A novel missense mutation of CCDC34 causes male infertility with oligoasthenoteratozoospermia in a consanguineous Pakistani family.

ABSTRACT: Male infertility is a worldwide health issue, affecting 8%-12% of the global population. Oligoasthenoteratozoospermia (OAT) represents a severe type of male infertility, characterized by reduced sperm count and motility and an increased frequency of sperm with aberrant morphology. Using whole-exome sequencing, this study identified a novel missense mutation (c.848C>A, p.A283E) in the coiled-coil domain-containing 34 gene (CCDC34) in a consanguineous Pakistani family. This rare mutation was predicted to be deleterious and to affect the protein stability. Hematoxylin and eosin staining of spermatozoa from the patient with OAT revealed multiple morphological abnormalities of the flagella and transmission electron microscopy indicated axonemal ultrastructural defects with a lack of outer dynein arms. These findings indicated that CCDC34 plays a role in maintaining the axonemal ultrastructure and the assembly or stability of the outer dynein arms, thus expanding the phenotypic spectrum of CCDC34 missense mutations.

Linking the relationship between dietary folic acid intake and risk of osteoporosis among middle-aged and older people: A nationwide population-based study.

Among middle-aged and older people, balanced and nutritious diets are the foundation for maintaining bone health and preventing osteoporosis. This study is aimed at investigating the link between dietary folic acid intake and the risk of osteoporosis among middle-aged and older people. A total of 20,686 people from the National Health and Nutritional Examination Survey (NHANES) 2007-2010 are screened and included, and 5312 people aged ≥45 years with integral data are ultimately enrolled in evaluation. Demographics and dietary intake-related data are gathered and analyzed, and the odds ratio (OR) and 95% confidence interval (CI) of each tertile category of dietary folic acid intake and each unit increase in folic acid are assessed via multivariate logistic regression models. On this basis, the receiver operating characteristic (ROC) curve is used to identify the optimal cutoff value of dietary folic acid intake for indicating the risk of osteoporosis. Of 5312 people with a mean age of 62.4 ± 11.0 years old, a total of 513 people with osteoporosis are screened, and the dietary folic acid intake amount of the osteoporosis group is significantly lower than that of the non-osteoporosis group (p < .001). The lowest tertile category is then used to act as a reference category, and a higher dietary folic acid intake amount is observed to be positively related to lower odds for risk of osteoporosis. This trend is also not changed in adjustments for combinations of different covariates (p all < .05). Based on this, a dietary folic acid intake of 475.5 µg/day is identified as an optimal cutoff value for revealing osteoporosis. Collectively, this nationwide population-based study reveals that a higher daily dietary folic acid intake has potential protective effects on osteoporosis in middle-aged and older people.

Dislocations deteriorate postoperative functional outcomes in supination-external rotation ankle fractures.

PURPOSE: To assess the relationship between dislocation and functional outcomes in supination-external rotation (SER) ankle fractures. METHODS: A retrospective case series study was performed on patients with ankle fractures treated surgically at a large trauma center from January 2015 to December 2021. The inclusion criteria were young and middle-aged patients of 18-65 years with SER ankle fractures that can be classified by Lauge-Hansen classification and underwent surgery at our trauma center. Exclusion criteria were serious life-threatening diseases, open fractures, fractures delayed for more than 3 weeks, fracture sites ≥2, etc. Then patients were divided into dislocation and no-dislocation groups. Patient demographics, injury characteristics, surgery-related outcomes, and postoperative functional outcomes were collected and analyzed. The functional outcomes of SER ankle fractures were assessed postoperatively at 1-year face-to-face follow-up using the foot and ankle outcome score (FAOS) and American orthopedic foot and ankle society score and by 2 experienced orthopedic physicians. Relevant data were analyzed using SPSS version 22.0 by Chi-square or t-test. RESULTS: During the study period, there were 371 ankle fractures. Among them, 190 (51.2%) were SER patterns with 69 (36.3%) combined with dislocations. Compared with the no-dislocation group, the dislocation group showed no statistically significant differences in gender, age composition, fracture type, preoperative complications with diabetes, smoking history, preoperative waiting time, operation time, and length of hospital stay (all p > 0.05), but a significantly higher Lauge-Hansen injury grade (p < 0.001) and syndesmotic screw fixation rate (p = 0.033). Moreover, the functional recovery was poorer, revealing a significantly lower FAOS in the sport/rec scale (p < 0.001). Subgroup analysis showed that among SER IV ankle fracture patients, FAOS was much lower in pain (p = 0.042) and sport/rec scales (p < 0.001) for those with dislocations. American orthopedic foot and ankle society score revealed no significant difference between dislocation and no-dislocation patients. CONCLUSION: Dislocation in SER ankle fractures suggests more severe injury and negatively affects functional recovery, mainly manifested as more pain and poorer motor function, especially in SER IV ankle cases.

