Tandem mass tag-based quantitative proteomics analyses of the spermatogenesis-ameliorating effect of Youjing granule on rats.

RATIONALE: Male infertility is a common reproductive system disease manifested as aberrant spermatogenesis and identified as "kidney deficiency and dampness" in Chinese traditional medicine. Youjing granule (YG) is a Chinese material medica based on tonifying kidneys and removing dampness. It has proven to be able to regulate semen quality in clinical application, but the underlying mechanism has not been clarified. METHODS: Using serum containing YG to treat primarily cultured spermatogonial stem cells (SSCs), the apoptotic rate and mitosis phase ratio of SSCs were measured. The liquid chromatography-tandem mass spectrometry with tandem mass tags method was applied for analyzing the serum of rats treated with YG/distilled water, and proteomic analyses were performed to clarify the mechanisms of YG. RESULTS: Totally, 111 proteins in YG-treated serum samples were differentially expressed compared with control groups, and 43 of them were identified as potential target proteins, which were further annotated based on their enrichment in Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways. Proteomic analyses showed that the mechanisms of YG may involve regulation of glycolysis, gluconeogenesis and nucleotide-binding and oligomerization domain-like receptor signaling pathway. In addition, RhoA and Lamp2 were found to be possible responders of YG through reviewing the literature. CONCLUSIONS: The results demonstrate that our serum proteomics platform is clinically useful in understanding the mechanisms of YG.

Methionine sulfoxide suppresses adipogenic differentiation by regulating the mitogen-activated protein kinase signaling pathway.

In this study, methionine sulfoxide (MetO) was identified as an active metabolite that suppresses adipogenesis after screening obese individuals versus the normal population. MetO suppressed the gene and protein expression of CCAAT/enhancer binding protein (C/EBP) α, adipocyte fatty acid binding protein 4 (FABP4), and the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) during human preadipocyte (HPA) differentiation. Adipogenesis decreased following MetO treatment; however, the preadipocyte number, proliferation, and apoptosis were unaffected. The activity of phosphorylated extracellular signal-related kinase (P-ERK) of the mitogen-activated protein kinase (MAPK) pathway was significantly inhibited in HPA after MetO treatment. Furthermore, treatment of preadipocytes with the selective P-ERK1/2 agonist Ro 67-7476 abolished the effect of MetO against adipogenesis suggesting that MetO function is dependent on the MAPK pathway. The mechanistic insights of adipogenesis suppression by MetO presented in this study shows its potential as an antiobesity drug.

[Efficacy of Yu Si Granules on methyl methanesulphonate-induced oligoasthenozoospermia in mice].

OBJECTIVE: To investigate the effect and action mechanism of Yu Si Granules (YSG) in the treatment methyl methanesulphonate (MMS)-induced oligoasthenozoospermia (OAZ) in mice. METHODS: Thirty adult male mice were randomly divided into three groups of equal number, normal control, OAZ model control and YSG intervention. The OAZ model was established by oral administration of MMS and the model mice in the YSG intervention group were treated intragastrically with YSG suspension at 0.144 g/100 g of the body weight per day for 48 successive days. Then, all the mice were sacrificed and their epididymides harvested for detection of the sperm count and motility, observation of the morphology of the seminiferous tubules by HE staining, determination of the expressions of the germ cell-, sperm cell-, spermatocyte-, Sertoli cell- and blood-testis barrier-related genes by RT-PCR, and measurement of the levels of oxidative stress in the blood. RESULTS: Compared with the normal control, the OAZ model mice showed significantly decreased sperm count (ï¼»49.2 ± 0.7ï¼½ vs ï¼»23.6 ± 0.4ï¼½ ×107/ml/g, P < 0.05) and sperm motility (ï¼»76.3 ± 0.7ï¼½% vs ï¼»5.0 ± 5.8ï¼½%, P < 0.05), which were both remarkably increased after YSG intervention (ï¼»38.4 ± 0.5ï¼½ ×107/ml/g and ï¼»71.5 ± 0.5ï¼½%) (P < 0.05). The OAZ model mice also exhibited degenerated and atrophic seminiferous tubules, thinner seminiferous epithelia, disorderly arranged cells at different levels, reduced number of sperm in the lumen and unclear layers of germ cells in the epididymis, while those after YSG intervention manifested regularly organized seminiferous tubules with orderly arrangement and clear layers. The expressions of the Vasa, Dazl and Snd1 genes were significantly decreased (P < 0.05), but not those of Gfra, Plzf, Stra8, Spo11, Sycp3, Sox9 and Vim (P > 0.05) in the OAZ model and YSG intervention groups as compared with those in the normal control group. The superoxide dismutase (SOD) activity in the serum was markedly reduced in the OAZ model mice as compared with that in the normal controls (P < 0.05) and increased again after YSP intervention (P < 0.05), but the opposite was the case with the expression of the superoxide anion. CONCLUSIONS: YSG can significantly reduce MMS-induced OAZ in mice, which may be associated with oxidative stress.

