% and 20.0%, respectively (P=0.022). The 5-year OS rates of with or without neoadjuvant chemotherapy were 78.4% and 30.1% (P=0.002), and the 5-year PFS rates were 49.1% and 25.1% (P=0.087), respectively. The 5-year OS rates with or without TURBT before radiotherapy were 45.5% and 51.9% (P=0.233) and the 5-year PFS rates were 30.8% and 39.9% (P=0.198), respectively. Multivariate Cox regression analysis results showed that the clinical stage (HR=0.422, 95% CI: 0.205-0.869) was independent prognostic factor for PFS of invasive bladder cancer. The multivariate analysis showed that clinical stages (HR=0.278, 95% CI: 0.114-0.678), concurrent chemoradiotherapy (HR=0.391, 95% CI: 0.165-0.930), neoadjuvant chemotherapy (HR=0.188, 95% CI: 0.058-0.611), and recurrences (HR=10.855, 95% CI: 3.655-32.638) were independent prognostic factors for OS of invasive bladder cancer. Conclusion: Unresectable localized invasive bladder cancer can achieve satisfactory long-term outcomes with bladder-preserving combination therapy based on radiotherapy, most patients can retain normal bladder function with acceptable late adverse effects and improved survival particularly evident in patients with early, concurrent chemoradiotherapy and neoadjuvant chemotherapy.
Humans ; Aged ; Treatment Outcome ; Retrospective Studies ; Combined Modality Therapy ; Chemoradiotherapy/methods* ; Urinary Bladder Neoplasms/radiotherapy* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Neoplasm Staging

Objective: To describe the prevalence of alcohol consumption and the burden of hemorrhagic stroke and hypertensive heart disease attributed to alcohol consumption in adults aged ≥20 years in 31 provinces in China from 2005 to 2018. Methods: Data from several national representative surveys was used to estimate provincial alcohol exposure level of adults aged ≥20 years from 2005 to 2018 by using kriging interpolation and locally weighted regression methods. Global disease burden research method and data, and China's death cause surveillance data were used to calculate the population attributable fraction (PAF) of hemorrhagic stroke and hypertensive heart disease and the deaths due to alcohol consumption in men and women aged ≥20 years in 31 provinces in China. China census data of 2010 were used to calculate the attributable standardized mortality rate. Results: In 2005 and 2018, the prevalence of alcohol consumption was 58.7% (95%CI: 57.8%-59.5%) and 58.4% (95%CI: 57.6%-59.3%), respectively, in men and 17.0% (95%CI: 16.6%-17.4%) and 18.7% (95%CI:18.1%-19.3%), respectively, in women. The daily alcohol intake was 24.6 (95%CI: 23.8-25.3) g and 27.7 (95%CI: 26.8-28.7) g, respectively, in men and 6.3 (95%CI: 6.0-6.5) g and 5.3 (95%CI: 5.0-5.6) g, respectively, in women. Alcohol exposure level was higher in the provinces in central and eastern China than in western provinces. The lowest exposure level was found in northwestern provinces. From 2005 to 2018, the PAF of hemorrhagic stroke death due to alcohol consumption increased from 5.5% to 6.8%, the attributable deaths increased from 50 200 to 59 100, while the PAF of hypertensive heart disease death due to alcohol consumption increased from 7.0% to 7.7%, the attributable deaths increased from 15 200 to 29 300. The PAF of hypertensive heart disease and hemorrhagic stroke was higher in men than in women, and in central and eastern provinces than in western provinces. In 2018, the standardized mortality rates of hemorrhagic stroke and hypertensive heart disease attributed to alcohol consumption were 4.58/100 000 and 2.11/100 000, respectively. Conclusions: The prevalence of alcohol consumption in men and daily alcohol intake of drinkers were relatively high in China, especially in eastern provinces. Alcohol exposure level was lower in women than in men. Regional measures should be taken to reduce the alcohol intakes in men and current drinkers in order to reduce the health problems caused by alcohol consumption.
Adult ; Male ; Humans ; Female ; Hemorrhagic Stroke ; Hypertension/epidemiology* ; Alcohol Drinking/epidemiology* ; Heart Diseases/epidemiology* ; China/epidemiology*

Objective: To estimate the risk for type 2 diabetes mellitus (T2DM) death attributed to insufficient whole grain intake in seven regions of China from 2005 to 2018. Methods: Based on China National Nutrition and Health Surveys and China Adult Chronic Disease and Nutrition Surveillance, ordinary Kriging method and locally weighted regression were used to estimate the level of whole grain intake of Chinese residents from 2005 to 2018. Based on the results of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 and Chronic Diseases Risk Factors Surveillance in China, we calculated the population attributable fraction (PAF), attributable death number and attributable mortality rate of T2DM due to insufficient whole grain intake in people aged ≥20 years in different regions of China, and we used the 2010 Chinese census data to compare the changes in T2DM deaths attributed to insufficient intake of whole grains in seven regions of China. Results: The whole grain intake levels of Chinese people over 20 years old in 2002, 2010 and 2015 were 19.0 g/d, 14.3 g/d and 19.8 g/d, respectively. The estimated overall whole grain intake level was 20.1 g/d in Chinese residents in 2018, and the intake level was 19.4 g/d in men and 20.8 g/d in women. Among the seven regions, the intake level was highest in northern China (47.4 g/d) and lowest in southwestern China (6.0 g/d). In 2018, the PAF was lowest in northern China (12.8%) and highest in southwestern China (19.3%). From 2005 to 2018, the PAF varied in the seven regions, and the PAF in northeastern China fluctuated around 18.5%. Other regions showed downward trends, especially in northern China and northwestern China, decreased by 26.4% and 21.2%, respectively. Over the past 14 years, the number of attributable deaths in the seven regions showed upward trends, with the highest annual average growth rate of 6.7% in southern China and the lowest annual average growth rate of 2.4% in northern China. In 2018, the standardized T2DM mortality rate attributed to insufficient whole grain intake in China was 3.13/100 000, and the attributable mortality was 3.21/100 000 in men and 3.05/100 000 in women. The standardized attributable mortality rate was highest in southwestern China (3.97/100 000) and lowest in northern China (1.78/100 000). From 2005 to 2018, the standardized attributable mortality rate increased by 11.5% in men and decreased by 8.1% in women. The standardized attributable mortality rate in southwestern, southern and central China increased by 23.7%, 21.3% and 4.2%, respectively. The standardized attributable mortality rate in northern, northwestern, eastern and northeastern China decreased by 20.9%, 11.0%, 4.5% and 3.9%, respectively. Conclusion: The whole grain intake level of Chinese residents was low, and the whole grain intake of residents in all seven regions should be increased, especially in the southwest, and men should have more whole grain intake than women to reduce the death risk in patients with T2DM.
Adult ; Male ; Humans ; Female ; Young Adult ; Whole Grains ; Diabetes Mellitus, Type 2/epidemiology* ; Risk Factors ; Chronic Disease ; China/epidemiology*