Enhanced understanding of cinnamaldehyde's therapeutic potential in osteoarthritis through bioinformatics and mechanistic validation of its anti-apoptotic effect.

Introduction: Osteoarthritis (OA) is a globally prevalent joint disorder affecting approximately 240 million individuals worldwide. Cinnamaldehyde, known for its broad anti-inflammatory and anti-aging effects across various cell types, has not been investigated for its potential impact on apoptosis in OA chondrocytes. Methods: To explore the effectiveness of cinnamaldehyde in mitigating knee osteoarthritis by reducing chondrocyte apoptosis, bioinformatics analysis was first conducted to identify apoptosis-associated differentially expressed genes (APDEGs). Gene expression datasets GSE55235 and GSE114007 were analyzed using weighted gene co-expression network analysis (WGCNA). Gene modules of interest were cross-referenced with APDEGs to identify those specific to OA. LASSO regression analysis was employed to build a risk model, and this model, along with datasets GSE114007, GSE55457, and GSE12021, was validated using ROC analysis. Cellular experiments and blood analyses from OA patients were performed to evaluate the effects of cinnamaldehyde on apoptosis-related gene expression. Results: Cinnamaldehyde administration was found to rectify the abnormal expression of key apoptosis-related genes in OA patients. Specifically, cinnamaldehyde may affect knee osteoarthritis by regulating apoptosis-related genes such as ZFAND5, BCL6, ELL2, FOSL2, MARCKS, and SGCD. Additionally, three novel apoptotic targets in OA chondrocytes-ZFAND5, ELL2, and SGCD-were identified. Discussion: These findings provide significant theoretical support for the clinical use of cinnamaldehyde in OA treatment. The discovery of novel apoptotic targets presents new therapeutic possibilities for future OA interventions.

The novel HSP90 monoclonal antibody 9B8 ameliorates articular cartilage degeneration by inhibiting glycolysis via the HIF-1 signaling pathway.

Osteoarthritis (OA) is a prevalent chronic degenerative disease that affects the bones and joints, particularly in middle-aged and elderly individuals. It is characterized by progressive joint pain, swelling, stiffness, and deformity. Notably, treatment with a heat shock protein 90 (HSP90) inhibitor has significantly curtailed cartilage destruction in a rat model of OA. Although the monoclonal antibody 9B8 against HSP90 is recognized for its anti-tumor properties, its potential therapeutic impact on OA remains uncertain. This study investigated the effects of 9B8 on OA and its associated signaling pathways in interleukin-1ß (IL-1ß)-stimulated human chondrocytes and a rat anterior cruciate ligament transection (ACLT) model. A specific concentration of 9B8 preserved cell viability against IL-1ß-induced reduction. In vitro, 9B8 significantly reduced the expression of extracellular matrix-degrading enzyme such as disintegrin and metallopeptidase-4 (ADAMTS4) of thrombospondin motifs, matrix metalloproteinase-13 (MMP-13), as well as cellular inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which were upregulated by IL-1ß. In vivo, 9B8 effectively protected the articular cartilage and subchondral bone of the rat tibial plateau from ACLT-induced damage. Additionally, gene microarray analysis revealed that IL-1ß substantially increased the expression of SLC2A1, PFKP, and ENO2 within the HIF-1 signaling pathway, whereas 9B8 suppressed the expression of these genes. Thus, 9B8 effectively mitigates ACLT-induced osteoarthritis in rats by modulating the HIF-1 signaling pathway, thereby inhibiting overexpression involved in glycolysis. These results collectively indicate that 9B8 is a promising novel drug for the prevention and treatment of OA.

Fabrication of a novel macrophage-targeted biomimetic delivery composite hydrogel with multiple-sensitive properties for tri-modal combination therapy of rheumatoid arthritis.

