2025年 · 第138卷第04期

Male infertility has become a global concern, accounting for 20-70% of infertility. Dysfunctional spermatogenesis is the most common cause of male infertility; thus, treating abnormal spermatogenesis may improve male infertility and has attracted the attention of the medical community. Mitochondria are essential organelles that maintain cell homeostasis and normal physiological functions in various ways, such as mitochondrial oxidative phosphorylation (OXPHOS). Mitochondrial OXPHOS transmits electrons through the respiratory chain, synthesizes adenosine triphosphate (ATP), and produces reactive oxygen species (ROS). These mechanisms are vital for spermatogenesis, especially to maintain the normal function of testicular Sertoli cells and germ cells. The disruption of mitochondrial OXPHOS caused by external factors can result in inadequate cellular energy supply, oxidative stress, apoptosis, or ferroptosis, all inhibiting spermatogenesis and damaging the male reproductive system, leading to male infertility. This article summarizes the latest pathological mechanism of mitochondrial OXPHOS disorder in testicular Sertoli cells and germ cells, which disrupts spermatogenesis and results in male infertility. In addition, we also briefly outline the current treatment of spermatogenic malfunction caused by mitochondrial OXPHOS disorders. However, relevant treatments have not been fully elucidated. Therefore, targeting mitochondrial OXPHOS disorders in Sertoli cells and germ cells is a research direction worthy of attention. We believe this review will provide new and more accurate ideas for treating male infertility.

This review aimed to provide a comprehensive analysis of the etiology, epidemiology, pathology, and conventional treatment of heterotopic ossification (HO), especially emerging potential therapies. HO is the process of ectopic bone formation at non-skeletal sites. HO can be subdivided into two major forms, acquired and hereditary, with acquired HO predominating. Hereditary HO is a rare and life-threatening genetic disorder, but both acquired and hereditary form can cause severe complications, such as peripheral nerve entrapment, pressure ulcers, and disability if joint ankylosis develops, which heavily contributes to a reduced quality of life. Modalities have been proposed to treat HO, but none have emerged as the gold standard. Surgical excision remains the only effective modality; however, the optimal timing is controversial and may cause HO recurrence. Recently, potential therapeutic strategies have emerged that focus on the signaling pathways involved in HO, and small molecule inhibitors have been shown to be promising. Moreover, additional specific targets, such as small interfering RNAs (siRNAs) and non-coding RNAs, could be used to effectively block HO or develop combinatorial therapies for HO.

Hypotension is a leading cause of age-related cognitive impairment. The available literature evidences that vascular factors are associated with dementia and that hypotension alters cerebral perfusion flow and can aggravate the neurodegeneration of Alzheimer’s disease (AD). Despite the discovery of biomarkers and the recent progress made in neurovascular biology, epidemiology, and brain imaging, some key issues remain largely unresolved: the potential mechanisms underlying the neural deterioration observed in AD, the effect of cerebrovascular alterations on cognitive deficits, and the positive effects of hypotension treatment on cognition. Therefore, further well-designed studies are needed to unravel the potential association between hypotension and cognitive dysfunction and reveal the potential benefits of hypotension treatment for AD patients. Here, we review the current epidemiological, pathobiological, and treatment-related literature on neurovascular changes and hypotension-related cognitive dysfunction and highlight the unsettled but imminent issues that warrant future research endeavors.

The main cause of restenosis after percutaneous transluminal angioplasty (PTA) is the excessive proliferation and migration of vascular smooth muscle cells (VSMCs). Lin28a has been reported to play critical regulatory roles in this process. However, whether CCAAT/enhancer-binding proteins β (C/EBPβ) binds to the Lin28a promoter and drives the progression of restenosis has not been clarified. Therefore, in the present study, we aim to clarify the role of C/EBPβ-Lin28a axis in restenosis.

Restenosis and atherosclerosis rat models of type 2 diabetes (n = 20, for each group) were established by subjecting to PTA. Subsequently, the difference in DNA methylation status and expression of C/EBPβ between the two groups were assessed. EdU, Transwell, and rescue assays were performed to assess the effect of C/EBPβ on the proliferation and migration of VSMCs. DNA methylation status was further assessed using Methyltarget sequencing. The interaction between Lin28a and ten-eleven translocation 1 (TET1) was analysed using co-immunoprecipitation (Co-IP) assay. Student’s t-test and one-way analysis of variance were used for statistical analysis.

