YTHDF1's grip on CRC vasculature: insights into LINC01106 and miR-449b-5p-VEGFA axis.

BACKGROUND: Investigating the unexplored territory of lncRNA m6A modification in colorectal cancer (CRC) vasculature, this study focuses on LINC01106 and YTHDF1. METHODS: Clinical assessments reveal upregulated LINC01106 promoting vascular generation via the miR-449b-5p-VEGFA pathway. RESULTS: YTHDF1, elevated in CRC tissues, emerges as an adverse prognostic factor. Functional experiments showcase YTHDF1's inhibitory effects on CRC cell dynamics. Mechanistically, Me-CLIP identifies m6A-modified LINC01106, validated as a YTHDF1 target through Me-RIP. CONCLUSIONS: This study sheds light on the YTHDF1-mediated m6A modification of LINC01106, presenting it as a key player in suppressing CRC vascular generation.

Clinical pathological characteristics of "crawling-type" gastric adenocarcinoma cancer: A case report.

BACKGROUND: Gastric cancer (GC) is a significant health problem worldwide, and early detection and accurate diagnosis are crucial for improving patient outcomes. Crawling-type gastric adenocarcinoma is a rare subtype of GC that has unique histopathological and clinical characteristics, and its diagnosis and management can be challenging. This pathological type of GC is also rare. CASE SUMMARY: Here, we report the case of a patient who underwent ordinary endoscopy, narrow-band imaging, and endoscopic ultrasonography intending to determine the extent of tumor invasion and upper abdominal enhanced computed tomography and whether there was tumor metastasis. Then, endoscopic submucosal dissection was performed. After pathological and immunohistochemical examination, the pathological diagnosis was crawling-type gastric adenocarcinoma. This is a very rare and special pathological type of tumor. This case highlights the importance of using advanced endoscopic techniques and pathological examination in diagnosing and managing gastric crawling-type adenocarcinoma. Moreover, the findings underscore the need for continued research and clinical experience in this rare subtype of GC to improve patient outcomes. CONCLUSION: The "crawling-type" GC is a rare and specific tumor pathology. It is difficult to identify and diagnose gliomas via endoscopy. The tumor is ill-defined, with a flat appearance and indistinct borders due to the lack of contrast against the background mucosa. Pathology revealed that the tumor cells were hand-like, so the patient has diagnosed with "crawling-type" gastric adenocarcinoma.

Self-assembly of differentiated dental pulp stem cells facilitates spheroid human dental organoid formation and prevascularization.

BACKGROUND: The self-assembly of solid organs from stem cells has the potential to greatly expand the applicability of regenerative medicine. Stem cells can self-organise into microsized organ units, partially modelling tissue function and regeneration. Dental pulp organoids have been used to recapitulate the processes of tooth development and related diseases. However, the lack of vasculature limits the utility of dental pulp organoids. AIM: To improve survival and aid in recovery after stem cell transplantation, we demonstrated the three-dimensional (3D) self-assembly of adult stem cell-human dental pulp stem cells (hDPSCs) and endothelial cells (ECs) into a novel type of spheroid-shaped dental pulp organoid in vitro under hypoxia and conditioned medium (CM). METHODS: During culture, primary hDPSCs were induced to differentiate into ECs by exposing them to a hypoxic environment and CM. The hypoxic pretreated hDPSCs were then mixed with ECs at specific ratios and conditioned in a 3D environment to produce prevascularized dental pulp organoids. The biological characteristics of the organoids were analysed, and the regulatory pathways associated with angiogenesis were studied. RESULTS: The combination of these two agents resulted in prevascularized human dental pulp organoids (Vorganoids) that more closely resembled dental pulp tissue in terms of morphology and function. Single-cell RNA sequencing of dental pulp tissue and RNA sequencing of Vorganoids were integrated to analyse key regulatory pathways associated with angiogenesis. The biomarkers forkhead box protein O1 and fibroblast growth factor 2 were identified to be involved in the regulation of Vorganoids. CONCLUSION: In this innovative study, we effectively established an in vitro model of Vorganoids and used it to elucidate new mechanisms of angiogenesis during regeneration, facilitating the development of clinical treatment strategies.

ODF3B affects the proliferation and apoptosis of glioma via the JAK/STAT pathway.

