Exploring disparities in HIV-1 pretreatment and acquired drug resistance in China from 2003 to 2022.

OBJECTIVES: To investigate the epidemic patterns of pretreatment drug resistance (PDR) and acquired drug resistance (ADR) in HIV-1 sequences from China. METHODS: HIV-1 pol sequences and associated epidemiological data were collected from the Los Alamos HIV Sequence Database, NCBI, HIV Gene Sequence Database and PubMed. Genotypic resistance and subtypes were identified using the Stanford HIV Drug Resistance Database. RESULTS: A total of 36 263 sequences from ART-naïve individuals and 1548 sequences from ART-experienced individuals with virological failure were evaluated. PDR prevalence was 6.64%, initially decreasing and then increasing to 7.84% (2018-22) due to NNRTI. Pooled ADR prevalence (44.96%) increased, with NNRTI and NRTI aligning with the overall trend. The percentage of multidrug resistance was more than that of single-drug resistance in PDR and especially ADR annually. PDR was most prevalent in Central China followed by Southwest and North. ADR prevalence was highest in North China followed by Northwest and Southwest. In ADR sequences, high-level resistance was more common, especially in NRTI. PDR sequences exhibited low-level or intermediate resistance, especially PI. Drug resistance mutations revealed distinct patterns in PDR and ADR. CRF01_AE, the predominant subtype in China, exhibited the highest proportions among most ART drugs and drug resistance mutations, with a few exceptions where CRF07_BC (prominent in the Northwest), CRF55_01B and CRF08_BC (prominent in the Southwest) showed the highest proportions. CONCLUSIONS: HIV-1 PDR and ADR prevalence in China exhibited diverse epidemiological characteristics, underscoring the importance of ongoing national monitoring of PDR, ADR and subtype; patient education on adherence; and personalized regimens.

Melatonin Alleviates Osteoarthritis by Regulating NADPH Oxidase 4-Induced Ferroptosis and Mitigating Mitochondrial Dysfunction.

Recent evidence indicates that the damaged regions in osteoarthritis are accompanied by the accumulation of iron ions. Ferroptosis, as an iron-dependent form of cell death, holds significant implications in osteoarthritis. Melatonin, a natural product with strong scavenging abilities against reactive oxygen species and lipid peroxidation, plays a crucial role in the treatment of osteoarthritis. This study aims to demonstrate the existence of ferroptosis in osteoarthritis and explore the specific mechanism of melatonin in suppressing ferroptosis and alleviating osteoarthritis. Our findings reveal that melatonin reverses inflammation-induced oxidative stress and lipid peroxidation while promoting the expression of extracellular matrix components in chondrocytes, safeguarding the cells. Our research has revealed that NADPH oxidase 4 (NOX4) serves as a crucial molecule in the ferroptosis process of osteoarthritis. Specifically, NOX4 is located on mitochondria in chondrocytes, which can induce disorders in mitochondrial energy metabolism and dysfunction, thereby intensifying oxidative stress and lipid peroxidation. LC-MS analysis further uncovered that GRP78 is a downstream binding protein of NOX4. NOX4 induces ferroptosis by weakening GRP78's protective effect on GPX4 and reducing its expression. Melatonin can inhibit the upregulation of NOX4 on mitochondria and mitigate mitochondrial dysfunction, effectively suppressing ferroptosis and alleviating osteoarthritis. This suggests that melatonin therapy represents a promising new approach for the treatment of osteoarthritis.

Targeting Cartilage miR-195/497 Cluster for Osteoarthritis Treatment Regulates the Circadian Clock.

