Is Type 2 Diabetes Mellitus Associated with Spinal Degenerative Disorders?: Evidence from Observational and 2-Sample Mendelian Randomization Analyses.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and spinal degenerative disorders (SDD) are common diseases that frequently coexist. However, both traditional observational studies and recent Mendelian randomization (MR) studies have demonstrated conflicting evidence on the association between T2DM and SDD. This comparative study explored and compared the association between T2DM and SDD using observational and MR analyses. METHODS: For observational analyses, cross-sectional studies (44,972 participants with T2DM and 403,095 participants without T2DM), case-control studies (38,234 participants with SDD and 409,833 participants without SDD), and prospective studies (35,550 participants with T2DM and 392,046 participants without T2DM with follow-up information until 2022) were performed to test the relationship between T2DM and SDD using individual-level data from the U.K. Biobank from 2006 to 2022. For MR analyses, the associations between single-nucleotide polymorphisms with SDD susceptibility obtained using participant data from the U.K. Biobank, which had 407,938 participants from 2006 to 2022, and the FinnGen Consortium, which had 227,388 participants from 2017 to 2022, and genetic predisposition to T2DM obtained using summary statistics from a pooled genome-wide association study involving 1,407,282 individuals were examined. The onset and severity of T2DM are not available in the databases being used. RESULTS: Participants with T2DM were more likely to have SDD than their counterparts. Logistic regression analysis identified T2DM as an independent risk factor for SDD, which was confirmed by the Cox proportional hazard model results. However, using single-nucleotide polymorphisms as instruments, the MR analyses demonstrated no causal relationship between T2DM and SDD. The lack of such an association was robust in the sensitivity analysis, and no pleiotropy was seen. CONCLUSIONS: Our results suggest that the association between T2DM and SDD may be method-dependent. Researchers and clinicians should be cautious in interpreting the association, especially the causal association, between T2DM and SDD. Our findings provide fresh insights into the association between T2DM and SDD by various analysis methods and guide future research and clinical efforts in the effective prevention and management of T2DM and SDD. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

A CEBPB/miR-32-5p/GATA6 axis promotes vascular calcification in type 2 diabetes.

Vascular calcification in diabetes patients is a major independent risk factor for developing diabetic cardiovascular complications. However, the mechanisms by which diabetes leads to vascular calcification are complex and not yet fully understood. Our previous study revealed that miR-32-5p is a potential new diagnostic marker for coronary artery calcification. In this study, we found that miR-32-5p levels were significantly greater in the plasma of type 2 diabetes patients with coronary artery calcification and were positively correlated with the coronary artery calcification score. In type 2 diabetic mice, miR-32-5p levels were also elevated in the aorta, and knockout of miR-32-5p inhibited the osteogenic differentiation of vascular smooth muscle cells in vivo. Furthermore, overexpression of miR-32-5p promoted vascular smooth muscle cell calcification, while antagonism of miR-32-5p inhibited vascular smooth muscle cell calcification under high-glucose conditions. GATA binding protein 6 (GATA6) was identified as the key target gene through which miR-32-5p promotes vascular smooth muscle cell calcification. Overexpression of GATA6 antagonized the effects of miR-32-5p on vascular calcification. Additionally, high glucose levels were shown to induce the upregulation of miR-32-5p by activating CCAAT/enhancer binding protein beta (CEBPB). These results suggest that miR-32-5p is an important procalcification factor in vascular calcification associated with type 2 diabetes and identify the CEBPB/miR-32-5p/GATA6 axis as a potential biomarker and therapeutic target for preventing and treating vascular calcification in type 2 diabetes.

miRNA-206-3p alleviates LPS-induced acute lung injury via inhibiting inflammation and pyroptosis through modulating TLR4/NF-κB/NLRP3 pathway.