C/EBPβ expression was upregulated and accompanied by hypomethylation of its promoter in restenosis when compared with atherosclerosis. In vitro C/EBPβ overexpression facilitated the proliferation and migration of VSMCs and was associated with increased Lin28a expression. Conversely, C/EBPβ knockdown resulted in the opposite effects. Chromatin immunoprecipitation assays further demonstrated that C/EBPβ could directly bind to Lin28a promoter. Increased C/EBPβ expression and enhanced proliferation and migration of VSMCs were observed after decitabine treatment. Further, mechanical stretch promoted C/EBPβ and Lin28a expression accompanied by C/EBPβ hypomethylation. Additionally, Lin28a overexpression reduced C/EBPβ methylation via recruiting TET1 and enhanced C/EBPβ-mediated proliferation and migration of VSMCs. The opposite was noted in Lin28a knockdown cells.

Our findings suggest that the C/EBPβ-Lin28a axis is a driver of restenosis progression, and presents a promising therapeutic target for restenosis.

To evaluate the efficacy and safety of the first cohort of people in China treated with a responsive neurostimulation system (Epilcure^TM, GenLight MedTech, Hangzhou, China) for focal drug-resistant epilepsy in this study.

This multicenter, before-and-after self-controlled study was conducted across 8 centers from March 2022 to June 2023, involving patients with drug-resistant epilepsy who were undergoing responsive neurostimulation (RNS). The study was based on an ongoing multi-center, single-blind, randomized controlled study. Efficacy was assessed through metrics including median seizure count, seizure frequency reduction (SFR), and response rate. Multivariable linear regression analysis was conducted to explore the relationships of basic clinical factors and intracranial electrophysiological characteristics with SFR. The postoperative quality of life, cognitive function, depression, and anxiety were evaluated as well.

The follow-up period for the 19 participants was 10.7 ± 3.4 months. Seizure counts decreased significantly 6 months after device activation, with median SFR of 48% at the 6th month (M6) and 58% at M12 (P <0.05). The average response rate after 13 months of treatment was 42%, with 21% (n = 4) of the participants achieving seizure freedom. Patients who have previously undergone resective surgery appear to achieve better therapeutic outcomes at M11, M12 and M13 (β <0, P <0.05). No statistically significant differences were observed in patients’ scores of quality of life, cognition, depression and anxiety following stimulation when compared to baseline measurements. No serious adverse events related to the devices were observed.

The preliminary findings suggest that Epilcure^TM exhibits promising therapeutic potential in reducing the frequency of epileptic seizures. However, to further validate its efficacy, larger-scale randomized controlled trials are required.

Chinese Clinical Trial Registry (No. ChiCTR2200055247)

G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA).

The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism.

In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (T_regs), an increase in the cluster of differentiation 8 positive (CD8⁺) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8⁺ T cells, and induced the proportion of T_regs. Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells.

Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cells in RA.

Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS.

This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide.

Eighty-two patients were assigned to variant (n = 42) and wild type groups (n = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] µg/mL; wild type, 49.1 [32.0] µg/mL) and area under plasma concentration-time curve over a dosing interval (AUC_tau) (variant, 1731.3 [769.0] µg·h/mL; wild type, 1564.5 [1053.0] µg·h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study.

ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients.

NCT04410965, https://clinicaltrials.gov.

This study aims to compare the efficacy between neoadjuvant immune checkpoint inhibitors (ICIs) plus chemotherapy vs. chemotherapy, and neoadjuvant triplet vs. doublet chemotherapeutic regimens in locally advanced gastric/esophagogastric junction cancer (LAGC).

We included LAGC patients from 47 hospitals in China’s National Cancer Information Database (NCID) from January 2019 to December 2022. Using propensity score matching (PSM), we retrospectively analyzed the efficacy between neoadjuvant ICIs plus chemotherapy vs. chemotherapy alone, and neoadjuvant triplet vs. doublet chemotherapeutic regimens. The primary study result was the pathologic complete response (pCR) rate. The secondary study results were disease-free survival (DFS) and overall survival (OS).

A total of 1205 LAGC patients were included. After PSM, the ICIs plus chemotherapy and the chemotherapy cohorts had 184 patients each, while the doublet and triplet chemotherapy cohorts had 246 patients each. The pCR rate (14.13% vs. 7.61%, χ² = 4.039, P = 0.044), and the 2-year (77.60% vs. 61.02%, HR = 0.67, 95% confidence interval [CI] 0.43-0.98, P = 0.048) and 3-year (70.55% vs. 61.02%, HR = 0.58, 95% CI 0.32-0.93, P = 0.048) DFS rates in the ICIs plus chemotherapy cohort were improved compared to those in the chemotherapy cohort. No significant increase was observed in the OS rates at both 1 year and 2 years. The pCR rates, DFS rates at 1-3 years, and OS rates at 1-2 years did not differ significantly between the doublet and triplet cohorts, respectively. No differences were observed in postoperative complications between any of the group comparisons.