Efficacy and Safety of Orally and Intravenously Administration of Tranexamic Acid in Patients with Elderly Femoral Neck Fracture.

OBJECTIVE: For elderly femoral neck fracture patients, anemia is one of the most common complications, increasing the risk of postoperative adverse events. Tranexamic acid (TXA) has been widely applied to the perioperative blood management. However, the optimal route of TXA administration in elderly femoral neck fracture remains unclear. The aim of this study is to evaluate the efficacy and safety of oral and intravenous (IV) application of TXA in elderly patients with femoral neck fracture undergoing total hip arthroplasty (THA) and hemiarthroplasty (HA). METHODS: All elderly patients aged over 65 years old diagnosed with femoral neck fracture admitted to the trauma orthopedics from August 1, 2020 to February 28, 2022 were enrolled in this prospective cohort study. Participants were divided into three groups: oral group: TXA 2g orally 2 h before incision; IV group: intravenous infusion of TXA 1g 15 min before incision; and control group: usual hemostatic method. The primary outcomes were total blood loss, allogeneic transfusion rate, and postoperative thromboembolic events. SPSS 23.0 (IBM, Armonk, NY, USA) was used for statistical analysis, and p ≤ 0.05 was considered statistically significant. RESULTS: A total of 100 patients were enrolled, including 32 cases in the oral group, 34 cases in the IV group and 34 cases in the control group. Compared with the control group, the total perioperative blood loss in the oral and IV groups was significantly decreased (763.92 ± 358.64 mL vs 744.62 ± 306.88 mL vs 1250.60 ± 563.37 mL, p = 0.048). No significant difference was identified between the oral and IV groups (p = 0.970). The rate of allogeneic transfusion was lower in the oral and IV groups than in the control group, but the difference had no statistical significant (6 vs 5 vs 12, p = 0.108), However, subgroup analysis showed that the IV and oral groups in patients who underwent THA have significant lower transfusion rate compared with the control group (1 vs 3 vs 7, p = 0.02). During 6 months follow-up, no thromboembolic events were identified. Two patients (one from the oral group and one from the control group) died of respiratory failure. The cost of blood management from the oral group was significantly lower than IV (p < 0.001) and control groups (p = 0.009). CONCLUSION: Elderly patients with femoral neck fracture undergoing THA can benefit from both IV and oral administration of tranexamic acid. The results of these two administration routes are similar in safety and effectiveness. A similar tendency was observed in patients undergoing HA. Oral TXA is more cost-benefit compared with intravenous applications.

A Conserved Intramolecular Ion-Pair Plays a Critical but Divergent Role in Regulation of Dimerization and Transport Function among the Monoamine Transporters.