In this study, a porous polydopamine (PDA) nanoparticle-decorated ß-glucan microcapsules (GMs) nanoplatform (PDA/GMs) were developed with macrophage-targeted biomimetic features and a carriers-within-carriers structure. Indocyanine green (ICG) and catalase (CAT) were subsequently co-encapsulated within the PDA/GMs to create a multifunctional nanotherapeutic agent, termed CIPGs. Furthermore, CIPGs and sinomenine (SIN) were co-loaded within a thermo-sensitive hydrogel to design an injectable delivery system, termed CIPG/SH, with potential for multi-modal therapy of rheumatoid arthritis (RA). Photothermal studies indicated that the CIPGs hold excellent photothermal conversion ability and thermal stability, as they combined the photothermal performance of both PDA and ICG. Meanwhile, the CIPGs displayed favorable oxygen self-supplying and photodynamic performance. The CIPGs showed near-infrared (NIR)-induced phototoxicity, effectively inhibiting macrophage proliferation and displaying remarkable antibacterial activity. In vitro drug release from the prepared CIPG/SH showed a controlled release pattern. Animal experiments conducted on an RA mice model confirmed that the formulated CIPG/SH exhibited significant therapeutic effects. By integrating the biological advantages, photothermal/photodynamic performance of the CIPGs, and controlled drug release performance of the thermo-sensitive hydrogels in a single delivery system, the prepared injectable CIPG/SH represents a novel versatile delivery system with great potential for multi-modal combination targeting therapy in RA.

Identification and verification of four candidate biomarkers for early diagnosis of osteoarthritis by machine learning.

Background: Osteoarthritis (OA) is a common chronic joint disease. This study aimed to investigate possible OA diagnostic biomarkers and to verify their significance in clinical samples. Methods: We exploited three datasets from the Gene Expression Omnibus (GEO) database, serving as the training set. We first determined differentially expressed genes and screened candidate diagnostic biomarkers by applying three machine learning algorithms (Random Forest, Least Absolute Shrinkage and Selection Operator logistic regression, Support Vector Machine-Recursive Feature Elimination). Another GEO dataset was used as the validation set. The test set consisted of RNA-sequenced peripheral blood samples collected from patients and healthy donors. Blood samples and chondrocytes were collected for quantitative real-time PCR to confirm expression levels. Receiver operating characteristic curves were generated for individual and combined biomarkers. Results: In total, 251 DEGs were screened, where B3GALNT1, SCRG1 and ZNF423 were screened by all three algorithms. The area under the curve (AUC) of various biomarkers in our test set did not reach as high as that in public datasets. GRB10 exhibited highest AUC of 0.947 in the training set but 0.691 in our test set, while the favorable combined model comprising B3GALNT1, GRB10, KLF9 and SCRG1 demonstrated an AUC of 0.986 in the training set, 1.000 in the validation set and 0.836 in our test set. Conclusion: We identified a combined model for early diagnosis of OA that includes B3GALNT1, GRB10, KLF9 and SCRG1. This finding offers new avenues for further exploration of mechanisms underlying OA.

[Analysis of genetic variants and molecular pathogenesis in a Chinese pedigree affected with Multiple epiphyseal dysplasia].

OBJECTIVE: To analyze the genetic variant and molecular pathogenesis in a Chinese pedigree affected with Multiple epiphyseal dysplasia (MED). METHODS: A MED pedigree which had presented at the Beijing Jishuitan Hospital Affiliated to Capital Medical University on September 13, 2020 was selected as the study subject. Clinical data of the pedigree were collected. Peripheral blood samples were drawn from pedigree members for the extraction of genomic DNA. Whole exome sequencing (WES) was carried out for the pedigree. Candidate variant was verified by Sanger sequencing. Wild type and mutant SLC26A2 expression plasmids were constructed and transfected into human primary chondrocytes. The effect of the variants on the protein localization and cell proliferation was determined by immunofluorescence and CCK8 assays. RESULTS: WES and Sanger sequencing revealed that the proband has harbored compound heterozygous variants of the SLC26A2 gene, including a paternally derived c.484G>T (p.Val162Leu) missense variant and a maternally derived c.485_486delTG (p.Val162Glyfs*12) frameshifting variant. The SLC26A2WT and its mutant SLC26A2Val162Leu and SLC26A2Val162Glyfs*12 expression plasmids were distributed in the nuclei and cytoplasm of human primary chondrocytes. Compared with SLC26A2WT, the expressions of SLC26A2Val162Leu and SLC26A2Val162Glyfs*12 were decreased, along with reduced proliferation of human primary chondrocytes. CONCLUSION: The c.484G>T and c.485_486delTG compound heterozygous variants of the SLC26A2 gene may affect the proliferation of human primary chondrocytes and underlay the pathogenesis of MED in this pedigree.