Neoadjuvant ICIs plus chemotherapy improved the pCR rate and 2-3 years DFS rates of LAGC compared to chemotherapy alone, but whether short-term benefit could translate into long-term efficacy is unclear. The triplet regimen was not superior to the doublet regimen in terms of efficacy. The safety after surgery was similar between either ICIs plus chemotherapy and chemotherapy or the triplet and the doublet regimen.

To the Editor:Patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) have a poor prognosis, with a 5-year overall survival (OS) ranging from 25% to 50%, and remission induction therapy is challenging.^[1]Allogeneic hematopoietic stem cell transplantation (HSCT) is the golden standard treatment for patients with R/R ALL. Before immunotherapy was introduced into clinical practice, a significant proportion of patients could not undergo HSCT because of serious adverse events from chemotherapy or the inability to achieve an acceptably deep remission. Novel immunotherapies, including blinatumomab and chimeric antigen receptor T (CAR-T) cells, have been shown to enhance the immune response in R/R B-ALL and improve the cure rate. However, studies on direct treatment comparisons between CAR-T cells and blinatumomab, and those elucidating the best combination of haplo-HSCT and novel immune therapies for ALL, are lacking.

To the Editor: Chronic obstructive pulmonary disease (COPD) is a global health challenge because of its high prevalence and associated mortality.^[1]Multimorbidity is a distinguishing feature of COPD in addition to airflow obstruction. Evaluation from a comorbidity perspective forms part of the comprehensive assessment of COPD. The aim of this study was to analyze the distribution of comorbidities and their impact on the prognosis of patients who are hospitalized with COPD.

To the Editor: Lung cancer is characterized by its high incidence and mortality rates, imposing a significant burden of disease globally.^[1]Liver metastasis is associated with poorer clinical outcomes and shorter life expectancy in non-small cell lung cancer (NSCLC).^[2]Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment of NSCLC, existing predictive and prognostic biomarkers have limited effectiveness and pose a clinical challenge, particularly for patients with liver metastasis. The albumin-bilirubin (ALBI) grading system, an evidence-based measure of liver dysfunction calculated from blood albumin and bilirubin levels, has shown promise in predicting prognosis and ICI efficacy in NSCLC.^[3]Nonetheless, high body mass index (BMI) was independently associated with improved overall survival (OS) with ICI therapy in NSCLC.^[4]Given that the prognosis is worse for patients with liver metastasis and low BMI despite receiving ICI treatment, we proposed that assessing both the ALBI score and BMI together could offer valuable prognostic information for patients with NSCLC and liver metastasis who are undergoing ICI therapy. This retrospective multicenter study assessed the utility of ALBI-B, a logistic regression-based model that integrates pretreatment ALBI score and BMI, in predicting clinical outcomes with ICIs for patients with NSCLC and liver metastases.

To the Editor: Gastroscopy is considered to be the main method for diagnosing gastric lesions.^[1]But correctly diagnosing different gastric lesions under white light endoscopy (WLE) may be challenging as the morphological manifestations of gastric lesions are varied and some are even subtle. Due to the uneven diagnostic levels across various regions and the scarcity of experienced endoscopists, misdiagnosis and missed diagnosis may occur. In addition, endoscopists are overwhelmed by heavy workloads, and fatigue may lead to a further decline in diagnostic performance, even for experienced endoscopists.

To the Editor: Currently, most research on the relationships between lipids, immune cells, and intracranial aneurysms (IAs), including unruptured intracranial aneurysms (uIAs) and aneurysmal subarachnoid hemorrhage (aSAH), originates from observational studies.^[1]There are inevitable confounding factors in the research design, thus the research conclusions cannot reveal the causal relationship between lipids, immune cells, and IAs. More importantly, it remains unclear whether immune responses mediate the relationship between lipids and IAs. Thus, we performed a Mendelian randomization (MR) analysis, a method that can avoid the interference of confounding factors and determine the correct causal relationships.^[2]The purposes of this study are: (1) to determine the causal relationships between gene-mediated serum lipids and IAs; (2) to identify the causal relationships between immune cells and IAs; and (3) to investigate whether immune cells mediate the relationships between lipids and IAs.