Associations between ERα/ß gene polymorphisms and osteoporosis susceptibility and bone mineral density in postmenopausal women: a systematic review and meta-analysis.

BACKGROUND: Many studies have reported associations between estrogen receptor (ER) gene polymorphisms and postmenopausal osteoporosis (PMOP) risk and bone mineral density (BMD), but the results are controversial. The aim of the present meta-analysis is to verify the association between ERα and ERß gene polymorphisms and osteoporosis susceptibility and BMD in postmenopausal women. METHODS: PubMed, EMBASE, Web of Science, the Cochrane Library and China WeiPu Library were searched. OR and WMD with 95% CI were calculated to assess the association. RESULTS: Overall, no significant association was observed between ERα XbaI, ERα PvuII and PMOP susceptibility in either overall, Caucasian or Asian populations. ERα G2014A was significantly associated with a decreased risk of PMOP in Caucasian populations. There was a significant association between ERß RsaI and PMOP risk in both overall and Asian populations. Caucasian PMOP women with ERα XbaI XX and Xx genotypes had a higher LS Z value than women with xx genotype. ERα XbaI XX genotype was associated with increased FN BMD in overall and Caucasian populations, an increased FN Z value in Asians, and a decreased FN Z value in Caucasians. There was also a significant association between ERα XbaI Xx genotype and an increased FN Z value in either Asians or Caucasians. ERα PvuII PP genotype was associated with a low LS Z value in Caucasians and a low FN BMD and Z value in Asians. Pp genotype in PMOP women was significantly correlated with low LS BMD in overall populations, a low FN Z value in either overall, Caucasian or Asian populations. CONCLUSION: Each ERα and ERß gene polymorphism might have different impact on PMOP risk and BMD in various ethnicities.

The atrophy and laterality of the hippocampal subfields in parents with or without posttraumatic stress disorder who lost their only child in China.

Investigating hippocampal subfields may provide new and important insights into the pathophysiology of posttraumatic stress disorder (PTSD). However, no study has examined the hippocampal subfield volume changes in parents with or without PTSD who had lost their only child and could no longer conceive in China. Fifty-seven parents with PTSD (PTSD+), 11 trauma-exposed parents without PTSD (PTSD-), and 39 non-traumatized controls were recruited to examine the hippocampal subfield volumes using magnetic resonance imaging. Correlations of the volumes with the time since trauma and Clinician-Administered PTSD Scale (CAPS) scores were investigated in the PTSD+ group. The volumes of the bilateral cornu ammonis (CA) 2-3, CA4-dentate gyrus (DG), and left subiculum were significantly smaller in the PTSD+ and PTSD- groups than in the controls, but there were no significant differences between the PTSD+ and PTSD- groups. Additionally, the left CA2-3 and CA4-DG volumes reduced more than those on the right side in the PTSD+ and PTSD- groups. The subfield volumes were not related to the time since trauma and the CAPS scores in the PTSD+ group. In conclusion, hippocampal subfield volumes decreased in parents who lost their only child with or without PTSD, and the volumetric reduction may be independent of PTSD and trauma-related. Moreover, the hippocampal volume deficits showed laterality that the left side was affected more than the right, and the hippocampal subfields may show differential vulnerabilities to trauma/PTSD, with the CA2-3 and CA4-DG subfields more sensitive than others.