Clinical characteristics and analysis of vestibular-evoked myogenic potentials in patients with sudden sensorineural hearing loss in different ages.

BACKGROUND: Numerous studies have found that patients experiencing sudden sensorineural hearing loss (SSHL), with or without accompanying vertigo, often show impaired vestibular function. However, there is a dearth of studies analyzing vestibular-evoked myogenic potentials (VEMPs) in SSHL patients across various age groups. AIM: To investigate vestibular condition in SSHL patients across various age demographics. METHODS: Clinical data of 84 SSHL patients were investigated retrospectively. Audiometry, cervical vestibular evoked myogenic potentials (c-VEMPs), and ocular vestibular evoked myogenic potentials (o-VEMPs) were conducted on these patients. Parameters assessed included the latencies of P1 and N1 waves, as well as the amplitudes of P1-N1 waves. Moreover, the study evaluated the influence of factors such as sex, affected side, configuration of hearing loss, and presence of accompanying vertigo. RESULTS: Among the 84 SSHL patients, no significant differences were observed among the three groups in terms of gender, affected side, and the presence or absence of vertigo. Group II (aged 41-60 years) had the highest number of SSHL cases. The rates of absent o-VEMPs in the affected ears were 20.83%, 31.58%, and 22.72% for the three age groups, respectively, with no statistically significant difference among them. The rates of absent c-VEMPs in the affected ears were 8.3%, 34.21%, and 18.18% for the three age groups, respectively, with significant differences. In the unaffected ears, there were differences observed in the extraction rates of o-VEMPs in the unaffected ears among the age groups. In the three age groups, no significant differences were noted in the three age groups in the latencies of P1 and N1 waves or in the amplitude of N1-P1 waves for c-VEMPs and o-VEMPs, either on the affected side or on the unaffected side, across the three age groups. CONCLUSION: The extraction rate of VEMPs is more valuable than parameters. Regardless of the presence of vertigo, vestibular organs are involved in SSHL. Notably, SSHL patients aged 41-60 appear more susceptible to damage to the inferior vestibular nerve and saccule.

Biallelic variants in SLC26A2 cause multiple epiphyseal dysplasia-4 by disturbing chondrocyte homeostasis.

BACKGROUND: Multiple epiphyseal dysplasia-4 (MED-4, MIM 226900) is a rare autosomal recessive disease characterized by disproportionate height and early onset osteoarthritis of the lower limbs. MED-4 is caused by homozygous or compound heterozygous pathogenic variants in the SLC26A2 gene. However, the underlying pathogenic mechanisms in chondrocytes remains unknown. This study aimed to identify the pathogenic variants within a MED-4 family and explore the molecular etiology of this condition in human primary chondrocyte cells. METHODS: Clinical data were recorded and peripheral blood samples were collected for analysis. Whole exome sequencing (WES) and bioinformatic analyses were performed to determine causative variants. Wild-type SLC26A2 and corresponding mutant expression plasmids were constructed and transfected into human primary chondrocytes. The expression and subcellular distribution of SLC26A2 protein in chondrocytes were detected by immunoblotting and immunofluorescence. Effects of these variants on chondrocytes viability and apoptosis were measured by Cell Counting Kit-8 (CCK-8) assay. Expression of genes related to cartilage homeostasis was subsequently analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: We identified two compound heterozygous variants c.1020_1022delTGT(p.Val341del) and c.1262 T > C(p.Ile421Thr) in the SLC26A2 gene in the patients. Mutant SLC26A2Val341del and SLC26A2Ile421Thr proteins were distributed in relatively few cells and were observed only within the nucleus. The viability of chondrocytes with the SLC26A2 variant group was similar to the wild-type (WT) group. However, the protein expressions of SLC26A2Val341del and SLC26A2Ile421Thr were decreased compared with SLC26A2WT. Expression levels of matrix metallopeptidase 13 (MMP13), α-1 chain of type X collagen (COL10A1), and Runt-related transcription factor 2 (RUNX2) were significantly decreased in the variant group. However, aggrecan (ACAN) expression was higher in the variant group than the WT group. CONCLUSIONS: Overall, our data demonstrate that the variants p.Val341del and p.Ile421Thr in SLC26A2 cause MED-4 and that these two variants promote chondrocyte proliferation while inhibiting chondrocyte differentiation.