The monoamine transporters, including the serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET), are the therapeutic targets for the treatment of many neuropsychiatric disorders. Despite significant progress in characterizing the structures and transport mechanisms of these transporters, the regulation of their transport functions through dimerization or oligomerization remains to be understood. In the present study, we identified a conserved intramolecular ion-pair at the third extracellular loop (EL3) connecting TM5 and TM6 that plays a critical but divergent role in the modulation of dimerization and transport functions among the monoamine transporters. The disruption of the ion-pair interactions by mutations induced a significant spontaneous cross-linking of a cysteine mutant of SERT and an increase in cell surface expression but with an impaired specific transport activity. On the other hand, similar mutations of the corresponding ion-pair residues in both DAT and NET resulted in an opposite effect on their oxidation-induced dimerization, cell surface expression, and transport function. Reversible biotinylation experiments indicated that the ion-pair mutations slowed down the internalization of SERT but stimulated the internalization of DAT. In addition, cysteine accessibility measurements for monitoring SERT conformational changes indicated that substitution of the ion-pair residues resulted in profound effects on the rate constants for cysteine modification in both the extracellular and cytoplasmatic substrate permeation pathways. Furthermore, molecular dynamics simulations showed that the ion-pair mutations increased the interfacial interactions in a SERT dimer but decreased it in a DAT dimer. Taken together, we propose that the transport function is modulated by the equilibrium between monomers and dimers on the cell surface, which is regulated by a potential compensatory mechanism but with different molecular solutions among the monoamine transporters. The present study provided new insights into the structural elements regulating the transport function of the monoamine transporters through their dimerization.

Identification of the potassium-binding site in serotonin transporter.

Clearance of serotonin (5-hydroxytryptamine, 5-HT) from the synaptic cleft after neuronal signaling is mediated by serotonin transporter (SERT), which couples this process to the movement of a Na+ ion down its chemical gradient. After release of 5-HT and Na+ into the cytoplasm, the transporter faces a rate-limiting challenge of resetting its conformation to be primed again for 5-HT and Na+ binding. Early studies of vesicles containing native SERT revealed that K+ gradients can provide an additional driving force, via K+ antiport. Moreover, under appropriate conditions, a H+ ion can replace K+. Intracellular K+ accelerates the resetting step. Structural studies of SERT have identified two binding sites for Na+ ions, but the K+ site remains enigmatic. Here, we show that K+ antiport can drive substrate accumulation into vesicles containing SERT extracted from a heterologous expression system, allowing us to study the residues responsible for K+ binding. To identify candidate binding residues, we examine many cation binding configurations using molecular dynamics simulations, predicting that K+ binds to the so-called Na2 site. Site-directed mutagenesis of residues in this site can eliminate the ability of both K+ and H+ to drive 5-HT accumulation into vesicles and, in patch clamp recordings, prevent the acceleration of turnover rates and the formation of a channel-like state by K+ or H+. In conclusion, the Na2 site plays a pivotal role in orchestrating the sequential binding of Na+ and then K+ (or H+) ions to facilitate 5-HT uptake in SERT.

Reciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer.

Squamous cell carcinomas (SCCs) are common and aggressive malignancies. Immune check point blockade (ICB) therapy using PD-1/PD-L1 antibodies has been approved in several types of advanced SCCs. However, low response rate and treatment resistance are common. Improving the efficacy of ICB therapy requires better understanding of the mechanism of immune evasion. Here, we identify that the SCC-master transcription factor TP63 suppresses interferon-γ (IFNγ) signaling. TP63 inhibition leads to increased CD8+ T cell infiltration and heighten tumor killing in in vivo syngeneic mouse model and ex vivo co-culture system, respectively. Moreover, expression of TP63 is negatively correlated with CD8+ T cell infiltration and activation in patients with SCC. Silencing of TP63 enhances the anti-tumor efficacy of PD-1 blockade by promoting CD8+ T cell infiltration and functionality. Mechanistically, TP63 and STAT1 mutually suppress each other to regulate the IFNγ signaling by co-occupying and co-regulating their own promoters and enhancers. Together, our findings elucidate a tumor-extrinsic function of TP63 in promoting immune evasion of SCC cells. Over-expression of TP63 may serve as a biomarker predicting the outcome of SCC patients treated with ICB therapy, and targeting TP63/STAT/IFNγ axis may enhance the efficacy of ICB therapy for this deadly cancer.