Incidence and risk factors of chronic pain following hysterectomy among Southern Jiangsu Chinese Women.

BACKGROUND: Chronic post-surgical pain (CPSP) after hysterectomy has been recognized as a major clinical problem in the Western World. Reports on post-hysterectomy pain are relatively scarce in China. The aim of the current study was to prospectively investigate the incidence and the potential risk factors of CPSP at 3 months following hysterectomy in Chinese population. METHODS: We assessed and collected data on preoperative socio-demographic characteristics, preexisting pain, anxiety and depression, sexual satisfaction, intra-operative variables, and acute postoperative pain intensity in a cohort of 870 women undergoing hysterectomy. The participants were interviewed to determine their suitability to diagnostic criteria of CPSP 3 months later. Logistic regression analyses were subsequently performed to identify predictors for CPSP. RESULTS: The incidence of CPSP at 3 months after hysterectomy was 27.7%. Most of the women with CPSP suffered from mild pain and had a slight impact on daily life with sleep and emotion functional limitation. Risk factors for CPSP after hysterectomy were preoperative anxiety, depression, pelvic pain, preexisting pain, very-moderate sexual dissatisfaction, and acute postoperative pain at movement. Intra-operative dexmedetomidine infusion with 0.5 µg/kg/h was associated with a decreased incidence rate of chronic post-hysterectomy pain. CONCLUSION: Twenty-eight percent of patients after hysterectomy in southern Jiangsu china had CPSP with 92% of those women describing it as mild with sleep and emotion functional limitation. Patients with preoperative anxiety and depression, poor sexual satisfaction, preexisting pain, and acute postoperative pain on movement have been identified to be at risk to develop CPSP.

T2 signal intensity and volume abnormalities of hippocampal subregions in patients with amnestic mild cognitive impairment by magnetic resonance imaging.

BACKGROUND: The volumetry of the hippocampal subregion may provide additional information in the early investigation of amnestic mild cognitive impairment (aMCI) and the T2 signal intensity (T2-SI) of the hippocampal subregion has not been well studied quantitatively by magnetic resonance imaging (MRI) in aMCI. METHODS: Using combined MRI-based hippocampal volumetry and T2-SI at the levels of the whole hippocampus and hippocampal subregion, 18 patients with aMCI and 18 age-matched controls were investigated. RESULTS: Significantly lower left whole hippocampal and hippocampal head volumes and higher T2-SI in the bilateral whole hippocampus and hippocampal head were shown, whereas atrophy of the right whole hippocampus and hippocampal subregion was not significant in aMCI. Additionally, correlations were found among the hippocampal volume, T2-SI and Mini-Mental State Examination (MMSE) scores for aMCI in the whole hippocampus and some hippocampal subregions and an almost perfect correlation was found between T2-SI of the left hippocampal head and MMSE scores regarding aMCI (r = -0.831, P = 0.000). CONCLUSION: Abnormalities of the hippocampal volume and T2-SI were documented in aMCI, whereas T2-SI was implied to be more susceptible than the volume in the pathohistological progression in aMCI. Additionally, T2-SI in the left hippocampal head may be a potential biomarker to facilitate the early diagnosis of aMCI.

Comparison of early and late decompressive craniectomy on the long-term outcome in patients with moderate and severe traumatic brain injury: a meta-analysis.