Acute lung injury (ALI) is life-threatening. MicroRNAs (miRNAs) are often abnormally expressed in inflammatory diseases and are closely associated with ALI. This study investigates whether miRNA-206-3p attenuates pyroptosis in ALI and elucidates the underlying molecular mechanisms. ALI mouse and cell models were established through lipopolysaccharide (LPS) treatment for 24 h. Subsequently, the models were evaluated based on ultrasonography, the lung tissue wet/dry (W/D) ratio, pathological section assessment, electron microscopy, and western blotting. Pyroptosis in RAW264.7 cells was then assessed via electron microscopy, immunofluorescence, and western blotting. Additionally, the regulatory relationship between miRNA-206-3p and the Toll-like receptor (TLR)4/nuclear factor (NF)-κB/Nod-like receptor protein-3 (NLRP3) pathway was verified. Finally, luciferase reporter gene and RNA pull-down assays were used to verify the targeting relationship between miRNA-206-3p and TLR4. miRNA206-3p levels are significantly decreased in the LPS-induced ALI model. Overexpression of miRNA-206-3p improves ALI, manifested as improved lung ultrasound, improved pathological changes of lung tissue, reduced W/D ratio of lung tissue, release of inflammatory factors in lung tissue, and reduced pyroptosis. Furthermore, overexpression of miRNA-206-3p contributed to reversing the ALI-promoting effect of LPS by hindering TLR4, myeloid differentiation primary response 88 (MyD88), NF-κB, and NLRP3 expression. In fact, miRNA-206-3p binds directly to TLR4. In conclusion, miRNA-206-3p alleviates LPS-induced ALI by inhibiting inflammation and pyroptosis via TLR4/NF-κB/NLRP3 pathway modulation.

MicroRNAs regulate the vicious cycle of vascular calcification-osteoporosis in postmenopausal women.

Menopause is a normal physiological process accompanied by changes in various physiological states. The incidence of vascular calcification (VC) increases each year after menopause and is closely related to osteoporosis (OP). Although many studies have investigated the links between VC and OP, the interaction mechanism of the two under conditions of estrogen loss remains unclear. MicroRNAs (miRNAs), which are involved in epigenetic modification, play a critical role in estrogen-mediated mineralization. In the past several decades, miRNAs have been identified as biomarkers or therapeutic targets in diseases. Thus, we hypothesize that these small molecules can provide new diagnostic and therapeutic approaches. In this review, we summarize the close interactions between VC and OP and the role of miRNAs in their interplay.

METTL14/YTHDC1-Mediated m6A Modification in Hippocampus Improves Pentylenetetrazol-Induced Acute Seizures.

Epilepsy is a common neurological disorder which can cause significant morbidity and mortality. N6-methyladenosine (m6A), the most common chemical epigenetic modification among mRNA post-transcriptional modifications, implicated in various physiological and pathological processes, but its role in epilepsy is still unknown. Here, we provide strong evidences in support of an association of m6A and its regulatory proteins with epilepsy. Our results indicated that the level of m6A was declined significantly in the dentate gyrus (DG) of hippocampus of pentylenetetrazol (PTZ)-induced seizure mice. Both the seizure-like behaviors and the excessive activation of DG area neuron were significantly mitigated after the administration of m6A agonist betaine. Mechanically, we found that both the m6A methyltransferase METTL14 and recognition protein YTHDC1 were decreased by PTZ stimulation, which might contribute to the reduced m6A level. Additionally, DG-specific over-expression of METTL14 or YTHDC1 by lentivirus injection could significantly ameliorate seizure-like behaviors and prevent the excessive activation of neuron in epilepsy mice induced by PTZ injection, which might be due to the normalized m6A level. Together, this study identified that METTL14/YTHDC1-mediated m6A modification could participate in seizure-like behaviors, which might provide m6A regulation as a potential and novel therapeutic strategy for epilepsy.

[Application of anterior region suture of popliteal hiatus in treatment of discoid lateral meniscus injury with instability in popliteal tendon region].