The pathogenesis of glioma has remained unclear. In this study, it was found that high expression of the outer dense fibers of sperm tail 3B (ODF3B) in gliomas was positively correlated with the grade of glioma. The higher the grade, the worse the prognosis. ODF3B is closely related to the growth and apoptosis of glioma. In terms of mechanism, ODF3B was found to affect the proliferation and apoptosis of glioma through the JAK1 and JAK2/STAT3 pathways. ODF3B was also found to affect the growth and apoptosis of glioma in vivo. We conclude that ODF3B affects glioma proliferation and apoptosis via the JAK/STAT pathway and is a potential therapeutic target.

Telocinobufagin, a PLK1 suppressor that inhibits tumor growth and metastasis by modulating CDC25c and CTCF in HNSCC cells.

BACKGROUND: The high metastasis and mortality rates of head and neck squamous cell carcinoma (HNSCC) urgently require new treatment targets and drugs. A steroidal component of ChanSu, telocinobufagin (TBG), was verified to have anti-cancer effects in various tumors, but its activity and mechanism in anti-HNSCC were still unknown. PURPOSE: This study tried to demonstrate the anti-tumor effect of TBG on HNSCC and verify its potential mechanism. METHODS: The effect of TBG on cell proliferation and metastasis were performed and the TBG changed genes were detected by RNA-seq analysis in HNSCC cells. The GSEA and PPI analysis were used to identify the pathways targeted for TBG-regulated genes. Meanwhile, the mechanism of TBG on anti-proliferative and anti-metastasis were investigated in vitro and in vivo. RESULTS: The in vitro and in vivo experiments confirmed that TBG has favorable anti-tumor effects by induced G2/M phase arrest and suppressed metastasis in HNSCC cells. Further RNA-seq analysis demonstrated the genes regulated by TBG were enriched at the G2/M checkpoint and PLK1 signaling pathway. Then, the bioinformatic analysis of clinical data found that high expressed PLK1 were closely associated with poor overall survival in HNSCC patients. Furthermore, PLK1 directly and indirectly modulated G2/M phase and metastasis (by regulated CTCF) in HNSCC cells, simultaneously. TBG significantly inhibited the protein levels of PLK1 in both phosphorylated and non-phosphorylated forms and then, in one way, inactivated PLK1 failed to activate G2/M phase-related proteins (including CDK1, CDC25c, and cyclin B1). In another way, be inhibited PLK1 unable promote the nuclear translocation of CTCF and thus suppressed HNSC cell metastasis. In contrast, the anti-proliferative and anti-metastasis effects of TBG on HNSCC cell were vanished when cells high-expressed PLK1. CONCLUSION: The present study verified that PLK1 mediated TBG induced anti-tumor effect by modulated G2/M phase and metastasis in HNSCC cells.

Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors.

PURPOSE: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. PATIENTS AND METHODS: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. RESULTS: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. CONCLUSIONS: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.

CD206 modulates the role of M2 macrophages in the origin of metastatic tumors.

Tumor metastasis is a key factor affecting the life of patients with malignant tumors. For the past hundred years, scientists have focused on how to kill cancer cells and inhibit their metastasis in vivo, but few breakthroughs have been made. Here we hypothesized a novel mode for cancer metastasis. We show that the phagocytosis of apoptotic tumor cells by macrophages leads to their polarization into the M2 phenotype, and that the expression of stem cell related as well as drug resistance related genes was induced. Therefore, it appears that M2 macrophages have "defected" and have been transformed into the initial "metastatic cancer cells", and thus are the source, at least in part, of the distal tissue tumor metastasis. This assumption is supported by the presence of fused cells with characteristics of both macrophage and tumor cell observed in the peripheral blood and ascites of patients with ovarian cancer. By eliminating the expression of CD206 in M2 macrophages using siRNA, we show that the growth and metastasis of tumors was suppressed using both in vitro cell line and with experimental in vivo mouse models. In summary, we show that M2 macrophages in the blood circulation underwent a "change of loyalty" to become "cancer cells" that transformed into distal tissue metastasis, which could be suppressed by the knockdown of CD206 expression.

PET/CT Examination of Teratomas after Stem Cell Transplantation for a Spinal Cord Injury: A Case Report.