BACKGROUND: Several studies have searched whether early decompressive craniectomy (DC) can improve the long-term outcome of patients with moderate and severe traumatic brain injury (TBI). However, the effects of early DC remain unclear. The purpose of this meta-analysis was to assess whether early DC (time to surgery after injury <24 h) is better than late DC (>24 h) after moderate and severe TBI. METHOD: Two reviewers independently searched Pubmed, Embase, ISI web of science, the Cochrane Library and Scopus databases from inception to 4 November 2014. Studies comparing the long-term outcome of patients following early and late DC after TBI were included. The long-term outcomes were evaluated by Glasgow Outcome Score, Extended Glasgow Outcome Score. Newcastle-Ottawa Scale was used to assess the methodological quality of included studies. Characteristics of the selected studies were extracted. Pooled results were presented by odds ratios (ORs) with 95% CIs. I(2) was used to test heterogeneity. Pearson correlation coefficient was used to detect the relationship between bilateral pupil abnormality and unfavourable outcome. RESULTS: Five articles were eligible for this meta-analysis. The pooled results of comparison of unfavourable outcome and mortality revealed no significant difference in the early and late groups (ORs: 1.469; 95% CIs: 0.495-4.362; p > 0.05; I(2 )=70.5% and ORs: 1.262; 95% CIs: 0.385-4.137; p > 0.05; I(2 )=77.6%, respectively). Pearson correlation coefficient indicated that bilateral pupil abnormality was positive related to the unfavourable outcomes and mortality (r = 0.833; p < 0.05) (0.829; p < 0.05). CONCLUSION: Bilateral pupil abnormality is positive related to unfavourable outcome and mortality in the patients following DC after moderate and severe TBI. Early DC may be more helpful to improve the long-term outcome of patients with refractory raised intracranial cerebral pressure after moderate and severe TBI. However, more RCTs with better control of patients with bilateral pupil abnormality divided into the early and late groups are needed in the future.

Specific deletion of Cdh2 in Sertoli cells leads to altered meiotic progression and subfertility of mice.

CDH2 (cadherin 2, Neural-cadherin, or N-cadherin) is the predominant protein of testicular basal ectoplasmic specializations (basal ES; a testis-specific type of adhesion junction), one of the major cell junctions composing the blood-testis barrier (BTB). The BTB is found between adjacent Sertoli cells in seminiferous tubules, which divides the tubules into basal and adluminal compartments and prevents the deleterious exchange of macromolecules between blood and seminiferous tubules. However, the exact roles of basal ES protein CDH2 in BTB function and spermatogenesis is still unknown. We thus generated mice with Cdh2 specifically knocked out in Sertoli cells by crossing Cdh2 loxP mice with Amh-Cre mice. Cdh2 deletion in Sertoli cells did not affect Sertoli cell counts, but led to compromised BTB function, delayed meiotic progression from prophase to metaphase I in testes, increased germ cell apoptosis, sloughing of meiotic cells, and, subsequently, reduced sperm counts in epididymides and subfertility of mice. However, the testes with Cdh2-specific deletion in germ cells did not show any difference from the normal control testes, and phenotypes observed in Sertoli cell and germ cell Cdh2 double-knockout mice were indistinguishable from those in mice with Cdh2 specifically knocked out only in Sertoli cells. Taken together, our data demonstrate that the adhesion junction component, Cdh2, functions just in Sertoli cells, but not in germ cells during spermatogenesis, and is essential for the integrity of BTB function, its deletion in Sertoli cells would lead to the BTB damage and subsequently meiosis and spermatogenesis failure.

Antifibrotic properties of receptor for advanced glycation end products in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic interstitial lung disease with poor survival. Previous reports suggested the contributory effect of receptor for advanced glycation end products (RAGE) to the pathogenesis of IPF. But the findings are controversial. The present in vivo study with RAGE null mice, we further confirmed the evidence that lack of RAGE evolves worse bleomycin-induced pulmonary fibrosis compared with control mice. Moreover, RAGE null mice spontaneously developed similar pathogenesis of lung fibrosis via immunohistochemical staining. In addition, we investigated the negative roles of RAGE on epithelial-mesenchymal transition (EMT) indicated by elevated α-smooth muscle actin (α-SMA) and collagen-I (Col-I) deposition in A549 cell treated with transforming growth factor-ß (TGF-ß), all of which were blocked by sRAGE, a decoy receptor. Furthermore, interacting with the specific ligand as AGE, RAGE blocked TGF-ß-induced activation of Smad2, ERK and JNK signals in A549 cells, which were also challenged by sRAGE administration. This present study confirmed an important role of RAGE in vivo and vitro models of pulmonary fibrosis and suggested the therapeutic possibility for pulmonary fibrosis via RAGE regulation.

microRNA 376a regulates follicle assembly by targeting Pcna in fetal and neonatal mouse ovaries.