Objective: To discuss the application of anterior region suture of the popliteal hiatus (PH) under arthroscopy in the treatment of discoid lateral meniscus (DLM) injury with instability in the popliteal tendon region. Methods: The clinical data of 53 patients (56 knees) with DLM injury who met the selection criteria between March 2014 and November 2022 were retrospectively analyzed. There were 15 males and 38 females, aged 8-55 years with an average age of 36.5 years. Fourteen cases had a history of trauma, while the remaining 39 cases had no clear history of trauma. The disease duration ranged from 1 day to 6 years, with an average duration of 15.6 months. According to the Watanabe classification, there were 40 knees of complete type and 16 knees of incomplete type. The preoperative International Knee Documentation Committee (IKDC) knee joint score was 51.2±8.3, the Lysholm score was 59.6±11.2, and the visual analogue scale (VAS) score was 4.7±1.3. After the arthroscopic meniscal plasty, the instability of the popliteal tendon region meniscus was checked by probing traction. Subsequently, the Out-inside technique or a combination of Out-inside and All-inside techniques was used to suture the anterior region of the PH. The stability of the meniscus after suturing was assessed, and if necessary, further suturing using the All-inside technique at the posterior region of the PH, the posterior horn of the meniscus, and using the Out-inside technique at the anterior horn of the meniscus was performed. Postoperative complications were recorded. The effectiveness was evaluated using pre- and post-operative IKDC scores, Lysholm scores, and VAS scores. Results: After operation, knee joint pain, crepitus, and locking disappeared, with McMurray and grinding tests turning negative. All patients were followed up 12-93 months with an average of 57.5 months. There was no complication such as common peroneal nerve injury, deep vein thrombosis of the lower limbs, joint infection, or joint stiffness. At last follow-up, the IKDC knee joint score was 76.7±5.5, the Lysholm score was 94.0±4.1, and the VAS score was 1.1±0.8. The differences compared with preoperative scores were significant ( t=-22.090, P<0.001; t=-23.704, P<0.001; t=19.767, P<0.001). Conclusion: Suturing of the anterior region of the PH is crucial in the treatment of DLM injury with instability in the popliteal tendon region.

Value of serum iron and urine neutrophil gelatinase-associated lipocalin in predicting the mortality of critically ill patients with sepsis.

INTRODUCTION: We aimed to investigate the association of iron metabolism-related parameters with 60-day mortality in critically ill patients with sepsis. METHODS: Serum or urine concentrations of iron metabolism-related parameters on intensive care unit admission were measured in a prospective cohort of 133 eligible patients with sepsis according to the Sepsis-3 criteria, and these values were compared between survivors and nonsurvivors, categorized according to their 60-day survival status. Cox regression analyses were performed to examine the association between iron parameters and 60-day mortality. Kaplan-Meier methods were used to illustrate the differences in survival between different iron parameters. RESULTS: Of the 133 patients included in the study, 61 (45.8%) had died by day 60. After adjusting for confounding variables, higher concentrations of serum iron (cut-off 9.5 µmol/mL) and higher concentrations of urine neutrophil gelatinase-associated lipocalin (uNGAL; cut-off 169.3 ng/mL) were associated with a significantly greater risk of death in the Cox regression analysis. These two biomarkers combined with Sequential Organ Failure Assessment (SOFA) scores increased the area under the receiver operating characteristic (AUROC) curve to 0.85. DISCUSSION: These findings suggest that higher concentrations of serum iron and uNGAL are each associated with higher 60-day mortality, and they add significant accuracy to this prediction in combination with SOFA. Abbreviations: uNGAL: urine neutrophil gelatinase-associated lipocalin; ICU: intensive care unit; SOFA: Sequential Organ Failure Assessment; APACHE II: the Acute Physiology and Chronic Health Evaluation II; ELISA: enzyme-linked immunosorbent assay; HR: hazard ratio; CIs: confidence intervals; WBC: white blood cell; TBIL: total bilirubin.

Exponential super-twisting control for nonlinear systems with unknown polynomial perturbations.