BACKGROUND: In clinical practice, stem cell transplantation has become an effective method for treating spinal cord nerve injury. Up to now, there has been no report on teratoma caused by transplanted stem cell's abnormal differentiation in the clinic, especially in the analysis of imaging manifestations. Therefore, this article aims to analyze the PET/CT imaging manifestations of teratoma caused by stem cell transplantation to improve the imaging diagnosing capability. CASE PRESENTATION: A patient with a spinal cord injury who had received a stem cell transplant was examined by PET/CT on September 10th, 2020. The PET/CT images of the lesion showed irregular mixed low density on the right side of the erector spinae muscle area at the level of the cervical 3-5 vertebral body, with a maximum cross-section of 9.1×3.9 cm. The 18F-FDG metabolism of the lesion was increased, and the maximum standard uptake value (SUVmax) was 10.7. The boundary was unclear with the third cervical vertebra and cervical 3 and 4-level vertebral plates. Based on the patient's medical history, the lesion was diagnosed as an abnormal proliferative tumor, which was consistent with the pathological examination results. CONCLUSION: To date, there have been no clinical reports on teratomas caused by stem cell transplantation for spinal cord injury at home or abroad. This case report enhances the knowledge of the diagnosis and treatment methods of this type of disease and confirms the diagnostic value of PET/CT examination.

Gender determination and long-time follow-up analysis of mixed gonadal dysgenesis.

INTRODUCTION: Mixed gonadal dysgenesis (MGD) is a rare disorder of sexual development. The management of MGD is challenging since the disease significantly impacts a patient's growth, hormone balance, and gonadal development. This article used a large population and a long follow-up period for its analysis. OBJECTIVES: This study aims to summarize the gender determination basis and analyze the long-term follow-up of mixed gonadal dysgenesis. METHODS: A total of 45 patients' clinical data were summarized and analyzed. Patients were divided by gender. Next, we followed up regarding the occurrence of complications after surgery, the patients' satisfaction with external genitalia appearance, the growth of the patients, counting the surgical pattern the incidence of surgical complications and the development of the patients' growth. All patients included in this study underwent chromosomal karyotype analysis, abdomen exploration, and pathological biopsy. After sex determination, 7 patients who were raised as female underwent clitoroplasty, and bilateral gonadectomy. 38 male patients underwent urethroplasty + one-sided gonadectomy. RESULTS: Patient follow-up started in the third month after surgery. Female patients reported no surgery-related complications, while 14 male patients showed surgery-related complications. Additionally, 20 male patients (60.6 %) had a lower height compared to normal peers, 12 of which (36.4 %) were lower than the second standard deviation of the height of normal peers. CONCLUSION: The clinical manifestations of mixed gonadal dysgenesis are variable, and the management is complicated. Children's gonadal function, external genital conditions, psychological evaluation, and parents' wishes should be considered before sex determination. In China, most patients are raised as males with a high incidence of postoperative complications. We found that short stature is a common feature in male patients, thus their height and growth should be carefully supervised. Patients should pay attention to their sexual function and sexual potential during adulthood.

Assessment of clinical prognosis improvement in children with concomitant anterior and posterior urethral valves: A case series report.

BACKGROUND: Concomitant anterior urethral valves (AUVs) and posterior urethral valves (PUVs) is an extremely rare congenital urologic anomaly, which may be easily overlooked in the clinic. OBJECTIVE: This study assessed the prognosis of children with concomitant PUVs and AUVs. METHODS: The clinical data of inpatients with concomitant AUVs and PUVs in our hospital were collected from January 1983 to June 2022. The clinical manifestations, auxiliary inspection, and treatment were described in detail. RESULTS: In total, 6 cases of concomitant AUVs and PUVs in boys were found in our hospital, with ages ranging from 3 months to 9 years; the main clinical manifestation was abnormal urination. Four patients exhibited concomitant AUVs and PUVs preoperatively and underwent simultaneous anterior and posterior urethral valvotomy. Follow-up studies showed that 3 patients' clinical symptoms substantially improved with well-maintained renal function. One patient died of renal failure. In the other 2 patients, PUVs were initially identified and excised, but their clinical symptoms did not show substantial improvement. Following voiding cystourethrography (VCUG), the AUVs were found and obstructions were then completely relieved. However, 2 patients died of renal failure. CONCLUSIONS: If urinary symptoms cannot be substantially relieved after posterior urethral valvotomy, VCUG and cystoscopy should be repeated to shorten the interval between anterior and posterior urethral valvotomies to improve patient prognosis.