In mammals, the primordial follicle pool, providing all oocytes available to a female throughout her reproductive life, is established perinatally. Dysregulation of primordial follicle assembly results in female reproductive diseases, such as premature ovarian insufficiency and infertility. Female mice lacking Dicer1 (Dicer), a gene required for biogenesis of microRNAs, show abnormal morphology of follicles and infertility. However, the contribution of individual microRNAs to primordial follicle assembly remains largely unknown. Here, we report that microRNA 376a (miR-376a) regulates primordial follicle assembly by modulating the expression of proliferating cell nuclear antigen (Pcna), a gene we previously reported to regulate primordial follicle assembly by regulating oocyte apoptosis in mouse ovaries. miR-376a was shown to be negatively correlated with Pcna mRNA expression in fetal and neonatal mouse ovaries and to directly bind to Pcna mRNA 3' untranslated region. Cultured 18.5 days postcoitum mouse ovaries transfected with miR-376a exhibited decreased Pcna expression both in protein and mRNA levels. Moreover, miR-376a overexpression significantly increased primordial follicles and reduced apoptosis of oocytes, which was very similar to those in ovaries co-transfected with miR-376a and siRNAs targeting Pcna. Taken together, our results demonstrate that miR-376a regulates primordial follicle assembly by modulating the expression of Pcna. To our knowledge, this is the first microRNA-target mRNA pair that has been reported to regulate mammalian primordial follicle assembly and further our understanding of the regulation of primordial follicle assembly.

DNA damage in peripheral blood lymphocytes from patients with OSAHS.

PURPOSE: Obstructive sleep apnea hypopnea syndrome (OSAHS) is characterized by intermittent hypoxia during sleep time, followed by oxidative stress. Hypoxia-induced oxidative stress can lead to DNA damage, which is related to chromosome aberrations and micronuclei. The purpose of this study is to investigate the level of DNA damage in peripheral blood of patients with OSAHS. METHODS: Thirty patients with OSAHS diagnosed by polysomnography and 28 healthy volunteers were assessed by the Epworth sleepiness scale. The levels of DNA damage were investigated through the cytokinesis-blocked micronucleus assay. RESULTS: In the group of patients with OSAHS, the mean frequency of binucleated cells with micronuclei were significantly higher than that in the control group (P<0.01), and the frequency of micronuclei among the patients in mild, moderate, and severe stages differed significantly (P<0.05). The mean frequency of nucleoplasmic bridge in OSAHS group was also higher than that in the control group (P<0.05). Nasal continuous positive airway pressure treatment decreased the frequencies of binucleated cells with micronuclei, nucleoplasmic bridge, and nuclear buds. CONCLUSIONS: Oxidative DNA damage increased in peripheral blood lymphocytes of OSAHS patients. It may be related to oxidative stress induced by intermittent hypoxia and may be involved in the pathogenesis of cardiovascular and other target organ injuries.

Effect of Subanesthetic Dose of Esketamine on Perioperative Neurocognitive Disorders in Elderly Undergoing Gastrointestinal Surgery: A Randomized Controlled Trial.

Background: Perioperative neurocognitive disorders (PND), including delayed neurocognitive recovery (dNCR) and postoperative cognitive dysfunction (POCD), are common postoperative complications in elderly patients and adversely affect their prognosis. The study was designed to explore the effects of esketamine on postoperative cognitive function in elderly patients who underwent gastrointestinal surgery under general anesthesia and its potential mechanism. Methods: Eighty-four patients aged 65 and above undergoing gastrointestinal surgery were randomly divided into 2 groups: the esketamine group (group S) and the control group (group C). Group S received intravenous sub-anesthetic doses of esketamine (0.15 mg/kg) 5 minutes before the initiation of surgery, while group C received the same volume of saline. A battery of neuropsychological tests was used to assess cognitive function before surgery, 7 days, and 3 months after surgery. The primary outcome was the incidence of dNCR at 7 days postoperatively and POCD at 3 months postoperatively in both groups. The secondary outcome measures included changes in the levels of serum interleukin-6 (IL-6) and calcium-binding protein ß (S100ß) before and 1 day after surgery. Results: The incidence of dNCR in group S was lower than that of group C (18.15% vs 38.24% P=0.033). Contrarily, there was no difference in both groups regarding POCD 3 months postoperatively (6.06% vs 14.37% P=0.247). Plasma IL-6 and S100ß levels were significantly elevated in both groups on postoperative day 1 (p<0.05), but esketamine pretreatment reduced these levels to some extent compared with group C (p<0.05). Conclusion: Sub-anesthetic doses of esketamine might reduce the incidence of dNCR and improve early postoperative cognitive function in elderly patients undergoing gastrointestinal surgery, which might be related to the anti-neuroinflammation effects of esketamine.