The study focuses on the control of nonlinear dynamic systems in the presence of parameter uncertainties, unmodeled dynamics, and external disturbances. The lumped perturbation is assumed to be bounded within a polynomial in the system state with the polynomial parameters and degrees unknown a priori such that it accommodates a quite wider range dynamic systems. Based on the studies in recent super-twisting algorithm designs and the idea from adaptive sliding mode control for nonlinear systems with uncertainties, we propose a novel adaptive super-twisting algorithm with exponential reaching law, or exponential super-twisting algorithm (ESTA), for the high-stability and acceptable accuracy control of the aimed nonlinear dynamics. The stability analysis and practical finite-time (PFT) convergence are proven using Lyapunov theory and an intuitive analysis of the control behaviour. Simulations are performed to compare the proposed ESTA with the existing super-twisting method and the traditional proportional integral differential control. The simulation results demonstrate the effectiveness of the proposed ESTA in terms of the fastest settling time and the smallest overshoot.

Locking plate versus K-wires and cast fixation in lateral closing-wedge osteotomy for cubitus varus deformity.

Background: The aim of this study was to assess the clinical and radiographic outcomes of cubitus varus treatments based on different fixation methods: Locking plate vs. Kirschner-wires (K-wires) and cast fixation. Methods: This retrospective study of 28 patients was performed in lateral-wedge osteotomy for cubitus varus deformity in our hospital from July 2018 to July 2020. 14 patients in group A were treated by locking plate after lateral closing-wedge osteotomy, whereas other 14 patients were treated by K-wires in group B. We measured the bony union and carrying angle. The clinical and radiographic outcomes were assessed according to the Bellemore criteria. Results: No nonunion, neurovascular injury or myositis ossificans was noted at follow-up. In group A, 1 patient with lateral condylar prominence was found. In group B, 2 patients with pinning site infection were treated successfully with oral antibiotics and 2 patients needed revision surgery for residual varus. According to the Bellemore criteria, statistically significant difference was noted between the two groups (P = 0.0458). In the present study, no statistically significant difference was noted in the length of incision and operation time between the 2 groups (P > 0.05). However, the postoperative carrying angle was significantly different at final follow-up between the 2 groups (P < 0.01). Conclusions: Compared with K-wires and cast fixation, we recommend the wedge osteotomy with lateral locking plate to treat the cubitus varus deformity because locking plate could achieve better functional and cosmetic results and stabilize the distal humerus rigidly.

A New Strategy for Obesity Treatment: Revealing the Frontiers of Anti-obesity Medications.

Obesity dramatically increases the risk of type 2 diabetes, fatty liver, hypertension, cardiovascular disease, and cancer, causing both declines in quality of life and life expectancy, which is a serious worldwide epidemic. At present, more and more patients with obesity are choosing drug therapy. However, given the high failure rate, high cost, and long design and testing process for discovering and developing new anti-obesity drugs, drug repurposing could be an innovative method and opportunity to broaden and improve pharmacological tools in this context. Because different diseases share molecular pathways and targets in the cells, anti-obesity drugs discovered in other fields are a viable option for treating obesity. Recently, some drugs initially developed for other diseases, such as treating diabetes, tumors, depression, alcoholism, erectile dysfunction, and Parkinson's disease, have been found to exert potential anti-obesity effects, which provides another treatment prospect. In this review, we will discuss the potential benefits and barriers associated with these drugs being used as obesity medications by focusing on their mechanisms of action when treating obesity. This could be a viable strategy for treating obesity as a significant advance in human health.

COL3A1 is a potential diagnostic biomarker for synovial chondromatosis and affects the cell cycle and migration of chondrocytes.