Targeting the gut microbiota-related metabolites for osteoporosis: The inextricable connection of gut-bone axis.

Osteoporosis is a systemic skeletal disease characterized by decreased bone mass, destruction of bone microstructure, raised bone fragility, and enhanced risk of fractures. The correlation between gut microbiota and bone metabolism has gradually become a widespread research hotspot in recent years, and successive studies have revealed that the alterations of gut microbiota and its-related metabolites are related to the occurrence and progression of osteoporosis. Moreover, several emerging studies on the relationship between gut microbiota-related metabolites and bone metabolism are also underway, and extensive research evidence has indicated an inseparable connection between them. Combined with latest literatures and based on inextricable connection of gut-bone axis, this review is aimed to summarize the relation, potential mechanisms, application strategies, clinical application prospects, and existing challenges of gut microbiota and its-related metabolites on osteoporosis, thus updating the knowledge in this research field and providing certain reference for future researches.

Establishing mouse and human oral esophageal organoids to investigate the tumor immune response.

Organoid culture systems are very powerful models that recapitulate in vivo organ development and disease pathogenesis, offering great promise in basic research, drug screening and precision medicine. However, the application of organoids derived from patients with cancer to immunotherapeutic research is a relatively untapped area. Esophageal cancer is one of the most lethal malignancies worldwide, including two major pathological subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma. ESCC shares many biological and genomic features with oral squamous cell cancers. Herein, we provide a versatile protocol for the establishment and maintenance of oral and esophageal organoid cultures derived from both murine and human samples. We describe culture conditions for organoids derived from normal tongue, esophagus and gastroesophageal junction, esophageal cancer and Barrett's esophagus. In addition, we establish an ex vivo model by co-culturing patient tumor-derived organoids and autologous CD8+ T lymphocytes to assess CD8+ T cell-mediated tumor killing. Our protocol can also be modified for organoid establishment from other squamous epithelia and carcinomas. The co-culture model can serve as a template for studies of other tumor-immune cell interactions and the efficacy of immune checkpoint blockade therapy.

Diets intervene osteoporosis via gut-bone axis.

Osteoporosis is a systemic skeletal disease that seriously endangers the health of middle-aged and older adults. Recently, with the continuous deepening of research, an increasing number of studies have revealed gut microbiota as a potential target for osteoporosis, and the research concept of the gut-bone axis has gradually emerged. Additionally, the intake of dietary nutrients and the adoption of dietary patterns may affect the gut microbiota, and alterations in the gut microbiota might also influence the metabolic status of the host, thus adjusting bone metabolism. Based on the gut-bone axis, dietary intake can also participate in the modulation of bone metabolism by altering abundance, diversity, and composition of gut microbiota. Herein, combined with emerging literatures and relevant studies, this review is aimed to summarize the impacts of different dietary components and patterns on osteoporosis by acting on gut microbiota, as well as underlying mechanisms and proper dietary recommendations.

Expansion and contraction of lake basin shape the genetic structure of Sinocyclocheilus (Osteichthyes: Cypriniformes: Cyprinidae) populations in Central Yunnan, China.

Geological events can strongly affect the genetic structures and differentiation of fish populations. Especially, as an endemic fish of the genus Sinocyclocheilus in the Yunnan-Guizhou Plateau, the effects of key geological events on the distributions and genetic structures remain poorly understood. Examining the phylogeographic patterns of Sinocyclocheilus fishes can be useful for elucidating the spatio-temporal dynamics of their population size, dispersal history and extent of geographical isolation, thereby providing a theoretical basis for their protection. Here, we used single nucleotide polymorphisms (SNP) method to investigate the phylogeographic patterns of Sinocyclocheilus fishes. Our analysis supports the endemicity of Sinocyclocheilus, but the samples of different regions of Sinocyclocheilus contain multiple ancestral components, which displayed more admixed and diversified genetic components, this may be due to the polymorphism of the ancestors themselves, or gene infiltration caused by hybridization between adjacent species of Sinocyclocheilus. We estimate that the most recent common ancestor (MRCA) of Sinocyclocheilus fish in the Central Yunnan Basin at approximately 3.75~3.11 Ma, and infer that the evolution of Sinocyclocheilus in the central Yunnan Basin is closely related to the formation of plateau lakes (around 4.0~0.02 Ma), and identifies the formation of Dianchi Lake and Fuxian Lake as key geological events shaping Sinocyclocheilus population structure. It is also the first time to prove that the altitude change has a great influence on the genetic variation among the populations of Sinocyclocheilus.