Influence of microplastics and environmentally persistent free radicals on the ability of biochar components to promote degradation of antibiotics by activated peroxymonosulfate.

Microplastics (MPs) in sludge can affect the ability of biochar-activated peroxymonosulfate (PMS) to degrade antibiotics. In this work, biochar was prepared by mixing sludge and polystyrene (PS) through hydrothermal carbonization (HTC) and high-temperature pyrolysis processes. The resulting biochar was used to activate PMS to degrade ofloxacin (OFX), levofloxacin (LEV), and pefloxacin (PFX). The addition of PS significantly enhanced the ability of biochar/PMS to degrade antibiotics and the levels of environmentally persistent free radicals (EPFRs, 4.59 × 1020 spin/g) due to the decomposition of PS. The addition of PS resulted in a slight decrease in the specific surface area of biochar (2-3 m2/g on average), but a significant increase in the concentration of EPFRs increased the removal efficiency. The activation of PMS by biochar is dominated by free radicals, accounting for about 70%, in which SO4•- and •OH contribute the most and O2•- the least. However, 1O2 contributes 15-20% to the degradation of antibiotics in non-free radical processes. Overall, the process of biochar/PMS degradation of antibiotics is mainly dominated by free radicals, and the effect of non-free radicals is not obvious. Both hydrochar and pyrocarbon samples showed good hydrophilicity, and this property should improve the ability of active sites on biochar to degrade antibiotics. In the HTC process, PS can decompose during hydrochar preparation, with a maximum reduction value of 40.09%. The three-dimension excitation emission matrix fluorescence spectroscopy (3D-EEM) and total organic carbon (TOC) results show that the protein content in sludge plays a major role in reducing PS, with little effect of polysaccharide and SiO2. There are six to seven degradation intermediates of quinolone antibiotics, which are eventually degraded into CO2, H2O, and inorganic substances. The regeneration experiment showed good reusability of hydrochar and pyrocarbon, further demonstrating the suitability of biochar for the degradation of antibiotics.

Crucial role of lncRNA NONHSAG037054.2 and GABPA, and their related functional networks, in ankylosing spondylitis.

Long non-coding RNAs (lncRNAs) have been previously researched in ankylosing spondylitis (AS). Nevertheless, there are few studies of lncRNAs and mRNAs associated with the pathogenesis of AS. Differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between AS and normal samples were assessed using the R limma package. DOSE packages and 'clusterProfiler' were exploited for gene enrichment analysis. The functional association of proteins and protein interactions was assessed using the STRING database. To investigate the important genes and subnetworks in the protein-protein interaction network, the MCODE plug-in in the Cytoscape software was utilized. The gene mRNA was examined via reverse transcription-quantitative PCR. In total, 152 DEmRNAs and 204 DElncRNAs were observed between normal and AS samples. A total of 68 candidate genes related to DElncRNA were identified. These candidate genes were enriched in 30 cellular component terms, 22 molecular functions, 83 biological processes, 9 Kyoto Encyclopedia of Genes and Genomes, and 36 disease ontology pathways. NONHSAG037054.2 was the most related lncRNA to genes, and GABPA was the most connected gene to lncRNA in AS. The NCBI/GenBank accession number of the lncRNA NONHSAG037054.2 was not found because it is not included in NCBI. The information of lncRNA NONHSAG037054.2 can be found at the website (http://www.noncode.org/show_gene.php?id=NONHSAG037054 and https://www.genecards.org/cgi-bin/carddisp.pl?gene=ACAP2-IT1). In total, 13 microRNAs (miRNAs) and 46 miRNAs associated with NONHSAG037054.2 and GABPA, respectively, were found. A total of 173 RNA-binding protein genes were associated with both NONHSAG037054.2 and GABPA. In addition, GABPA was downregulated in AS samples, suggesting it may have diagnostic value in AS. In conclusion, NONHSAG037054.2 and GABPA are associated with AS. GABPA was downregulated in AS, and it could serve as a novel diagnostic factor for AS.