INTRODUCTION: Osteoarthritis (OA) is the most prevalent and debilitating joint disease without an effective therapeutic option. Multiple risk factors for OA have been identified, including abnormal chondrocyte miRNA secretion and circadian rhythms disruption, both of which have been found to cause progressive damage and loss of articular cartilage. Environmental disruption of circadian rhythms in mice predisposes animals to cartilage injury and OA. METHODS: The role of miR-195/497 cluster during OA progression was verified by mouse OA model with intra-articular injection of Agomir and Antagomir. We performed micro-CT analysis, Osteoarthritis Research Society International scores, and histological analysis in mouse knee joints. RNA sequencing was performed on the mouse cartilage cell line to explore the molecular mechanism of the miR-195/497 cluster and proteins in signaling pathway were evaluated using Western blot. Senescence-associated phenotypes were detected by Western blot, senescence ß-galactosidase staining, and immunofluorescence. RESULTS: This study demonstrated that miR-195/497-5p expression is disrupted in OA with senescent chondrocytes. In addition, miR-195/497-5p influenced the circadian rhythm of mice chondrocytes by modulating the expression of the Per2 protein, resulting in the gradual degradation of articular cartilage. We found that the miR-195/497 cluster targets DUSP3 expression. The deletion of the miR-195/497 cluster increased the level of DUSP3 expression and decreased the levels of phosphorylated ERK 1/2 and CREB. Per2 transcription is upregulated by stimulating CREB and ERK 1/2 phosphorylation. CONCLUSION: Our findings identify a regulatory mechanism connecting chondrocyte miR-195/497-5p to cartilage maintenance and repair and imply that circadian rhythm disturbances affected by miR-195/497-5p are risk factors for age-related joint diseases such as OA.

Functionalized Metal-Organic Framework-Modified Hydrogel That Breaks the Vicious Cycle of Inflammation and ROS for Repairing of Diabetic Bone Defects.

The regeneration of diabetic bone defects remains challenging. Hyperglycemia causes inflammation state and excessive reactive oxygen species (ROS) during bone regeneration period. These two effects reinforce one another and create an endless loop that is also accompanied by mitochondrial dysfunction. However, there is still no effective and inclusive method targeting at the two aspects and breaking the vicious cycle. Herein, nanoparticles-Met@ZIF-8(metformin loaded zeolitic imidazolate frameworks) modified hydrogel that is capable of releasing metformin and Zn elements are constructed. This hydrogel treats hyperglycemia while also controlling mitochondrial function, reducing inflammation, and restoring homeostasis. In addition, the synergetic effect from metformin and Zn ions inhibits ROS-inflammation cascade generation and destroys the continuous progress by taking effects in both ROS and inflammation and further keeping organelles' homeostasis. Furthermore, with the recovery of mitochondria and breakdown of the ROS-inflammation cascade cycle, osteogenesis under a diabetic microenvironment is enhanced in vivo and in vitro. In conclusion, the study provides critical insight into the biological mechanism and potential therapy for diabetic bone regeneration.

A novel degradable PCL/PLLA strapping band for internal fixation of fracture.

Early fracture fixation is the critical factor in fracture healing. Common internal fracture implants are made of metallic materials, which often affects the imaging quality of CT and MRI. Most patients will choose secondary surgery to remove the internal fixation implants, which causes secondary damage to them. The development of new degradable internal fracture implants has attracted more and more attention from orthopedic surgeons and researchers. Based on these problems, we improved the various properties of medical grade polycaprolactone (PCL) by adding poly(L-lactide) (PLLA). We produced PCL/PLLA strapping bands with different mass ratios by injection molding. We compared the mechanical properties, degradation properties, cell biocompatibility, bone marrow mesenchymal stem cells (BMSCs) adhesion, proliferation, osteogenic differentiation and fracture fixation effect of these strapping bands. The results showed that the tensile strength and yield force of the strapping bands increased with the increase of the content of PLLA. The addition of PLLA could significantly improve the mechanical strength in the early stage and accelerate the degradation rate of the strapping band. PCL/PLLA (80/20) strapping band had no significant cytotoxicity toward rBMSCs and could promote osteogenic differentiation of rBMSCs. The strapping band could ensure femoral fracture healing of beagles in 3 months and didn't cause damage to the surrounding tissues and main organs. This study will provide some new insights into the biodegradable products of PCL/PLLA blends for internal fixation of fracture. We produced novel degradable PCL/PLLA strapping bands with different mass ratios by injection molding. We tested the biological safety of the prepared internal fixation strapping bands for fracture, such as cell experiment in vitro and animal experiment, and studied the degradation behavior in vitro. The strapping bands could ensure femoral fracture healing of beagles. This study will provide some new insights into the biodegradable products of PCL/PLLA blends for internal fixation of fracture. A Immunofluorescence staining of rBMSCs (live cells: green; dead cells: red). B Young's modulus change curve during strapping bands degradation. C The implantation process of strapping bands. D Micro-CT images of the beagle's fracture recovery after the operation.