BACKGROUND: Synovial chondromatosis (SC) primarily affects the major joints and is characterized by the formation of benign cartilaginous nodules. In the present study, we evaluated the differences in the histology and gene expression of SC and normal cartilages and further elucidated the function of hub genes in SC. METHODS: Histological staining and biochemical analysis were performed to measure collagen and glycosaminoglycan (GAG) contents in SC and normal cartilage samples. Then, microarray analysis was performed using knee joint samples (three normal and three SC samples) to identify the differentially expressed genes (DEGs). Subsequently, bioinformatics analysis was performed to identify the hub genes and explore the mechanisms underlying SC. The intersection of the top 10 upregulated DEGs, top 10 downregulated DEGs, and hub genes was validated in SC tissues. Lastly, in vitro experiments and our clinical cohort were used to determine the potential biological functions and diagnostic value, respectively, of the most significant gene. RESULTS: The GAG and collagen contents were comparable to or higher in SC tissues than in normal tissues. Microarray analysis revealed 143 upregulated and 107 downregulated DEGs in SC. Furthermore, functional enrichment analysis revealed an association between immunity and metabolism-related pathways and SC development. Among 20 hub genes, two intersection genes, namely, collagen type III alpha 1 chain (COL3A1) and HSPA8, were notably expressed in SC tissues, with COL3A1 exhibiting a more significant difference in mRNA expression. Furthermore, COL3A1 can promote chondrocyte migration and cell cycle progression. Additionally, clinical data revealed COL3A1 can be a diagnostic marker for primary SC (AUC = 0.82) and be a positive correlation with neutrophil-to-lymphocyte ratio. CONCLUSIONS: These results suggest that SC tissues contained the abundant GAG and collagen. COL3A1 can affect the function of chondrocytes and be a diagnostic marker of primary SC patients. These findings provide a novel approach and a fundamental contribution for diagnosis and treatment in SC.

Reassessing endothelial-to-mesenchymal transition in mouse bone marrow: insights from lineage tracing models.

Endothelial cells (ECs) and bone marrow stromal cells (BMSCs) play crucial roles in supporting hematopoiesis and hematopoietic regeneration. However, whether ECs are a source of BMSCs remains unclear. Here, we evaluate the contribution of endothelial-to-mesenchymal transition to BMSC generation in postnatal mice. Single-cell RNA sequencing identifies ECs expressing BMSC markers Prrx1 and Lepr; however, this could not be validated using Prrx1-Cre and Lepr-Cre transgenic mice. Additionally, only a minority of BMSCs are marked by EC lineage tracing models using Cdh5-rtTA-tetO-Cre or Tek-CreERT2. Moreover, Cdh5+ BMSCs and Tek+ BMSCs show distinct spatial distributions and characteristic mesenchymal markers, suggestive of their origination from different progenitors rather than CDH5+ TEK+ ECs. Furthermore, myeloablation induced by 5-fluorouracil treatment does not increase Cdh5+ BMSCs. Our findings indicate that ECs hardly convert to BMSCs during homeostasis and myeloablation-induced hematopoietic regeneration, highlighting the importance of using appropriate genetic models and conducting careful data interpretation in studies concerning endothelial-to-mesenchymal transition.

Microcapsules and Nanoliposomes Based Strategies to Improve the Stability of Blueberry Anthocyanins.

Blueberry anthocyanins are water-soluble natural pigments that can be used as both natural antioxidants and natural colorants. However, their structural instability greatly limits their application in the food, pharmaceutical, and cosmetic industries. In this study, blueberry anthocyanin microcapsules (BAM) and blueberry anthocyanin liposomes (BAL) were fabricated based on blueberry anthocyanins. Film dispersion methods were used to prepare the BAL. Their preparation processes were optimized and compared to improve the stability of the blueberry anthocyanins following exposure to light and high temperatures. The BAM were prepared through complex phase emulsification. The blueberry anthocyanins were protected by the shell materials composed of sodium alginate after being formed into BAM. Under the optimal conditions, the embedding rate of BAM and BAL can reach as high as 96.14% and 81.26%, respectively. In addition, the particle size, zeta potential, microtopography, and structure feature information of the BAM and BAL were compared. The average particle sizes of the BAM and BAL were 9.78 µm and 290.2 nm, respectively, measured using a laser particle size analyzer, and the zeta potentials of the BAM and BAL were 34.46 mV and 43.0 mV, respectively. In addition, the optimal preparation processes were determined through single-factor and response surface optimization experiments. The most important factors in the single-factor experiment for the preparation of microcapsules and liposomes were the content of CaCl2 and the amount of anthocyanin. The preservation rates in the light and dark were also compared, and the thermal stabilities of the BAM and BAL were characterized through differential thermal scanning. The results showed that both the BAM and BAL maintained the stability of blueberry anthocyanins, and no significant difference was found between the indices used to evaluate their stability. The results of this study provide theoretical support for the development of effective systems to maintain the stability of anthocyanins, thereby improving their bioavailability after ingestion by humans.