Non-filamentous bulking of activated sludge induced by graphene oxide: Insights from extracellular polymeric substances.

Widespread use of nanomaterials raises concerns. The underlying mechanism by which graphene oxide (GO) nanoparticles causes poor settleability of activated sludge remains unclear. To explore this mechanism, three reactors with different GO concentrations were established. Extended Derjaguin-Landau-Verwey-Overbeek theory indicated that GO destroyed the property of extracellular polymeric substances (EPS), increasing the energy barrier between bacteria. Low levels of uronic acid and hydrogen bonding in exopolysaccharide weakened the EPS gelation increasing aggregation repulsion. Lager amounts of hydrophilic amino acid and looser structure of extracellular proteins for exposing inner hydrophilic groups significantly contributed to the hydrophilicity of EPS. Both changes implied deterioration in EPS structure under GO stress. Metagenome demonstrated a decrease in genes responsible for capsular polysaccharide colonization and genes regulated the translocation of loose proteins were increased, which increased repulsion between bacteria. This study elucidated that changes in EPS secretion under GO exposure are the underlying causes of poor settleability.

The association between genetic polymorphisms of matrix metalloproteinases and knee osteoarthritis: A systematic review and meta-analysis.

AIM: To investigate the linkage of matrix metalloproteinase (MMP) gene polymorphisms with the pathogenesis of knee osteoarthritis (OA). METHODS: This meta-analysis study systematically retrieved relevant studies from PubMed, Embase, the Cochrane Central, Wanfang Data, CNKI, and SinoMed up to November 2020. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the association between MMP gene polymorphisms and OA. RESULTS: A total of nine case-control studies comprising 1719 knee OA patients and 1904 controls were included in this meta-analysis. The results revealed that MMP-1-1607 (rs1799750) 1G/2G polymorphism was not significantly associated with knee OA risk in four genetic models (OR (95% CI): allele model: 0.89 (0.57, 1.40), p = .615); dominant mode: 0.82 (0.47, 1.44), p = .486; recessive model: 0.88 (0.49, 1.57), p = .659; homozygote model: 0.79 (0.34, 1.82), p = .576. The association was significant for dominant model of MMP-3 C/T: 1.54 (1.10-2.15), p = .013, especially in Asian ethnicity (1.63 (1.11, 2.39), p = .013). Variants of MMP-13 C/T polymorphism were associated with increased risk of knee OA development based on dominant model: 1.56 (1.19, 2.06), p = .001 and homozygote model: 2.12 (1.44, 3.13), p < .001, and there were significant associations between MMP-13 C/T polymorphism and knee OA risk in Asian ethnicity under different genetic models (all p > .05). CONCLUSIONS: Present evidence suggested that the gene polymorphisms of MMP-1-1607 1G/2G may not be associated with the risk of OA. But, the dominant model of MMP-3 and MMP-13 polymorphisms in Asian ethnicity was significantly correlated with knee OA.

Integration analysis of lncRNA and mRNA expression data identifies DOCK4 as a potential biomarker for elderly osteoporosis.

BACKGROUND: We aimed to identify some potential biomarkers for elderly osteoporosis (OP) by integral analysis of lncRNA and mRNA expression data. METHODS: A total of 8 OP cases and 5 healthy participants were included in the study. Fasting peripheral venous blood samples were collected from individuals, and total RNA was extracted. RNA-seq library was prepared and sequenced on the Illumina HiSeq platform. Differential gene expression analysis was performed using "DESeq2" package in R language. Functional enrichment analysis was conducted using the "clusterProfiler" package, and the cis- and trans-regulatory relationships between lncRNA and target mRNA were analyzed by the lncTar software. A protein-protein interaction (PPI) network was constructed using the STRING database, and hub genes were identified through the MCODE plugin in Cytoscape. RESULTS: We identified 897 differentially expressed lncRNAs (DELs) and 1366 differentially expressed genes (DEGs) between normal and OP samples. After co-expression network analysis and cis-trans regulatory genes analysis, we identified 69 candidate genes regulated by lncRNAs. Then we further screened 7 genes after PPI analysis. The target gene DOCK4, trans-regulated by two lncRNAs, was found to be significantly upregulated in OP samples. Additionally, 4 miRNAs were identified as potential regulators of DOCK4. The potential diagnostic value of DOCK4 and its two trans-regulatory lncRNAs was supported by ROC analysis, indicating their potential as biomarkers for OP. CONCLUSION: DOCK4 is a potential biomarker for elderly osteoporosis diagnostic. It is identified to be regulated by two lncRNAs and four miRNAs.