Mesenchymal stem cells encapsulation in chitosan and carboxymethyl chitosan hydrogels to enhance osteo-differentiation.

BACKGROUND: Recently biomaterials utilized for designing scaffolds in tissue engineering are not cost-effective and eco-friendly. As a result, we design and develop biocompatible and bioactive hydrogels for osteo-tissue regeneration based on the natural polysaccharide chitosan. Three distinct hydrogel components were used for this. METHODS: Hydrogels networks were created using chitosan 2% (CTS 2%), carboxymethyl chitosan 2% (CMC 2%), and 50:50 mixtures of CTS and CMC (CTS/CMC 50:50). Furthermore, scanning electron microscopy (SEM), Fourier transforms infrared spectroscopy (FTIR), degradation, and swelling behavior of design hydrogels were studied. Also, the cytocompatibility and osteo-differentiation potency were examined by encapsulating mesenchymal stem cells derived from adipose tissue (AMSCs) on the designed hydrogels. RESULTS: According to the findings, our results showed an acceptable pore structure, functional groups, and degradation rate of the designed hydrogels for in vitro evaluation. In addition, employing CMC instead of CTS or adding 50% CMC to the hydrogel component could improve the hydrogel's osteo-bioactivity without the use of external osteogenic differentiation agents. CONCLUSION: The CMC-containing hydrogel not only caused early osteogenesis but also accelerated differentiation to the maturity phase of osteoblasts.

Power Line Communication with Robust Timing and Carrier Recovery against Narrowband Interference for Smart Grid.

Power line communication (PLC) is an important interconnection technology for the smart grid, but the robustness of PLC transmission is faced with a great challenge due to strong non-Gaussian noise and interference. In this paper, a narrowband interference (NBI) resistant preamble is designed, and an effective timing and frequency synchronization method is proposed for OFDM-based PLC systems in the smart grid, which is capable of simultaneously conveying some bits of transmission parameter signaling (TPS) as well. In the time domain, the cyclic extension of the training OFDM symbol is scrambled, which makes it feasible to combat against NBI contamination. More accurate timing detection and sharper correlation peak can be implemented under the power line channel and the AWGN channel in the presence of NBI, compared with the conventional Schmidl's and Minn's methods with the same preamble length. Furthermore, the TPS transmitted using the proposed method is also immune from the NBI. The proposed method is capable of improving the synchronization performance of the PLC transmission significantly, which is verified by theoretical analysis and computer simulations.

Construction of core-shell Fe3O4@GO-CoPc photo-Fenton catalyst for superior removal of tetracycline: The role of GO in promotion of H2O2 to •OH conversion.

A novel core-shell structured Fe3O4@GO-CoPc magnetic catalyst, which is with magnetite (Fe3O4) as the core, graphene oxide (GO) as the interlayer and cobalt-phthalocyanine (CoPc) as the shell, was successfully prepared and used as a heterogeneous photo-Fenton catalyst for tetracycline (TC) degradation in this work. The core-shell structure of the catalyst was confirmed by XRD, FTIR, SEM and TEM. BET and magnetic hysteresis loops measurements indicated that Fe3O4@GO-CoPc catalyst owned large specific surface area and could be easily recovered under an external magnetic field. Meanwhile, the experimental results of TC degradation demonstrated that the photo-Fenton efficiency of Fe3O4@GO-CoPc was excellent. When the reaction time was 120 min, TC could be degraded almost completely in the photo-Fenton system with Fe3O4@GO-CoPc. The high photo-Fenton catalytic activity of Fe3O4@GO-CoPc could be resulted from the effective transfer of photo-generated electrons between CoPc and Fe3O4 by GO. Moreover, the main reaction species, •OH, O2•-, 1O2 and h+, were verified by the analysis of active species in this system. Finally, the mechanism analyses and quantitative analysis results of active species indicated that the introduction of GO accelerated the cycle between Fe(II) and Fe(III) as well as improved the effective utilization of H2O2 (the efficiency of conversion of H2O2 to •OH).