[Treatment of tibial insertion avulsion fracture of anterior cruciate ligament involving anterior root of lateral meniscus with multi-point fixation with anchor and suture].

Objective: To investigate the effectiveness of arthroscopic multi-point fixation with anchor and suture in the treatment of tibial insertion avulsion fracture of anterior cruciate ligament (ACL) involving the anterior root of lateral meniscus (LM). Methods: A retrospective analysis was conducted on the clinical data of 28 patients with tibial insertion avulsion fracture of ACL involving the anterior root of LM who were treated with arthroscopic multi-point fixation with anchor and suture between October 2017 and January 2023. There were 12 males and 16 females with the mean age of 26 years (range, 13-57 years). There were 20 cases of sports injury and 8 cases of traffic accident injury. In 2 cases of old fracture, the time from injury to operation was 45 days and 90 days, respectively; in 26 cases of fresh fracture, the time from injury to operation was 3-20 days (mean, 6.7 days). According to the Meyers-McKeever classification, there were 4 cases of type Ⅱ, 11 cases of type Ⅲ, and 13 cases of type Ⅳ. The preoperative Lysholm knee function score was 42.1±9.0, the International Knee Documentation Committee (IKDC) score was 40.0±7.3, and the Tegner score was 0.7±0.7. Results: All operations were successfully completed, and the incisions healed by first intention. All the 28 patients were followed up 5-60 months (mean, 20.4 months). During the follow-up, there was nocomplication such as infection, vascular or nerve injury, loosening or breakage of internal fixator, or stiffness of knee joint. Postoperative X-ray films showed satisfactory fracture reduction and firm fixation. All fractures healed clinically, and the healing time was 8-16 weeks (mean, 10.3 weeks). At last follow-up, Lachman test and anterior drawer test were negative. At last follow-up, Lysholm knee function score was 92.4±5.5, IKDC score was 91.6±4.4, and Tegner score was 5.2±1.1, which significantly improved when compared with preoperative scores ( t=-22.899, P<0.001; t=-29.870, P<0.001; t=-19.979, P<0.001). Conclusion: Multi-point fixation with anchor and suture in the treatment of tibial insertion avulsion fracture of ACL involving the anterior root of LM can not only fix the LM, but also effectively reduce and fix the avulsion fracture, which can obtain good effectiveness.

IGF2/IGF2R/Sting signaling as a therapeutic target in DSS-induced ulcerative colitis.