The CREB1 inhibitor 666-15 maintains cartilage homeostasis and mitigates osteoarthritis progression.

Aims: cAMP response element binding protein (CREB1) is involved in the progression of osteoarthritis (OA). However, available findings about the role of CREB1 in OA are inconsistent. 666-15 is a potent and selective CREB1 inhibitor, but its role in OA is unclear. This study aimed to investigate the precise role of CREB1 in OA, and whether 666-15 exerts an anti-OA effect. Methods: CREB1 activity and expression of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) in cells and tissues were measured by immunoblotting and immunohistochemical (IHC) staining. The effect of 666-15 on chondrocyte viability and apoptosis was examined by cell counting kit-8 (CCK-8) assay, JC-10, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining. The effect of 666-15 on the microstructure of subchondral bone, and the synthesis and catabolism of cartilage, in anterior cruciate ligament transection mice were detected by micro-CT, safranin O and fast green (S/F), immunohistochemical staining, and enzyme-linked immunosorbent assay (ELISA). Results: CREB1 was hyperactive in osteoarthritic articular cartilage, interleukin (IL)-1ß-treated cartilage explants, and IL-1ß- or carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-treated chondrocytes. 666-15 enhanced cell viability of OA-like chondrocytes and alleviated IL-1ß- or CCCP-induced chondrocyte injury through inhibition of mitochondrial dysfunction-associated apoptosis. Moreover, inhibition of CREB1 by 666-15 suppressed expression of ADAMTS4. Additionally, 666-15 alleviated joint degeneration in an ACLT mouse model. Conclusion: Hyperactive CREB1 played a critical role in OA development, and 666-15 exerted anti-IL-1ß or anti-CCCP effects in vitro as well as joint-protective effects in vivo. 666-15 may therefore be used as a promising anti-OA drug.

Effects of excess sludge composting process, environmentally persistent free radicals, and microplastics on antibiotics degradation efficiency of aging biochar.

Simulation of microbial aging biochar in compost is an important index for evaluating the biochar degradation efficiency of antibiotics. In this study, biochar was prepared by adding microplastics (MPs) to sludge, and the degradation effect of biochar/(peroxymonosulfate, PMS) on antibiotics was evaluated during the compost aging process of biochar. After the compost aging of biochars, the antibiotic degradation efficiency of HPBC500, HPBC500 + polystyrene (PS), HPBC900/PMS, and HPBC900 + PS/PMS decreased by 6.47, 15.2, 10.16, and 10.33 %, respectively. Environmentally persistent free radicals (EPFRs) and defect structure were the main contributors to the activation of PMS. EPFRs produced through PS pyrolysis of biochar exhibited strong reactivity but poor stability during the degradation of antibiotics. Biochar enhanced the growth of microorganisms in compost but reduced its specific surface area. The antibiotic degradation efficiency of the biochar was positively correlated with the concentration of EPFRs. This study elucidated the durability of different biochar toward antibiotic degradation.

Dihydrotanshinone I protects human chondrocytes and alleviates damage from spontaneous osteoarthritis in a guinea pig model.

Osteoarthritis (OA) is the most common degenerative joint disease. Currently, no satisfactory pharmacological treatment exists for OA. The potential anti-inflammatory properties of Dihydrotanshinone I (DHT) have been reported, but its effects on OA are unclear. In this study, we assess the impact of DHT on the viability of human chondrocytes in vitro. We then use a guinea pig model to investigate the effects of DHT on knee osteoarthritis progression. Twelve-week-old Dunkin Hartley guinea pigs spontaneously developing OA were intraperitoneally injected with different doses of DHT for eight weeks. Micro-CT analysis was performed on the subchondral bone in the knee, and histological assessment of the knee joint was done using stained sections, the ratio of hyaline to calcified cartilage, and Mankin scores. DHT successfully restored IL-1ß-induced decreases in cell viability in human primary chondrocytes. In the guinea pig model, intraperitoneal injections of DHT ameliorated age-induced OA, effectively reduced the expression level of two cartilage metabolism-related genes (ADAMTS4 and MMP13) and decreased the inflammatory biomarker IL-6 in the serum of guinea pigs developing spontaneous osteoarthritis. These findings demonstrate DHT's protective effects on chondrocytes and suggest that it alleviates cartilage degradation and proteoglycan loss in OA.