Deficiency in the anti-apoptotic protein DJ-1 promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via p53.

Parkinson disease autosomal recessive, early onset 7 (PARK7 or DJ-1) is involved in multiple physiological processes and exerts anti-apoptotic effects on multiple cell types. Increased intestinal epithelial cell (IEC) apoptosis and excessive activation of the p53 signaling pathway is a hallmark of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). However, whether DJ-1 plays a role in colitis is unclear. To determine whether DJ-1 deficiency is involved in the p53 activation that results in IEC apoptosis in colitis, here we performed immunostaining, real-time PCR, and immunoblotting analyses to assess DJ-1 expression in human UC and CD samples. In the inflamed intestines of individuals with IBD, DJ-1 expression was decreased and negatively correlated with p53 expression. DJ-1 deficiency significantly aggravated colitis, evidenced by increased intestinal inflammation and exacerbated IEC apoptosis. Moreover, DJ-1 directly interacted with p53, and reduced DJ-1 levels increased p53 levels both in vivo and in vitro and were associated with decreased p53 degradation via the lysosomal pathway. We also induced experimental colitis with dextran sulfate sodium in mice and found that compared with DJ-1-/- mice, DJ-1-/-p53-/- mice have reduced apoptosis and inflammation and increased epithelial barrier integrity. Furthermore, pharmacological inhibition of p53 relieved inflammation in the DJ-1-/- mice. In conclusion, reduced DJ-1 expression promotes inflammation and IEC apoptosis via p53 in colitis, suggesting that the modulation of DJ-1 expression may be a potential therapeutic strategy for managing colitis.

Insights into homeobox B9: a propeller for metastasis in dormant prostate cancer progenitor cells.

BACKGROUND: Metastasis is the major cause of treatment failure and cancer-related deaths in prostate cancer (PCa) patients. Our previous study demonstrated that a CD44+ subpopulation isolated from PCa cells or tumours possesses both stem cell properties and metastatic potential, serving as metastatic prostate cancer stem cells (mPCSCs) in PCa metastasis. However, the underlying mechanisms remain unknown. METHODS: In this study, we established PCa models via the orthotopic and subcutaneous implantation of different human PCa cancer cell lines, and compared the metastatic efficacy, after which process function analysis of target genes was pinpointed. RESULTS: Several novel differentially expressed genes (DEGs) between orthotopic and ectopic tumours were identified. Among them, human homeobox B9 (HOXB9) transcription factor was found to be essential for PCa metastasis, as evidenced by the diminished number of lung metastatic foci derived from orthotopic implantation with HOXB9-deficient CWR22 cells, compared with the control. In addition, HOXB9 protein expression was upregulated in PCa tissues, compared with paracancer and benign prostate hyperplasia tissues. It was also positively correlated with Gleason scores. Gain- and loss-of-function assays showed that HOXB9 altered the expression of various tumour metastasis- and cancer stem cell (CSC) growth-related genes in a transforming growth factor beta (TGFß)-dependent manner. Moreover, HOXB9 was overexpressed in an ALDH+CD44+CXCR4+CD24+ subpopulation of PCa cells that exhibited enhanced TGFß-dependent tumorigenic and metastatic abilities, compared with other isogenic PCa cells. This suggests that HOXB9 may contribute to PCa tumorigenesis and metastasis via TGFß signalling. Of note, ALDH+CD44+CXCR4+CD24+-PCa cells exhibited resistance to castration and antiandrogen therapy and were present in human PCa tissues. CONCLUSION: Taken together, our study identified HOXB9 as a critical regulator of metastatic mPCSC behaviour. This occurs through altering the expression of a panel of CSC growth- and invasion/metastasis-related genes via TGFß signalling. Thus, targeting HOXB9 is a potential novel therapeutic PCa treatment strategy.

Gene knockout or inhibition of macrophage migration inhibitory factor alleviates lipopolysaccharide-induced liver injury via inhibiting inflammatory response.