Ulcerative colitis is an inflammatory bowel disease with increasing prevalence and incidence. Current treatments for ulcerative colitis are not generally applicative and are often accompanied by side effects. IGF2 is an endogenous protein that plays roles in anti-inflammation and stemness maintenance, but little is known about its mechanism and function in the progression of ulcerative colitis. In this study, mouse recombinant IGF2 was used in a mouse model of ulcerative colitis established by DSS. IGF2 expression was reduced in colon tissues but not plasma of DSS-induced colitis mice. IGF2R expression was also decreased in colitis colons, which was then elevated by recombinant IGF2. Recombinant IGF2 alleviated colon injury in colitis, which was evaluated by colon shortening, body weight loss and DAI score. IGF2 treatment also relieved the inflammatory response in colitis, which was assessed by the spleen weight index, MPO activity and proinflammatory cytokine expression and was also detected in LPS-stimulated RAW264.7 cells in vitro. Moreover, IGF2R was predicted and further verified to interact with the Sting protein, and the cGAS-Sting pathway as a key pathway for stemness regulation, was upregulated in colonic colons, which was blocked by IGF2 treatment. Additionally, IGF2 treatment can maintain colonic stemness and further repair colonic tight junction function in DSS-induced colitis. In conclusion, IGF2/IGF2R downregulated the cGAS-Sting pathway to sustain colonic stemness and barrier integrity to protect against ulcerative colitis induced by DSS.

Vascular calcification: from the perspective of crosstalk.

Vascular calcification (VC) is highly correlated with cardiovascular disease morbidity and mortality, but anti-VC treatment remains an area to be tackled due to the ill-defined molecular mechanisms. Regardless of the type of VC, it does not depend on a single cell but involves multi-cells/organs to form a complex cellular communication network through the vascular microenvironment to participate in the occurrence and development of VC. Therefore, focusing only on the direct effect of pathological factors on vascular smooth muscle cells (VSMCs) tends to overlook the combined effect of other cells and VSMCs, including VSMCs-VSMCs, ECs-VMSCs, Macrophages-VSMCs, etc. Extracellular vesicles (EVs) are a collective term for tiny vesicles with a membrane structure that are actively secreted by cells, and almost all cells secrete EVs. EVs docked on the surface of receptor cells can directly mediate signal transduction or transfer their contents into the cell to elicit a functional response from the receptor cells. They have been proven to participate in the VC process and have also shown attractive therapeutic prospects. Based on the advantages of EVs and the ability to be detected in body fluids, they may become a novel therapeutic agent, drug delivery vehicle, diagnostic and prognostic biomarker, and potential therapeutic target in the future. This review focuses on the new insight into VC molecular mechanisms from the perspective of crosstalk, summarizes how multi-cells/organs interactions communicate via EVs to regulate VC and the emerging potential of EVs as therapeutic methods in VC. We also summarize preclinical experiments on crosstalk-based and the current state of clinical studies on VC-related measures.

Lipid Metabolic Regulatory Crosstalk Between Cancer Cells and Tumor-Associated Macrophages.

In the tumor microenvironment, tumor-associated macrophages (TAMs) are one of the most abundant cell populations, playing key roles in tumorigenesis, chemoresistance, immune evasion, and metastasis. There is an important interaction between TAMs and cancer cells: on the one hand, tumors control the function of infiltrating macrophages, contributing to reprogramming of TAMs, and on the other hand, TAMs affect the growth of cancer cells. This review focuses on lipid metabolism changes in the complex relationship between cancer cells and TAMs. We discuss how lipid metabolism in cancer cells affects macrophage phenotypic and metabolic changes and, subsequently, how altered lipid metabolism of TAMs influences tumor progression. Identifying the metabolic changes that influence the complex interaction between tumor cells and TAMs is also an important step in exploring new therapeutic approaches that target metabolic reprogramming of immune cells to enhance their tumoricidal potential and bypass therapy resistance. Our work may provide new targets for antitumor therapies.

New insight of obesity-associated NAFLD: Dysregulated "crosstalk" between multi-organ and the liver?