The supplementation of Rothia as a potential preventive approach for bone loss in mice with ovariectomy-induced osteoporosis.

There is an inseparable link between bone metabolism and gut microbiota, and the supplementation of probiotics exhibits a significant role in maintaining the homeostasis of gut microbiota and inhibiting bone loss. This study aims to explore the preventive and therapeutic potentials and the specific mechanisms of Rothia on osteoporosis. The mice models of osteoporosis induced by ovariectomy (OVX) were built, and the regular (once a day) and quantitative (200 µL/d) gavage of Rothia was performed for 8 weeks starting from 1 week after OVX. Microcomputed tomography was used to analyze the bone mass and bone microstructure of mice in each group after sacrifice. Histological staining and immunohistochemistry were then applied to identify the expression of pro-inflammatory cytokines, intestinal permeability, and osteogenic and osteoclastic activities of mice. The collected feces of mice in each group were used for 16S rRNA high-throughput sequencing to detect the alterations in composition, abundance, and diversity of gut microbiota. This study demonstrated that the gavage of Rothia alleviated bone loss in mice with OVX-induced osteoporosis, improved OVX-induced intestinal mucosal barrier injury, optimized intestinal permeability (zonula occludens protein 1 and occludin), reduced intestinal inflammation (tumor necrosis factor-α and interleukin-1ß), and regulated imbalance of gut microbiota. Based on "gut-bone" axis, this study revealed that regular and quantitative gavage of Rothia can relieve bone loss in mice with OVX-induced osteoporosis by repairing the intestinal mucosal barrier injury, optimizing the intestinal permeability, inhibiting the release of pro-inflammatory cytokines, and improving the disorder of gut microbiota.

Efficacy and safety of tranexamic acid in elderly patients with femoral neck fracture treated with hip arthroplasty: A systematic review and meta-analysis.

BACKGROUND: Elderly patients with femoral neck fracture have high perioperative blood loss according to the trauma and hip arthroplasty surgery. Tranexamic acid is a fibrinolytic inhibitor and has been widely used in hip fracture patients to against perioperative anemia. The aim of the present meta-analysis was to evaluate the efficacy and safety of Tranexamic acid (TXA) in elderly patients with femoral neck fracture undergoing hip arthroplasty. METHODS: We performed search using Pubmed, EMBASE, Cochrane Reviews, and Web of Science databases to identify all relevant research studies published from inception to June 2022. Randomized controlled studies and high-quality cohort studies that reported the perioperative use of TXA in patients with femoral neck fractures treated with arthroplasty, and made a comparison with the control group were included. Meta-analysis was performed using Review Manager 5.3 to assess the efficacy and safety of TXA. Subgroup analysis was conducted to further investigate the impact caused by surgery types and administration routes on the efficacy and safety outcomes. RESULTS: Five randomized controlled trials (RCTs) and eight cohort studies published from January 2015 to June 2022 were included in this meta-analysis. The results showed significant reductions in the rate of allogeneic blood transfusion, total blood loss (TBL) and postoperative hemoglobin (Hb) drop in the TXA group compared with the control group, while no significant difference was found in the intraoperative blood loss, postoperative drainage, hospital length of stay (LOS), re-admission rate, and wound complications between the two groups. The incidence of thromboembolic events and mortality showed no significant difference. Subgroup analysis indicated that surgery types and administration routes did not change the overall tendency. CONCLUSION: The current evidence shows that both intravascular administration (IV) and topical administration of TXA can significantly decrease the perioperative transfusion rate and TBL without increasing the risk of thromboembolic complications in elderly patients with femoral neck fracture.