In silico and in vitro analyses of a novel FoxO1 agonist reducing Aß levels via downregulation of BACE1.

AIMS: FoxO1 is an important target in the treatment of Alzheimer's disease (AD). However, FoxO1-specific agonists and their effects on AD have not yet been reported. This study aimed to identify small molecules that upregulate the activity of FoxO1 to attenuate the symptoms of AD. METHODS: FoxO1 agonists were identified by in silico screening and molecular dynamics simulation. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to assess protein and gene expression levels of P21, BIM, and PPARγ downstream of FoxO1 in SH-SY5Y cells, respectively. Western blotting and enzyme-linked immunoassays were performed to explore the effect of FoxO1 agonists on APP metabolism. RESULTS: N-(3-methylisothiazol-5-yl)-2-(2-oxobenzo[d]oxazol-3(2H)-yl) acetamide (compound D) had the highest affinity for FoxO1. Compound D activated FoxO1 and regulated the expression of its downstream target genes, P21, BIM, and PPARγ. In SH-SY5Y cells treated with compound D, BACE1 expression levels were downregulated, and the levels of Aß1-40 and Aß1-42 were also reduced. CONCLUSIONS: We present a novel small-molecule FoxO1 agonist with good anti-AD effects. This study highlights a promising strategy for new drug discovery for AD.

Dimerized sesquiterpenoid [4 + 2] adducts with ferroptosis-promoting activity from Inula britannica Linn.

Inubritanolides C and D (1 and 2), two exo sesquiterpenoid [4 + 2] adducts with unprecedented interconverting conformations of twist-chair and chair, together with two previously undescribed endo [4 + 2] dimers (3 and 4) were discovered from Inula britannica flowers. Dimers 1 and 2 have an undescribed carbon skeleton comprising of eudesmanolide and guaianolide units with the linkage mode of C-11/C-1' and C-13/C-3' via a Diels-Alder cycloaddition reaction. Their structures were elucidated using 1D/2D NMR, X-ray diffraction, ECD, and variable-temperature NMR experiments. Dimer 2 displayed a strong inhibitory effect on breast cancer cells by promoting lipid ROS production, showing its potential as ferroptosis inducer.

Ochratoxin A Induces Renal Cell Ferroptosis by Disrupting Iron Homeostasis and Increasing ROS.

Mycotoxin ochratoxin A (OTA) is a critical food safety concern due to its nephron-toxic effects and is detected in a wide range of food and feedstuffs. OTA nephrotoxicity is related to oxidative stress and damage. However, the mediator(s) of the excessive oxidative stress is unclear. The current study used human kidney cell lines to investigate whether and how intracellular iron contributed to OTA-induced ROS accumulation and how OTA-induced iron-dependent ferroptotic cell death. Our results showed that OTA treatment affected the cell viability and induced the typical characteristics of cell ferroptosis. Furthermore, gene and protein expression results indicated that OTA disrupted iron homeostasis by upregulating the expression levels of iron importer TFR1 and FTH, while downregulating the expression level of iron exporter FPN and dramatically increasing its negative regulator Hepcidin. The changes were consistent with the induction of intracellular iron accumulation and elevated levels of oxidative stress and lipid peroxidation. Additionally, co-treatment with OTA and an iron chelator significantly improved cell viability, reduced cellular total iron and ROS, and reversed OTA-induced changes in iron metabolism gene expression levels. Interestingly, the addition of a ROS scavenger also reversed cell death and changes in mRNA and protein expression levels of iron metabolism genes but to a lesser degree than that of the iron-chelating agent. Our results revealed that OTA induced ferroptosis in renal cells by disrupting iron homeostasis and increasing ROS.

Revolutionizing cancer treatment: nanotechnology-enabled photodynamic therapy and immunotherapy with advanced photosensitizers.

Nanotechnology-enhanced photodynamic therapy (PDT) and immunotherapy are emerging as exciting cancer therapeutic methods with significant potential for improving patient outcomes. By combining these approaches, synergistic effects have been observed in preclinical studies, resulting in enhanced immune responses to cancer and the capacity to conquer the immunosuppressive tumor microenvironment (TME). Despite challenges such as addressing treatment limitations and developing personalized cancer treatment strategies, the integration of nanotechnology-enabled PDT and immunotherapy, along with advanced photosensitizers (PSs), represents an exciting new avenue in cancer treatment. Continued research, development, and collaboration among researchers, clinicians, and regulatory agencies are crucial for further advancements and the successful implementation of these promising therapies, ultimately benefiting cancer patients worldwide.