Construction of ultrasonically treated collagen/silk fibroin composite scaffolds to induce cartilage regeneration.

A novel tissue-specific functional tissue engineering scaffold for cartilage repair should have a three-dimensional structure, good biosafety and biological activity, and should be able to promote cartilage tissue regeneration. This study aimed to determine the effect of ultrasound-treated collagen/silk fibroin (Col/SF) composite scaffolds with good mechanical properties and high biological activity on cartilage repair. The characteristics of the scaffolds with different Col/SF ratios (7:3, 8:2, and 9:1) were determined by scanning electron microscopy, Fourier-transform infrared spectroscopy, and porosity, water absorption, and compression tests. In vitro evaluations revealed the biocompatibility of the Col/SF scaffolds. Results suggested that the optimal ratio of Col/SF composite scaffolds was 7:3. The Col/SF scaffolds induced adipose-derived stem cells to undergo chondrogenic differentiation under chondrogenic culture conditions. The efficiency of Col/SF scaffolds for cartilage regeneration applications was further evaluated using an in vivo model of full-thickness articular cartilage defects in New Zealand rabbits. The Col/SF scaffolds effectively promoted osteochondral regeneration as evidenced by macroscopic, histological, and immunohistochemical evaluation. The study demonstrates that ultrasound-treated Col/SF scaffolds show great potential for repairing cartilage defects.

Temporal trends in mortality of tuberculosis attributable to high fasting plasma glucose in China from 1990 to 2019: a joinpoint regression and age-period-cohort analysis.

Background: Nowadays, high fasting plasma glucose (HFPG) has been identified as the important risk factor contributing to the increased burden of diseases. But there remains a lack of research on tuberculosis (TB) mortality specifically attributable to HFPG. Thus, this study aims to explore the long-term trends in HFPG-related TB mortality in China from 1990 to 2019. Methods: Data on HFPG-related TB mortality were obtained from the Global Burden of Disease (GBD) Study 2019. Analyzing the data using joinpoint regression and age-period-cohort methods adjusting for age, period, and cohort allowed us to assess the trends in TB mortality due to HFPG. Results: The age-standardized mortality rates (ASMRs) of TB attributable to HFPG exhibited a downward trend in China from 1990 to 2019, with an average annual percentage change (AAPC) of -7.0 (95% CI, -7.5 to -6.6). Similar trends were found for male (AAPC of -6.5 [95% CI, -7.0 to -6.0]) and female (AAPC of -8.2 [95% CI, -8.5 to -7.9]), respectively. Local drifts curve with a U-shaped pattern reflected the AAPC of TB mortality due to HFPG across age groups. The greatest decline was observed in the age group of 60-64 years. The mortality rates related to HFPG first increased and then decreased with increasing age, peaking in the 55-59 age group. Our analysis of the period and cohort effects found that the rate ratios of TB mortality due to HFPG have decreased over the past three decades, more prominently in women. It is noteworthy that while both genders have seen a decline in HFPG-attributable TB mortality and risk, men have a higher risk and slightly less significant decline than women. Conclusion: The present study shows that HFPG-related ASMRs and risk of TB in China decreased over the last 30 years, with similar trends observed in both men and women. In order to attain the recommended level set by the WHO, the effective strategies for glycemic control and management still needed to be implemented strictly to further decrease the burden of TB.

Dexmedetomidine alleviates oxidative stress and mitochondrial dysfunction in diabetic peripheral neuropathy via the microRNA-34a/SIRT2/S1PR1 axis.