Development and Validation of a Delirium Risk Prediction Model for Elderly Patients Undergoing Elective Orthopedic Surgery.

Purpose: This study aimed to develop and validate a post-operative delirium (POD) nomogram in a population of elderly patients undergoing elective orthopedic surgery. Patients and Methods: A predictive model was developed based on a training dataset of 474 elderly patients undergoing elective orthopedic surgery from March 2021 to May 2022. POD was identified using the Confusion Assessment Methods (CAM). The least absolute shrinkage and selection operator (LASSO) method was used to screen risk factors, and prediction models were created by combining the outcomes with logistic regression analysis. We employ bootstrap validation for internal validation to examine the model's repeatability. The results were validated using a prospective study on 153 patients operated on from January 2022 to May 2022 at another institution. Results: The predictors in the POD nomogram included age, the Mini-Mental State Examination(MMSE), sleep disorder, neurological disorders, preoperative serum creatinine (Pre-SCR), and ASA classification. The c-index of the model was 0.928 (95% confidence interval 0.898 ~ 0.957) and the bootstrap validation still achieved a high c-index of 0.912. The c-index of the external validation was 0.921. The calibration curve for the diagnostic probability showed good agreement between prediction by nomogram and actual observation. Conclusion: By combining preoperative and intraoperative clinical risk factors, we created a POD risk nomogram to predict the probability of POD in elderly patients who undergo elective orthopedic surgery. It could be a tool for guiding individualized interventions.

Bioactive peptides PDBSN improve mitochondrial function and suppression the oxidative stress in human adiposity cells.

Introduction: Mitochondria are essential for generating cellular energy and are significant in the pathogenesis of obesity. Peptide PDBSN has been demonstrated to inhibit the adipogenic differentiation of adipocytes in vitro and improves metabolic homoeostasis in vivo. Therefore, in this study, we further investigated the effects of PDBSN on the morphology, synthesis, and function of adipocyte mitochondria. Methods: Human visceral and subcutaneous primary preadipocytes (HPA-v and HPA-s) were cultured into mature adipocytes. Intracellular triglyceride content was assessed using oil-red O staining and tissue triglyceride determination. Gene and protein levels associated with mitochondrial synthesis were detected using real-time quantitative polymerase chain reaction and western blotting. Mitochondrial membrane potentials and ROS were detected using fluorescent indicators. Morphological changes were observed by electron microscopy. Results: PDBSN significantly increased mitochondrial membrane potential (MMP), while decreasing intracellular triglyceride (TG) and intracellular reactive oxygen species (ROS) levels. On the other hand, the transcription and protein levels of genetic marker genes PGC1-α and MTFA were significantly up-regulated after PDBSN administration. Further studies showed that transcriptional and protein levels of mitochondrial fusion and fission genetic markers MFN1, MFN2, NRF1, and DRP1 increased. Conclusion: PDBSN significantly reduces intracellular TG and ROS levels and increases MMP. The maximum respiratory capacity in adults significantly increases after PDBSN administration, and ROS levels are significantly reduced. This suggests that PDBSN improves mitochondrial function to some extent, which not only provides an essential basis for the pathophysiology of obesity but also provides insights for the development of new drugs to treat obesity and metabolic diseases.

Safety, immunogenicity, and efficacy of the mRNA vaccine CS-2034 as a heterologous booster versus homologous booster with BBIBP-CorV in adults aged ≥18 years: a randomised, double-blind, phase 2b trial.