To the Editor: Depression is a common psychiatric disorder, affecting over 260 million people of all ages globally.^[1]Prior studies investigating the association between antidepressant use and stroke risk have yielded inconsistent results.^[2,3]Consequently, it remains unclear which of the various antidepressant categories may affect stroke. Thus, the rational use of antidepressants is important for reducing stroke risk and recurrence, while offering candidate therapeutic targets. Drug-target Mendelian randomization (MR) analysis, which uses genetic variants located in or near the region of drug target genes as proxies for drug effects, is a promising tool for identifying causal links between drug targets and diseases. This study aimed to evaluate the causal associations between antidepressant target genes and stroke and its various subtypes (including any stroke [AS], ischemic stroke [IS], large artery atherosclerosis stroke [LAA], cardioembolic stroke [CES], and small vessel stroke [SVS]) using drug-target MR analysis.

To the Editor: Thalassemia major (TM) is a prevalent public health issue in southern China, necessitating allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a curative treatment. Only a small proportion of TM patients have a sibling identical donor (SID), therefore alternative donors, including human leukocyte antigen (HLA) matched unrelated donors (MUDs) and haploidentical donors (HIDs), are increasingly being adopted by transplant centers. Several centers have indicated that MUD transplantation does not differ from SID transplantation in terms of overall survival (OS) or event-free survival (EFS) in recent years, although early complications such as graft versus host disease (GVHD) are more common among MUD transplantation.^[1]Therefore, MUD-HSCT is a suitable choice for TM patients who have no SIDs. In addition, the timing of transplantation constitutes another pivotal factor in determining the success of HSCT, because TM patients suffer from complications arising from blood transfusions and iron accumulation, resulting in a substantial disease burden. Consequently, HID-HSCT emerges as a potential solution to circumvent the challenge of lacking fully matched donors, thereby expanding the donor pool to include parents or mismatched siblings. Nevertheless, it is imperative to acknowledge that patients undergoing HID-HSCT encounter a heightened immune barrier, which imparts a greater risk of GVHD and compromises OS. However, recent years have witnessed significant advancements in immunosuppressive regimens and T-cell depletion strategies, collectively contributing to substantial improvements in the overall outcomes of HID-HSCT among TM patients.^[2]To date, comprehensive large-scale clinical investigations that directly compared the outcomes of HSCT in TM patients using HIDvs. MUD remain conspicuously absent. Consequently, the precise implications of these two donor types for the long-term prognosis of TM patients remain unclear and warrant further exploration. Our study aimed to investigate whether receiving HID-HSCT as soon as possible or waiting for a MUD can benefit the long-term prognosis of pediatrics with TM.

To the Editor: Obesity and type 2 diabetes (T2D) present significant health issues in China. Despite generally having lower body mass index (BMI) thresholds than Western populations, Chinese individuals often experience higher rates of central obesity, leading to increased metabolic risks even at lower BMI levels. The prevalence of T2D among adults in China is estimated to be 11.2%. Traditional treatments, including lifestyle interventions and medications, often fail to achieve sustained weight loss and effective glycemic control in the long term in patients with obesity and T2D.

To the Editor: Chemotherapy is one of the mainstay therapies for patients with breast cancer (BC),^[1,2]but it is often restricted by dose-limiting toxicities attributed to myelosuppression. Although recombinant human granulocyte colony-stimulating factors (rhG-CSF) are effective for treating and preventing chemotherapy-induced neutropenia, daily administration is inconvenient to patients.^[3,4]

To the Editor:Pathogenic copy number variants (CNVs) have been associated with congenital anomalies and neurodevelopmental disorders.^[1]However, some fetuses with pathogenic CNVs have structural abnormalities, whereas others appear phenotypically normal. Prenatal assessment of CNVs in fetuses with structural abnormalities currently relies on invasive prenatal diagnosis (IPD). However, the absence of routine screening for CNVs in pregnant women whose fetuses do not have structural abnormalities restricts the ability to identify clinically significant fetal CNVs.

Chronic kidney disease (CKD) is an important disease affecting human health, especially in developing countries where CKD has high prevalence and mortality rates.^[1]According to the latest CKD epidemiological data, the prevalence of CKD among Chinese people is 8.2%, of which 1.8% are patients with CKD stage 5 (known as end-stage renal disease [ESRD]).^[2]Hemodialysis (HD) is the main treatment for ESRD patients. According to the China National Renal Data System (CNRDS), the number of people receiving HD treatment in 2022, was as high as 844,000. Although dialysis can partially replace the function of the kidneys, distant complications in dialysis patients, such as cardiovascular disease (CVD), renal bone disease, and infections, seriously affect the quality of life and prognosis. Among these conditions, CVD is the leading cause of death in dialysis patients.^[3]In addition to traditional cardiovascular risk factors such as hypertension and diabetes, the development of CVD has been associated with alterations in the gut microbiota and its metabolites.