OBJECTIVE: Dexmedetomidine (Dex) is a highly selective α2-adrenoceptor agonist with sedative, analgesic, sympatholytic, and hemodynamic-stabilizing properties, which plays a neuroprotective role in diabetic peripheral neuropathy (DPN) and diabetes-induced nerve damage. However, the related molecular mechanisms are not fully understood. Therefore, our study explored the mechanism of Dex in DPN using rat and RSC96 cell models. METHODS: Sciatic nerve sections were observed under an optical microscope and the ultrastructure of the sciatic nerves was observed under a transmission electron microscope. Oxidative stress was assessed by detecting MDA, SOD, GSH-Px, and ROS levels. The motor nerve conduction velocity (MNCV), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL) of rats were measured. Cell viability, apoptosis, and the changes in the expression of related genes and proteins were examined. Furthermore, the relationship between microRNA (miR)-34a and SIRT2 or SIRT2 and S1PR1 was analyzed. RESULTS: Dex reversed DPN-induced decreases in MNCV, MWT, and TWL. Dex alleviated oxidative stress, mitochondrial damage, and apoptosis in both the rat and RSC96 cell models of DPN. Mechanistically, miR-34a negatively targeted SIRT2, and SIRT2 inhibited S1PR1 transcription. The overexpression of miR-34a or S1PR1 or the inhibition of SIRT2 counteracted the neuroprotective effects of Dex in DPN in vivo and in vitro. CONCLUSION: Dex alleviates oxidative stress and mitochondrial dysfunction associated with DPN by downregulating miR-34a to regulate the SIRT2/S1PR1 axis.

Characterization and role exploration of ferroptosis-related genes in osteoarthritis.

Osteoarthritis (OA), viewing as a degenerative aseptic inflammatory disease, is characterized by joint pain and inflammation that significantly affects the quality of patients' life, especially for the elder. Although rapid progress has been achieved in elucidating the underlying mechanisms of OA occurrence and progression, there is still a lack of effective clinical therapeutics for OA patients. Currently the most common treatments including drug therapy and surgical operations are not very satisfactory in majority of cases, so it is worthy to explore new remedies. During the past few decades, a number of novel forms of regulated cell death have been reported widely, typified by ferroptosis, with its prominent features including reactive oxygen species (ROS) elevation, lipid peroxidation, iron accumulation and glutathione deprivation. Our study was designed to identify the functional roles of differentially expressed ferroptosis-related genes in OA, which were screened out by referring to GEO database via bioinformatics analyses. Human chondrocytes were applied to validate the above findings in the scenario of ferroptosis inhibitors administration. Results partially proved the consistency with bioinformatics analyses that ATF3 and TFRC were highly expressed in interleukin-1ß (IL-1ß)-stimulated chondrocytes whereas CXCL2 and JUN were downregulated. Besides, TFRC was firstly validated to be upregulated in IL-1ß-stimulated chondrocytes, which could be reversed by ferroptosis inhibitors. In conclusion, our study reported two prominent ferroptosis-related genes, ATF3 and TFRC are upregulated in IL-1ß-stimulated chondrocytes while CXCL2 and JUN are downregulated. And preliminary results demonstrated that TFRC might serve as an accomplice of ferroptosis process in IL-1ß-stimulated chondrocytes and ferroptosis inhibitors have the potential to inhibit ROS in IL-1ß-stimulated chondrocytes.

Effect of aged biochar after microbial fermentation on antibiotics removal: Key roles of microplastics and environmentally persistent free radicals.

For the first time, biochar was prepared by changing the polystyrene (PS) content in sludge, and the efficiency of antibiotics removal by biochar was evaluated after fermentation aging. Fermentation aging affects the efficiency of antibiotics removal by reducing the specific surface area and active sites of biochar. The antibiotics removal efficiency of different types of biochar after aging decreased by 5.95%-13.59%. Owing to the biotoxicity of biochar, the relative abundance of most communities decreased during fermentation, whereas Anaerolineae still increased (14.29% to 33.05% or 33.02%). However, controlled experiments confirmed that biochar was much less toxic to Scenedesmus obliquus than to antibiotics, with concentrations of 11.09 × 105 cells/mL and 0.188 × 105 cells/mL, respectively. With the positive effect of environmentally persistent free radicals (EPFRs) considered, increasing the PS content in sludge facilitated the removal of antibiotics by biochar. This study assesses the stability of biochar in removing antibiotics after long-term microbial aging.