BACKGROUND: Heterologous boosting is suggested to be of use in populations who have received inactivated COVID-19 vaccines. We aimed to assess the safety and immunogenicity of a heterologous vaccination with the mRNA vaccine CS-2034 versus the inactivated BBIBP-CorV as a fourth dose, as well as the efficacy against the SARS-CoV-2 omicron (BA.5) variant. METHODS: This trial contains a randomised, double-blind, parallel-controlled study in healthy participants aged 18 years or older (group A) and an open-label cohort in participants 60 years and older (group B), who had received three doses of inactivated whole-virion vaccines at least 6 months before enrolment. Pregnant women and people with major chronic illnesses or a history of allergies were excluded. Eligible participants in group A were stratified by age (18-59 years and ≥60 years) and then randomised by SAS 9.4 in a ratio of 3:1 to receive a dose of the mRNA vaccine (CS-2034, CanSino, Shanghai, China) or inactivated vaccine (BBIBP-CorV, Sinopharm, Beijing, China). Safety and immunogenicity against omicron variants of the fourth dose were evaluated in group A. Participants 60 years and older were involved in group B for safety observations. The primary outcome was geometric mean titres (GMTs) of the neutralising antibodies against omicron and seroconversion rates against BA.5 variant 28 days after the boosting, and incidence of adverse reactions within 28 days. The intention-to-treat group was involved in the safety analysis, while all patients in group A who had blood samples taken before and after the booster were involved in the immunogenicity analysis. This trial was registered at the Chinese Clinical Trial Registry Centre (ChiCTR2200064575). FINDINGS: Between Oct 13, and Nov 22, 2022, 320 participants were enrolled in group A (240 in the CS-2034 group and 80 in the BBIBP-CorV group) and 113 in group B. Adverse reactions after vaccination were more frequent in CS-2034 recipients (158 [44·8%]) than BBIBP-CorV recipients (17 [21·3%], p<0·0001). However, most adverse reactions were mild or moderate, with grade 3 adverse reactions only reported by eight (2%) of 353 participants receiving CS-2034. Heterologous boosting with CS-2034 elicited 14·4-fold (GMT 229·3, 95% CI 202·7-259·4 vs 15·9, 13·1-19·4) higher concentration of neutralising antibodies to SARS-CoV-2 omicron variant BA.5 than did homologous boosting with BBIBP-CorV. The seroconversion rates of SARS-CoV-2-specific neutralising antibody responses were much higher in the mRNA heterologous booster regimen compared with BBIBP-CorV homologous booster regimen (original strain 47 [100%] of 47 vs three [18·8%] of 16; BA.1 45 [95·8%] of 48 vs two [12·5%] 16; and BA.5 233 [98·3%] of 240 vs 15 [18·8%] of 80 by day 28). INTERPRETATION: Both the administration of mRNA vaccine CS-2034 and inactivated vaccine BBIBP-CorV as a fourth dose were well tolerated. Heterologous boosting with mRNA vaccine CS-2034 induced higher immune responses and protection against symptomatic SARS-CoV-2 omicron infections compared with homologous boosting, which could support the emergency use authorisation of CS-2034 in adults. FUNDING: Science and Technology Commission of Shanghai, National Natural Science Foundation of China, Jiangsu Provincial Science Fund for Distinguished Young Scholars, and Jiangsu Provincial Key Project of Science and Technology Plan. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Stem Cell-Based Therapy for Diabetic Foot Ulcers.

Diabetic foot ulcer has become a worldwide clinical medical challenge as traditional treatments are not effective enough to reduce the amputation rate. Therefore, it is of great social significance to deeply study the pathogenesis and biological characteristics of the diabetic foot, explore new treatment strategies and promote their application. Stem cell-based therapy holds tremendous promise in the field of regenerative medicine, and its mechanisms include promoting angiogenesis, ameliorating neuroischemia and inflammation, and promoting collagen deposition. Studying the specific molecular mechanisms of stem cell therapy for diabetic foot has an important role and practical clinical significance in maximizing the repair properties of stem cells. In addition, effective application modalities are also crucial in order to improve the survival and viability of stem cells at the wound site. In this paper, we reviewed the specific molecular mechanisms of stem cell therapy for diabetic foot and the extended applications of stem cells in recent years, with the aim of contributing to the development of stem cell-based therapy in the repair of diabetic foot ulcers.