Unique Substrate Recognition and Sodium-Substrate Binding Stoichiometry in a Bacterial Serotonin Transporter, TuriSERT.

All resolved high-resolution structures of the transporters in the neurotransmitter sodium symporter (NSS) family revealed that the NSS members share common structural and mechanistic features for substrate and ion binding and transport. However, a recently reported bacterial orthologue of the human serotonin transporter (hSERT), TuriSERT, possesses a structural characteristic specific for amino acid substrate binding but does transport a biogenic amine. The unique structural feature of TuriSERT requires a novel configuration for coordinating its substrate and ions. In the present study, we characterized TuriSERT expressed in Escherichia coli cells with a fluorescent substrate by biochemical, structural, and pharmacological approaches. Substrate transport by TuriSERT requires Na+ but not Cl-. Replacement of Asp262 by asparagine renders TuriSERT Cl--dependent. Substitutions of the corresponding Na1 residues did not alter Na+ dependence on substrate transport, whereas the mutation of a Na2 site residue led to a loss of transport activity, suggesting that Na+ binds only to the Na2 site in TuriSERT. In addition, substitutions of several residues essential for recognizing 5-hydroxytryptamine (5-HT) in hSERT had little effect on 5-HT displacement potency in transport assay for TuriSERT. In contrast, mutations of the residues that are proposed to coordinate with 5-HT in our docking model dramatically reduced 5-HT displacement. Furthermore, our results indicated that all tested antidepressants showed a weak inhibitory effect on TuriSERT. The present study demonstrated the existence of a unique substrate binding site and 1:1 stoichiometry of sodium-substrate binding in TuriSERT, a novel structural finding for the NSS transporters.

Mephedrone induces partial release at human dopamine transporters but full release at human serotonin transporters.

Mephedrone (4-methylmethcathinone) is a cathinone derivative that is recreationally consumed for its energizing and empathogenic effects. The stimulating properties are believed to arise from the ability of mephedrone to interact with the high-affinity transporters for dopamine (DA) (DAT) and norepinephrine (NET), whereas the entactogenic effect presumably relies on its activity at the serotonin (5-HT) transporter (SERT). Early studies found that mephedrone acts as a releaser at NET, DAT and SERT, and thus promotes efflux of the respective monoamines. Evidence linked drug-induced reverse transport of 5-HT via SERT to prosocial effects, whereas activity at DAT is strongly correlated with abuse liability. Consequently, we sought to evaluate the pharmacology of mephedrone at human (h) DAT and SERT, heterologously expressed in human embryonic kidney 293 cells, in further detail. In line with previous studies, we report that mephedrone evokes carrier-mediated release via hDAT and hSERT. We found this effect to be sensitive to the protein kinase C inhibitor GF109203X. Electrophysiological recordings revealed that mephedrone is actively transported by hDAT and hSERT. However, mephedrone acts as a full substrate of hSERT but as a partial substrate of hDAT. Furthermore, when compared to fully efficacious releasing agents at hDAT and hSERT (i.e. S(+)-amphetamine and para-chloroamphetamine, respectively) mephedrone displays greater efficacy as a releaser at hSERT than at hDAT. In summary, this study provides additional insights into the molecular mechanism of action of mephedrone at hDAT and hSERT.

Relationships among body weight, lipids and bone mass in elderly individuals with fractures: A case-control study.