Obesity plays a crucial role in the development of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism for the pathogenesis of obesity-associated NAFLD remains largely obscure. Although the "multiple hit" theory provides a more accurate explanation of NAFLD pathogenesis, it still cannot fully explain precisely how obesity causes NAFLD. The liver is the key integrator of the body's energy needs, receiving input from multiple metabolically active organs. Thus, recent studies have advocated the "multiple crosstalk" hypothesis, highlighting that obesity-related hepatic steatosis may be the result of dysregulated "crosstalk" among multiple extra-hepatic organs and the liver in obesity. A wide variety of circulating endocrine hormones work together to orchestrate this "crosstalk". Of note, with deepening understanding of the endocrine system, the perception of hormones has gradually risen from the narrow sense (i.e. traditional hormones) to the broad sense of hormones as organokines and exosomes. In this review, we focus on the perspective of organic endocrine hormones (organokines) and molecular endocrine hormones (exosomes), summarizing systematically how the two types of new hormones mediate the dialogue between extra-hepatic organs and liver in the pathogenesis of obesity-related NAFLD.

miR-32-5p induces hepatic steatosis and hyperlipidemia by triggering de novo lipogenesis.

BACKGROUND AND OBJECTIVES: MicroRNA-dependent regulation of hepatic lipid metabolism has been recognized recently as a key pathological mechanism contributing to the development of NAFLD. However, whether miR-32-5p (miR-32) plays a role in lipid metabolism or contributes to NAFLD remains unclear. METHODS AND RESULTS: A marked increase in miR-32 expression was observed in liver samples from patients and mice with NAFLD, as well as in palmitate-induced hepatocytes. Hepatocyte-specific miR-32 knockout (miR-32-HKO) dramatically ameliorated hepatic steatosis and metabolic disorders in high-fat diet-fed mice. Conversely, hepatic miR-32 overexpression markedly exacerbated the progression of these abnormalities. Further, combinational analysis of transcriptomics and lipidomics suggested that miR-32 was a key trigger for de novo lipogenesis in the liver. Mechanistically, RNA sequencing, luciferase assay and adenovirus-mediated downstream gene rescue assay demonstrated that miR-32 directly bound to insulin-induced gene 1 (INSIG1) and subsequently activated sterol regulatory element binding protein-mediated lipogenic gene programs, thereby promoting hepatic lipid accumulation and metabolic disorders. Notably, pharmacological administration of miR-32 antagonist significantly inhibited palmitate-induced triglyceride deposition in hepatocytes and markedly mitigated hepatic steatosis and metabolic abnormalities in obesity-associated NAFLD mice. CONCLUSION: miR-32 is an important checkpoint for lipogenesis in the liver, and targeting miR-32 could be a promising therapeutic approach for NAFLD treatment.

[A study on repair method of type â ¡c injury in lateral meniscus popliteal tendon area of porcine knee].

Objective: To investigate the repair method of type Ⅱc injury in the lateral meniscus popliteal tendon area based on the porcine knee joint. Methods: Eighteen commercially available fresh porcine knee joints were randomly divided into 3 groups ( n=6). After preparing a type Ⅱc injury in the lateral meniscus popliteal tendon area, and the anterior (group A), posterior (group B), or anterior and posterior (group C) of the popliteal hiatus (PH) was sutured by vertical mattress. The tension meter was used to apply gradient tensions of 2, 4, 6, 8, and 10 N along the tibial plateau horizontally, respectively, to pull the midpoint of the lateral meniscus popliteal tendon area. The displacement values before modeling, after modeling, and after suture were recorded. The reduction value of lateral meniscus displacement and reduction rate after suture were calculated and compared between groups. Results: There was no significant difference between groups ( P>0.05) in the displacement values before modeling, after modeling, and after suture under different tensions. There was no significant difference between groups A and C ( P>0.05) in the reduction value of lateral meniscus displacement and reduction rate after suture under different tensions. The reduction value of lateral meniscus displacement and reduction rate after suture in group B were lower than those in groups A and C. The reduction value of lateral meniscus displacement under tension of 2 N and the reduction rates under tensions of 2, 4, and 6 N between groups A and B showed significant differences ( P<0.05). The reduction value of lateral meniscus displacement and the reduction rate under tensions of 2, 4, and 6 N between groups B and C showed significant differences ( P<0.05). Conclusion: Suturing the anterior area of PH is the key to repairing type Ⅱc injury of lateral meniscus popliteal tendon area.