ABCA7 rs3764650 Polymorphism is Associated with Delayed Neurocognitive Recovery.

Background: Several studies have shown that ATP-binding cassette transporter A7 (ABCA7) gene variation is associated with cognitive impairment. This study was aimed to investigate the relationship between ABCA7 rs3764650 polymorphism and perioperative neurocognitive disorder (pNCD). Methods: A total of 132 elderly patients aged 65 and over who underwent elective non-cardiac surgery were enrolled in the study, while 28 healthy volunteers matching age and sex were recruited as the control group. A battery of neuropsychological tests was conducted 1 day before, 7 days, and 3 months after surgeries. Delayed neurocognitive recovery (dNCR) and postoperative mild or major neurocognitive disorder (POCD) were determined using the Z value method. The venous blood sample of the surgical patients was taken before the operation. Genotyping of rs3764650 was performed using polymerase chain reaction amplification and restriction fragment length polymorphism analysis. Results: The incidences of dNCR and POCD were 29.7% and 16.8% at 7 days and 3 months after surgery, respectively. The G allele frequency and GG frequency of dNCR patients were significantly higher than that of non-dNCR patients (43.3% vs 28.2%, P=0.035; 23.3% vs 4.2%, P=0.013, respectively) at 7 days following surgery. No significant differences in ABCA7 alleles between POCD and non-POCD patients were observed 3 months postoperatively. Conclusion: ABCA7 rs3764650 gene polymorphism is associated with dNCR and GG genotype might be a predisposing factor for postoperative cognitive impairment in Chinese Han elderly populations.

Small extracellular vesicles isolation and separation: Current techniques, pending questions and clinical applications.

Extracellular vesicles, especially small extracellular vesicles (sEVs) are now accepted as important messengers in cell-to-cell communication and as a promising drug delivery platform. They are involved in nearly all physiological and pathological processes and are involved in disease diagnosis and therapy. However, their heterogeneity of physicochemical properties and functions is not fully understood, which hinders further clinical applications. To obtain highly bioactive sEVs with both high yield and purity, will certainly facilitate their future study and application. This review informs up-to-date research on frequently-used and cutting-edge technologies of sEVs isolation and makes a deep comparison and analysis of different methods, including their advantages, limitations and applications. Pending questions about the inherent property of these small vesicles as well as isolation strategies are discussed. Additionally, an overview of their applications in disease diagnosis and treatment, including some of the on-going clinical trials, are also reviewed.

Youjing granules ameliorate spermatogenesis in rats through regulating the prolifereation of spermatogonial stem cells.

Male infertility has evolved from a common reproductive system disease to a major social issue. Youjing granule (YG) is a Chinese medicinal material used as a therapy method for tonifying the kidneys and removing dampness due to its pathogenic characteristics. YG has been shown to regulate sperm quality in clinical trials, but the underlying mechanism is not fully understood. The present study was aimed to explore the protective effects and mechanism of action of YG on male reproductive system damage caused by methyl methane sulfonate (MMS). We first established an infertility model of rats through oral administration of MMS and then treated with YG. To determine the effect of YG, spermatogenesis, microvascular density, and secretory function of Leydig cells and Sertoli cells in rats were assessed. Spermatogonial stem cells (SSCs) were co-cultured with mouse embryo fibroblast (MEF) cells as an in vitro cell model before exposure to serum containing YG. Furthermore, the proliferation and apoptosis of SSCs were measured. Results indicated that YG increased the expression of self-renewal and proliferation-related molecules such as glial cell line derived neurotrophic factor (GDNF) and fibroblast growth factor-2 (FGF2), and improved the quality of sperm and the proliferation of SSCs. In conclusion, YG may protect spermatogenetic function of rats through regulating the proliferation and self-renewal of SSCs.