BACKGROUND: The prevalence of osteoporosis and low bone mass is steadily rising each year. Low body weight is commonly linked to diminished bone mass and serves as a robust predictor of osteoporosis. Nonetheless, the connection between body mass index (BMI), bone mineral density, and lipid profiles among the elderly remains elusive. AIM: To examine the association between BMI and bone mass, explore the correlation between lipid profiles and bone mass, and delve into the interplay between lipid metabolism and bone health. METHODS: The study included 520 patients aged ≥ 65 years (178 men and 342 women). Age, sex, weight, and height were recorded. Femoral neck bone mineral density and T scores were determined using a dual-energy X-ray absorptiometry scanner. Blood calcium (Ca), phosphorus (P), albumin (ALB), alkaline phosphatase (ALP), aspartate aminotransferase, alanine aminotransferase, triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels were measured. Patients were classified by sex (male and female), age (65-79 years and ≥ 80 years), and T score (normal bone mineral density, osteopenia and osteoporosis). RESULTS: Age, sex, BMI, and ALP and TG levels were independent risk factors for osteoporosis. For the 65-79- and ≥ 80-year-old groups, females presented lower T scores than males. Ca, P, ALB, ALP, TC, HDL and LDL levels were significantly different between men and women in the 65-79-year-old group. In addition, BMI and TG levels were significantly decreased in osteoporotic patients compared with patients with normal bone mass. TC levels declined in 65- to 79-year-old male and female osteoporosis patients. In the group of women aged ≥ 80 years, osteoporotic patients showed significantly increased ALP levels. Furthermore, we found positive correlations between BMI and TG levels in the male and female patient groups. However, we found no significant differences in ALB, Ca, P, HDL and LDL levels in osteoporotic patients compared to patients with normal bone mass. CONCLUSION: Osteoporotic patients showed significantly decreased BMI and TG levels compared with those with normal bone mass. BMI showed positive correlations with TG levels in male and female patients. These results indicate correlations between BMI and bone mass and between lipid profiles and bone mass.

The synergistic mechanism of action of Dajianzhong decoction in conjunction with ketamine in the treatment of depression.

Depression is a multifactorial syndrome with a variety of underlying pathological mechanisms. While ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exhibits a rapid antidepressant action in the central never system (CNS), the potential addiction and psychotomimetic adverse effects of ketamine limit its chronic use in clinical practice. Therefore, it is necessary to discover an additional agent that shows a synergistic antidepressant activity with ketamine to sustain its therapeutic action so as to reduce its use frequency in depression treatment. The present study indicated that Dajianzhong decoction (DJZT), an empirical herbal formula used for the clinical treatment of several inflammation-related intestinal disorders, sustains behavioral and synaptic action of ketamine in depressive mouse models. Additionally, ketamine was also demonstrated to exert a synergistic action with DJZT to alleviate the chronic unpredictable mild stress (CUMS)-induced abnormalities in gut barrier proteins and colonic histology, and subsequently to normalize the diversity and composition of gut microbiota. Furthermore, DJZT was shown to possess an anti-inflammatory activity to prevent activation of NF-κB from releasing proinflammatory cytokines, specifically through inhibiting Th17 cells/IL-17A pathway. Our results uncovered the mechanism of action of DJZT in conjunction with ketamine in depression treatment by which these agents target different pathological factors across biological systems and exert a synergistic activity through a bidirectional communication in the gut-brain axis, and also provided new insights into the systematic treatment of depression.

The Preventive Effects of Probiotic Prevotella histicola on the Bone Loss of Mice with Ovariectomy-Mediated Osteoporosis.

It has been demonstrated that the disturbance of gut microbiota (GM) is closely related to the reduction of bone mass and incidence of osteoporosis (OP). The aim of this study is to investigate whether the supplementation of Prevotella histicola (Ph) can prevent the bone loss in mice with ovariectomy (OVX)-mediated OP, and further explore relevant mechanisms. Regular (once a day for 8 consecutive weeks) and quantitative (200 µL/d) perfusion of Ph (the bacteria that orally gavaged) was conducted starting from 1 week after the construction of mice models. Bone mass and bone microstructure were detected by Micro-computed tomography (Micro-CT). Expressions of intestinal permeability, pro-inflammatory cytokines, and osteogenic and osteoclastic activities of mice were analyzed by histological staining and immunohistochemistry (IHC). 16S rRNA high throughput sequencing technique was applied to analyze the alterations of composition, abundance, and diversity of collected feces. Regular and quantitative perfusion of Ph mitigated the bone loss in mice with OVX-mediated OP. Compared with OVX + PBS group, perfusion of Ph repressed osteoclastogenesis and promoted osteogenesis, reduced release of pro-inflammatory cytokine cytokines (interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α)), and reversed expressions of tight junction proteins (zonula occludens protein 1 (ZO-1) and Occludin). Besides, the perfusion of Ph improved the composition, abundance, and diversity of GM. Collectively, this study revealed that regular and quantitative perfusion of Ph can improve the bone loss in mice with OVX-mediated OP by repairing intestinal mucosal barrier damage, optimizing intestinal permeability, inhibiting release of pro-osteoclastogenic cytokines, and improving disturbance of GM.