BACKGROUND: Liver injury is one of the most common complications during sepsis. Macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine. This study explored the role of MIF in the lipopolysaccharide (LPS)-induced liver injury through genetically manipulated mouse strains. METHODS: The model of LPS-induced liver injury was established in wild-type and Mif-knockout C57/BL6 mice. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil) were detected, and the expressions of MIF, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were measured. Liver histopathology was conducted to assess liver injury. Moreover, the inhibitions of MIF with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and 4-iodo-6-phenylpyrimidine (4-IPP) were used to evaluate their therapeutic potential of liver injury. RESULTS: Compared with wild-type mice, the liver function indices and inflammation factors presented no significant difference in the Mif-/- mice. After 72 h of the LPS-induced liver injury, serum levels of ALT, AST, and TBil as well as TNF-α and IL-1ß were significantly increased, but the knockout of Mif attenuated liver injury and inflammatory response. In liver tissue, mRNA levels of TNF-α, IL-1ß and NF-κB p65 were remarkably elevated in LPS-induced liver injury, while the knockout of Mif reduced these levels. Moreover, in LPS-induced liver injury, the inhibitions of MIF with ISO-1 and 4-IPP alleviated liver injury and slightly attenuated inflammatory response. Importantly, compared to mice with LPS-induced liver injury, Mif knockout or MIF inhibitions significantly prolonged the survival of the mice. CONCLUSIONS: In LPS-induced liver injury, the knockout of Mif or MIF inhibitions alleviated liver injury and slightly attenuated inflammatory response, thereby prolonged the survival of the mice. Targeting MIF may be an important strategy to protect the liver from injury during sepsis.

Cytisine attenuates bone loss of ovariectomy mouse by preventing RANKL-induced osteoclastogenesis.

Postmenopausal Osteoporosis (PMOP) is oestrogen withdrawal characterized of much production and activation by osteoclast in the elderly female. Cytisine is a quinolizidine alkaloid that comes from seeds or other plants of the Leguminosae (Fabaceae) family. Cytisine has been shown several potential pharmacological functions. However, its effects on PMOP remain unknown. This study designed to explore whether Cytisine is able to suppress RANKL-induced osteoclastogenesis and prevent the bone loss induced by oestrogen deficiency in ovariectomized (OVX) mice. In this study, we investigated the effect of Cytisine on RAW 264.7 cells and bone marrow monocytes (BMMs) derived osteoclast culture system in vitro and observed the effect of Cytisine on ovariectomized (OVX) mice model to imitate postmenopausal osteoporosis in vivo. We found that Cytisine inhibited F-actin ring formation and tartrate-resistant acid phosphatase (TRAP) staining in dose-dependent ways, as well as bone resorption by pit formation assays. For molecular mechanism, Cytisine suppressed RANK-related trigger RANKL by phosphorylation JNK/ERK/p38-MAPK, IκBα/p65-NF-κB, and PI3K/AKT axis and significantly inhibited these signalling pathways. However, the suppression of PI3K-AKT-NFATc1 axis was rescued by AKT activator SC79. Meanwhile, Cytisine inhibited RANKL-induced RANK-TRAF6 association and RANKL-related gene and protein markers such as NFATc1, Cathepsin K, MMP-9 and TRAP. Our study indicated that Cytisine could suppress bone loss in OVX mouse through inhibited osteoclastogenesis. All data provide the evidence that Cytisine may be a promising agent in the treatment of osteoclast-related diseases such as osteoporosis.

SP1-mediated upregulation of lncRNA LMCD1-AS1 functions a ceRNA for miR-106b-5p to facilitate osteosarcoma progression.