Efficacy and safety of photodynamic therapy for non-muscle-invasive bladder cancer: a systematic review and meta-analysis.

Background: Photodynamic therapy (PDT) is a promising treatment for non-muscle-invasive bladder cancer (NMIBC), we conducted this systematic review to comprehensively assess its efficacy and safety. Methods: A comprehensive literature research was conducted using PubMed, Web of Science, and Scopus, and studies reporting the safety and efficacy of PDT in NMIBC were included. Complete response (CR) rates, recurrence-free survival (RFS) at different time points, and complication incidences were extracted and synthesized. Pooled results were presented as rates with a 95% confidence interval (95% CI). Results: Overall, 28 single arm studies were included in the meta-analysis. For unresectable NMIBC, therapeutic PDT achieved CR in 68% (95% CI: 59%-77%) of patients. Among these CR cases, 71% (95% CI: 56%-85%) and 38% (95% CI: 12%-64%) have a RFS longer than 12 and 24 months, respectively. For Tis patients, the CR rate was 68% (95% CI: 56%-80%), and 84% (95% CI: 48%-100%) and 13% (95% CI: 1%-32%) have a RFS longer than 12 and 24 months. For patients with resectable tumors, post-resection adjuvant PDT could provide a 12 and 24 months RFS in 81% (95% CI:76%-87%) and 56% (95% CI:41%-71%) of them. Especially, for NMIBC patients who failed BCG therapy, adjuvant PDT could still achieve a 1-year and 2-year RFS in 68% (95% CI:51%-86%) and 56% (95% CI:32%-81%) patients. The complications were mostly mild and transient, including lower urinary tract symptoms and photosensitivity. Conclusion: Both therapeutic and adjuvant PDT present satisfying safety and efficacy for NMIBC, including these cases that are resistant to the standard of care. As a promising option for NMIBC, PDT deserves further exploration by future high-quality research. Systematic review registration: https://inplasy.com/inplasy-2022-11-0043/, INPLASY2022110043.

Combining network pharmacology and experimental verification to reveal the mechanism of Chaigui granules in the treatment of depression through PI3K/Akt/mTOR signaling pathways.

INTRODUCTION: Chaigui granules are a novel manufactured traditional Chinese antidepressant medicine, which is originated from the ancient classical prescription of Xiaoyaosan. It ameliorated depression-like behavior and concomitant symptoms in animal models. But its antidepressant mechanism is still unclear. Therefore, network pharmacology and molecular biology were used to explore underlying antidepressant mechanism in this study. METHODS: Firstly, network pharmacology was used to screen main active ingredients and potential targets in the treatment of depression with Chaigui granules, and to perform pathway enrichment analysis. Secondly, chronic and unpredictable mild stress-induced depression model rats were used, and behavioral tests were used to evaluate the antidepressant effect of Chaigui granules. Finally, the core targets and key pathways predicted by network pharmacology were validated by qRT-PCR and Western blot to determine the relevant gene and protein expression levels in rat hippocampus. RESULTS: The results of network pharmacology indicated that the PI3K/Akt signaling pathway may play a key role in antidepressant of Chaigui granules. The results of animal experiments showed that Chaigui granules significantly modulated behavioral indicators. Subsequently, the upregulation of relative mRNA levels of mTOR, Akt and PI3K and downregulation of GSK-3ß and FoxO3a were observed in rat hippocampus by molecular biology diagnosis. In addition, the decreased expression of Akt and mTOR in CUMS rats hippocampus was significantly reversed, and the expression levels of GSK-3ß and FoxO3a were upregulated. CONCLUSIONS: Based on the results of network pharmacology and animal experiment validation, Chaigui granules may reverse CUMS-induced depression-like behavior in rats through PI3K/Akt/mTOR signaling pathway.