Postoperative awake prone position in geriatric patients with hip fractures: a protocol for a randomized controlled trial on the efficacy of postoperative prone position in reducing pulmonary complications and improving oxygenation.

INTRODUCTION: Postoperative pulmonary complications (PPCs) are prevalent in geriatric patients with hip fractures. Low oxygen level is one of the most important risk factors for PPCs. Prone position has been proven efficacy in improving oxygenation and delaying the progress of pulmonary diseases, especially in patients with acute respiratory distress syndrome induced by multiple etiologies. The application of awake prone position (APP) has also attracted widespread attention in recent years. A randomized controlled trial (RCT) will be carried out to measure the effect of postoperative APP in a population of geriatric patients undergoing hip fracture surgery. METHODS: This is an RCT. Patients older than 65 years old admitted through the emergency department and diagnosed with an intertrochanteric or femoral neck fracture will be eligible for enrollment and assigned randomly to the control group with routine postoperative management of orthopedics or APP group with an additional prone position for the first three consecutive postoperative days (PODs). Patients receiving conservative treatment will not be eligible for enrollment. We will record the difference in the patient's room-air-breathing arterial partial pressure of oxygen (PaO2) values between the 4th POD (POD 4) and emergency visits, the morbidity of PPCs and other postoperative complications, and length of stay. The incidence of PPCs, readmission rates, and mortality rates will be followed up for 90 PODs. DISCUSSION: We describe the protocol for a single-center RCT that will evaluate the efficacy of postoperative APP treatment in reducing pulmonary complications and improving oxygenation in geriatric patients with hip fractures. ETHICS AND DISSEMINATION: This protocol was approved by the independent ethics committee (IEC) for Clinical Research of Zhongda Hospital, Affiliated to Southeast University, and is registered on the Chinese Clinical Trial Registry. The findings of the trial will be disseminated through peer-reviewed journals. ETHICS APPROVAL NUMBER: 2021ZDSYLL203-P01 TRIAL REGISTRATION: ChiCTR ChiCTR2100049311 . Registered on 29 July 2021. TRIAL STATUS: Recruiting. Recruitment is expected to be completed in December 2024.

Linking the relation between gut microbiota and glucocorticoid-induced osteoporosis.

Osteoporosis (OP) is the most prevalent metabolic bone disease, characterized by the low bone mass and microarchitectural deterioration of bone tissue. Glucocorticoid (GC) clinically acts as one of the anti-inflammatory, immune-modulating, and therapeutic drugs, whereas the long-term use of GC may cause rapid bone resorption, followed by prolonged and profound suppression of bone formation, resulting in the GC-induced OP (GIOP). GIOP ranks the first among secondary OP and is a pivotal risk for fracture, as well as high disability rate and mortality, at both societal and personal levels, vital costs. Gut microbiota (GM), known as the "second gene pool" of human body, is highly correlated with maintaining the bone mass and bone quality, and the relation between GM and bone metabolism has gradually become a research hotspot. Herein, combined with recent studies and based on the cross-linking relationship between GM and OP, this review is aimed to discuss the potential mechanisms of GM and its metabolites on the OP, as well as the moderating effects of GC on GM, thereby providing an emerging thought for prevention and treatment of GIOP.