Growing studies have indicated the involvements of long noncoding RNAs (lncRNAs) in the initiation and progression of various tumors. We aimed to investigated the role of lncRNA LMCD1 antisense RNA 1 (LMCD1-AS1) in osteosarcoma development. We found that LMCD1-AS1 and SP1 were highly expressed in osteosarcoma tissues and cell lines. High levels of LMCD1-AS1 were correlated with positively metastasis and poor clinical prognosis. Moreover, we showed that SP1 can bind to the promoter region of LMCD1-AS1, resulting in its overexpression in osteosarcoma. Functionally, silencing of LMCD1-AS1 suppressed the proliferation, migration, invasion and EMT progress of osteosarcoma cells. Mechanistic studies revealed that LMCD1-AS1 was a sponge of miR-106b-5p activity. LMCD1-AS1 modulated survival of osteosarcoma via targeting miR-106b-5p. Overall, we firstly indicated that LMCD1-AS1 overexpression contributes to osteosarcoma development and poor clinical outcome, suggesting that LMCD1-AS1 may be a novel diagnostic and prognostic biomarker for osteosarcoma and a target for osteosarcoma therapy.

Determination of ferric ion via its effect on the enhancement of the chemiluminescece of the permanganate-sulfite system by nitrogen-doped graphene quantum dots.

Nitrogen-doped graphene quantum dots (NGQDs) are shown to strongly enhance the integrated chemiluminescence (CL) of the permanganate-sulfite system. The mechanism of enhancement was investigated, and the catalytic effect of the NGQDs was proven. In contrast to other carbon-based nanomaterials, the enhancement by NGQDs is independent of particle size and surface. However, the pyridinic nitrogen on the surface of the NGQDs facilitates the transformation of dissolved oxygen into H2O2 and the generation of hydroxyl radicals. This induces the increase of CL intensity. However, in the presence of Fe3+, the nitrogen functions and phenol groups on the surface of the NGQDs will chelate it, and the CL signal is decreased as a result. This effect was used to design an assay for Fe3+ that has a wide response range (1 × 10-8 - 1 × 10-6 M) and a 4 nM detection limit. The method was successfully applied to the determination of Fe3+ in spiked real water samples. Graphical abstract Nitrogen-doped graphene quantum dots (NGQDs) are demonstrated to strongly enhance the integrated chemiluminescence (CL) of the permanganate-sulfite system. The pyridinic N-atoms in NGQDs facilitate the transformation from dissolved oxygen into H2O2 and the generation of •OH radicals. This leads to the highly enhanced CL of the system. In the presence of Fe3+, which will be chelated by the nitrogen functions and phenol groups on the surface of the NGQDs, the CL signal is decreased.

The Bare Area of the Proximal Ulna: An Anatomic Study With Relevance to Chevron Osteotomy.

PURPOSE: A chevron osteotomy of the ulna is widely used to obtain intra-articular access to the elbow in the treatment of type C distal humerus fractures. The trochlear notch of the proximal ulna is divided into 2 articular parts by the "bare area." Ideally, the olecranon osteotomy should be centered on the bare area to minimize damage to the joint cartilage. The goals of this study were to describe the anatomy of the bare area and design an ideal chevron-shaped osteotomy. METHODS: We dissected 38 cadaver elbows and measured the width of the bare area, the distance between the tip of the triceps insertion and the area on the olecranon cortex corresponding to the bare area. We then designed a chevron osteotomy to stay within the bare area and measured the distance from the tip of the triceps insertion to the osteotomy apex as well as the angle of the osteotomy plane and the angle of the chevron cuts. RESULTS: The bare area existed in all 38 cadavers. The mean longitudinal and transverse widths were 4.0 mm (range, 1.0-8.6 mm) and 19.0 mm (range, 16.9-23.8 mm), respectively. The mean distance between the tip of the triceps insertion and the area on the olecranon cortex corresponding to the bare area was 19.0 mm (range, 16.0-23.0 mm). The mean transverse and longitudinal widths of the cortical notch were 3.0 mm (range, 1.6-4.5 mm) and 8.0 mm (range, 6.5-14.8 mm), respectively. The mean distance between the tip of the triceps insertion and the osteotomy apex was 22.0 mm (range, 18.0-24.0 mm) and the mean angle between the osteotomy surface and the vertical plane corresponding to the tangent plane was 20° (range, 10° to 25°). The mean angle of the V shape was 140° (range, 130° to 150°). CONCLUSIONS: Using the narrowest edge lacking cartilage (lateral or medial side) as a point of reference to locate the bare area, the designed chevron osteotomy entered the joint in the bare area in most specimens and decreased associated damage to the joint cartilage. CLINICAL RELEVANCE: This study describes the anatomy of the bare area and the design of the ideal chevron-shaped osteotomy to treat type C distal humerus fractures.

Uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome-dependent mechanism.

BACKGROUND & AIMS: Hyperuricemia significantly increases risk of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. However, the mechanisms responsible for this association are as yet unclear. This study aimed to investigate the effects and underlying mechanisms of uric acid on development of NAFLD and insulin resistance. METHODS: We initially analyzed the impact of uric acid on the development of hepatic steatosis and insulin resistance in mice and in two cell models, HepG2 and L02. Subsequently, we studied the role of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in uric acid-induced fat accumulation and insulin signaling impairment. RESULTS: We found that uric acid directly induces hepatocyte fat accumulation, insulin resistance, and insulin signaling impairment both in vivo and in vitro. We also found that uric acid-induced NLRP3 inflammasome activation, whereas lowering uric acid by allopurinol inhibited NLRP3 inflammasome activation in a high fat diet mouse model of NAFLD. Moreover, knocking down NLRP3 expression significantly attenuated uric acid-induced fat accumulation both in HepG2 cells and L02 cells. Knocking down NLRP3 expression also rescued uric acid-induced insulin signaling impairment in both cell types. CONCLUSIONS: Uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome. Uric acid may be a new therapeutic target for NAFLD and insulin resistance.

Comparison of endoscopic submucosal dissection and surgery for the treatment of gastric submucosal tumors originating from the muscularis propria layer: a single-center study (with video).

INTRODUCTION: Endoscopic submucosal dissection (ESD) has been used for the treatment of gastric submucosal tumors (SMTs). This study aims to compare clinical outcomes of ESD versus laparoscopic wedge resection (LWR) for gastric SMTs. METHODS: This is a retrospective cohort study. Patients with SMTs who underwent ESD or LWR were enrolled in this study at a university-affiliated hospital from January 2010 to October 2015. Preoperative endoscopic ultrasound and computed tomography were performed to determine origin of layer and growth pattern. Clinical outcomes including baseline demographics, tumor size, operation time, blood loss, hospital stay, cost, pathology and postoperative complications were compared. RESULTS: From January 2010 to October 2015, 68 patients with SMTs received ESD and 47 patients with SMTs received LWR. There was no difference in age, gender, body mass index, origin of layer and proportion with symptoms between ESD group and LWR group. However, tumor size was significantly larger in the LWR group (37.1 mm) than in the ESD group (25.8 mm, P = 0.041). For patients with tumors smaller than 20 mm, ESD was associated with shorter mean operation time (89.7 ± 23.5 vs 117.6 ± 23.7 min, P = 0.043), less blood loss (4.9 ± 1.7 vs 72.3 ± 23.3 ml, P < 0.001), shorter length of hospital stay (3.6 ± 1.9 vs 6.9 ± 3.7 days, P = 0.024) and lower cost (2471 ± 573 vs 4498 ± 1257 dollars, P = 0.031) when compared with LWR. For patients with tumors between 20 mm and 50 mm, ESD was associated with shorter mean operation time (99.3 ± 27.8 vs 125.2 ± 31.5 min, P = 0.039), less blood loss (10.1 ± 5.3 vs 87.6 ± 31.3 ml, P < 0.001), shorter length of hospital stay (4.0 ± 1.7 vs 7.3 ± 4.5 days, P = 0.027) and lower cost (2783 ± 601 vs 4798 ± 1343 dollars, P = 0.033) when compared with LWR. There were no significant differences in terms of rates of en bloc resection, complete resection and complication and histological diagnosis regardless of tumor size. CONCLUSIONS: ESD can achieve similar oncological outcomes when compared with surgery for treatment of gastric SMT smaller than 50 mm.

Finite element analysis of a novel anatomical plate in posterolateral plateau fractures.