Comprehensive pulmonary rehabilitation for a 90-year-old patient with intertrochanteric fracture complicated by chronic obstructive pulmonary disease: a case report.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD)-induced osteoporosis, myasthenia, and disequilibrium are important risk factors for hip fracture, and decreased respiratory function after hip fracture surgery can decelerate recovery of activities of daily living (ADL) in elderly patients. CASE PRESENTATION: A 90-year-old male patient underwent an open reduction and intramedullary pinning surgery for right femoral intertrochanteric fracture. After surgery, he remained confined to bed with pain and swelling in the right lower extremity. Due to his history of COPD, he had a postoperative pulmonary infection and respiratory insufficiency. INTERVENTION: This patient received routine rehabilitation after surgery. However, severe respiratory symptoms prevented him from completing the rehabilitation procedure. Therefore, comprehensive pulmonary rehabilitation including airway clearance techniques, inspiratory resistance training, aerobic training, respiratory muscle training, and intermittent low-flow oxygen inhalation was carried out to enhance the recovery process. OUTCOMES: After 4 weeks of treatment, the patient improved from continuous oxygen inhalation to being able to complete bed resistance training without supplemental oxygen. After 8 weeks, ADL reached independence, while lower limb muscle strength, pulmonary function parameters, fatigue index, and cough efficiency were improved as compared to test values obtained before treatment. CONCLUSION: Compared with the 6-month recovery time reported in the literature for patients with hip fractures to achieve independence with basic ADLs, the recovery time of this patient was shortened to 2 months with the application of comprehensive pulmonary rehabilitation. It is feasible to carry out pulmonary rehabilitation for elderly patients after fracture surgery, but prospective clinical trials are needed to verify its efficacy.

Lactate-upregulated NADPH-dependent NOX4 expression via HCAR1/PI3K pathway contributes to ROS-induced osteoarthritis chondrocyte damage.

Increasing evidence shows that metabolic factors are involved in the pathological process of osteoarthritis (OA). Lactate has been shown to contribute to the onset and progression of diseases. While whether lactate is involved in the pathogenesis of OA through impaired chondrocyte function and its mechanism remains unclear. This study confirmed that serum lactate levels were elevated in OA patients compared to healthy controls and were positively correlated with synovial fluid lactate levels, which were also correlated with fasting blood glucose, high-density lipoprotein, triglyceride. Lactate treatment could up-regulate expressions of the lactate receptor hydroxy-carboxylic acid receptor 1 (HCAR1) and lactate transporters in human chondrocytes. We demonstrated the dual role of lactate, which as a metabolite increased NADPH levels by shunting glucose metabolism to the pentose phosphate pathway, and as a signaling molecule up-regulated NADPH oxidase 4 (NOX4) via activating PI3K/Akt signaling pathway through receptor HCAR1. Particularly, lactate could promote reactive oxygen species (ROS) generation and chondrocyte damage, which was attenuated by pre-treatment with the NOX4 inhibitor GLX351322. We also confirmed that lactate could increase expression of catabolic enzymes (MMP-3/13, ADAMTS-4), reduce the synthesis of type II collagen, promote expression of inflammatory cytokines (IL-6, CCL-3/4), and induce cellular hypertrophy and aging in chondrocytes. Subsequently, we showed that chondrocyte damage mediated by lactate could be reversed by pre-treatment with N-Acetyl-l-cysteine (NAC, ROS scavenger). Finally, we further verified in vivo that intra-articular injection of lactate in Sprague Dawley (SD) rat models could damage cartilage and exacerbate the progression of OA models that could be countered by the NOX4 inhibitor GLX351322. Our study highlights the involvement of lactate as a metabolic factor in the OA process, providing a theoretical basis for potential metabolic therapies of OA in the future.

Serum uric acid and triglycerides in clear cell renal cell carcinoma: A restrospective cross-sectional study.

The available evidence on the relationship between serum uric acid and triglycerides in clear cell renal cell carcinoma (ccRCC) is limited. The objective of this study is to investigate whether there is an independent association between serum uric acid and triglycerides in ccRCC, while adjusting for other variables. This cross-sectional study involved 1018 participants with ccRCC, who were admitted to a hospital in China from December 1st, 2013 to January 1st, 2023. The main independent variable investigated was serum uric acid, which was measured at baseline. The dependent variable was triglycerides. Covariates considered in this study included age, sex, body mass index, smoking status, hypertension, diabetes, coronary disease, High-density lipoprotein cholesterol, Low-density lipoprotein cholesterol, Total cholesterol, Blood urea nitrogen, and Creatinine. The study included 1018 participants with an average age of 56.92 ±â€…10.88 years old, and approximately 68% of them were male. The fully-adjusted linear regression analysis indicated a positive association between serum uric acid levels (100µmol/L) and triglyceride levels (mmol/L) after adjusting for confounding factors (ß = 0.13, 95% CI [0.07, 0.18]). Furthermore, a smooth curve was constructed between serum uric acid and triglycerides based on the fully-adjusted model. In patients with ccRCC, there was a positive association between serum uric acid and triglycerides.