Objective: This study aims to analyze the biomechanical characteristics of posterolateral plateau fractures fixed by a novel anatomical plate using finite element analysis. Methods: A three-dimensional digital model of the full length of right tibiofibula was obtained by CT scanning. A posterolateral tibial plateau fracture model was then created. The acquired fracture model was assembled with 4 groups of internal fixations: Group A, novel anatomical plate; Group B, straight buttress plate; Group C, oblique T-shaped locking plate; Group D, two lag screws. Axial loads of 500, 1,000 and 1,500 N perpendicular to the horizontal plane were used to simulate the stress on the lateral plateau of a 65 kg person standing, walking and fast running. Results: Vertical displacements of the posterolateral fragments in each of the four groups gradually increased under loads from 500 N to 1,500 N. The maximum displacement of the fracture fragment in four groups were all located on the lateral side of the proximal part, and the displacement gradually decreased from the proximal part to the distal end. The maximum displacement values under the axial load of 1,500 N was in the following order: novel anatomical plate (1.2365 mm) < oblique T-shaped locking plate (1.314 mm) < two lag screws (1.3747 mm) < straight buttress plate (1.3932 mm). As the axial load increased, the stress value of the different internal fixation models gradually increased. The stress behavior of the same internal fixation model under different loads was similar. The maximum stress value under the axial load of 1,500 N was in the following order: novel anatomical plate (114.63 MPa) < oblique T-shaped locking plate (277.17 MPa) < two lag screws (236.75 MPa) < straight buttress plate (136.2 MPa). Conclusion: The patients with posterolateral plateau fractures fixed with a novel anatomical plate in standing, walking and fast running can achieve satisfactory biomechanical results, which lays the foundation for future applications. At the same time, clinical fracture types are often diverse and accompanied by damage to the soft tissue. Therefore, the ideal surgical approach and appropriate internal fixation must be selected based on the patient's injury condition.

ZIF-8-based Nanoparticles for Inflammation Treatment and Oxidative Stress Reduction in Periodontitis.

Periodontitis, an inflammatory bone resorption disease associated with dental plaque, poses significant challenges for effective treatment. In this study, we developed Mino@ZIF-8 nanoparticles inspired by the periodontal microenvironment and the unique properties of zeolitic imidazolate framework 8, aiming to address the complex pathogenesis of periodontitis. Transcriptome analysis revealed the active engagement of Mino@ZIF-8 nanoparticles in innate and adaptive inflammatory host defense and cellular metabolic remodeling. Through sustained release of the anti-inflammatory and antibacterial agent minocycline hydrochloride (Mino) and the generation of Zn2+ with pro-antioxidant effects during degradation, Mino@ZIF-8 nanoparticles synergistically alleviate inflammation and oxidative damage. Notably, our study focuses on the pivotal role of zinc ions in mitochondrial oxidation protection. Under lipopolysaccharide (LPS) stimulation, periodontal ligament cells undergo a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, leading to reduced ATP production and increased reactive oxygen species levels. However, Zn2+ effectively rebalances the glycolysis-OXPHOS imbalance, restoring cellular bioenergetics, mitigating oxidative damage, rescuing impaired mitochondria, and suppressing inflammatory cytokine production through modulation of the AKT/GSK3ß/NRF2 pathway. This research not only presents a promising approach for periodontitis treatment but also offers novel therapeutic opportunities for zinc-containing materials, providing valuable insights into the design of biomaterials targeting cellular energy metabolism regulation.

Multiple applications of metal-organic frameworks (MOFs) in the treatment of orthopedic diseases.

Pharmacologic treatment of orthopedic diseases is a common challenge for clinical orthopedic surgeons, and as an important step in the stepwise treatment of orthopedic diseases, it is often difficult to achieve satisfactory results with existing pharmacologic treatments. Therefore, it is increasingly important to find new ways to effectively improve the treatment pattern of orthopedic diseases as well as to enhance the therapeutic efficacy. It has been found that metal-organic frameworks (MOFs) possess the advantages of high specific surface area, high porosity, chemical stability, tunability of structure and biocompatibility. Therefore, MOFs are expected to improve the conventional traditional treatment modality for bone diseases. This manuscript reviewed the applications of MOFs in the treatment of common clinical bone diseases and look forward to its future development.