[Electroacupuncture improves obesity and promotes white adipose tissue browning by regulating central glucagon-like peptide-1].

OBJECTIVE: To observe the effect of electroacupuncture （EA） on white adipose tissue （WAT） browning by regulating central glucagon-like peptide-1 （GLP-1）, so as to explore the possible central mechanisms of EA in improving obesity. METHODS: Thirty male Wistar rats were randomly divided into normal group, model group, EA group, HM3D group, and EA+HM4D group, with 6 rats in each group. The obesity rat model was obtained by feeding with high-fat diet for 8 weeks. Adeno-associated virus combined with DREADDs was injected into bilateral nucleus of solitary tract （NTS）, with rAAV-GLP-1+rAAV-4D applied to the EA+HM4D group, rAAV-GLP-1+rAAV-3D applied to the HM3D group, and rAAV-GLP-1+rAAV-GFP applied to other 3 groups. After modeling, rats in the EA and EA+HM4D groups received EA treatment at bilateral "Zusanli"（ST36）, "Fenglong"（ST40）, "Guanyuan"（CV4） and "Zhongwan"（CV12）, with successive waves （2 Hz, 1 mA） for 10 minutes, 3 times a week, for a total of 8 weeks. Body mass of rats in each group were measured before and 2, 4, 6, and 8 weeks after intervention. Abdominal and perirenal WAT mass was weighed, serum triglyceride （TG） and total cholesterol （TC） contents were detected by using automatic analyzer, and nonestesterified fatty acid （NEFA） content was detected by using colorimetric assay kit. The morphology of abdominal WAT lipid droplets was observed by HE staining. The mRNA expressions of GLP-1 in NTS, AMPK in ventromedial nucleus of hypothalamus（VMH）, UCP1 and PGC-1α in subcutaneous fat were detected by real-time PCR. The protein expression levels of GLP-1, AMPK, phosphorylated-AMPK, UCP1 and PGC-1α were detected by Western blot. The activation level of GLP-1 neurons in NTS was observed by immunofluorescence. RESULTS: Compared with the normal group, abdominal WAT lipid droplets were enlarged, body weight, serum TG, TC, NEFA contents, abdominal and perirenal WAT mass, mRNA and protein expression levels of AMPK were significantly increased（P<0.01, P<0.05）, while GLP-1 neurons activation level, mRNA and protein expression levels of GLP-1, UCP1 and PGC-1α, and AMPK protein phosphorylation were decreased （P<0.01） in the model group. After EA intervention, body weight at 6 and 8 weeks after intervention and other indexes mentioned above were all significantly reversed （P<0.01, P<0.05） in the EA group in comparison with those of the model group. Compared with the EA group, the HM3D group had reduced abdominal WAT lipid droplets size, decreased serum TG, TC, and NEFA contents, and protein expression level of AMPK（P<0.01, P<0.05）, with increased mRNA and protein expression levels of GLP-1, UCP1 and PGC-1α, and phosphorylation level of AMPK protein（P<0.01, P<0.05）, while the EA+HM4D group had enlarged abdominal WAT lipid droplets, increased body weight 6 and 8 weeks after intervention, abdominal and renal WAT mass, and NEFA content （P<0.01, P<0.05）, with decreased serum TG content, activation level of GLP-1 neurons in the NTS, mRNA and protein expression levels of GLP-1, UCP1 and PGC-1α （P<0.01, P<0.05）, as well as down-regulated phosphorylation of AMPK protein and mRNA （P<0.01, P<0.05）. CONCLUSION: EA can effectively promote the browning of WAT, which may be related to the activation of GLP-1 neurons in the NTS, as well as the promotion of the phosphorylation of AMPK in the VMH and up-regulation of UCP1.