Systemic immune profiling of Omicron-infected subjects inoculated with different doses of inactivated virus vaccine.

SARS-CoV-2 primary strain-based vaccination exerts a protective effect against Omicron variants-initiated infection, symptom occurrence, and disease severity in a booster-dependent manner. Yet, the underlying mechanisms remain unclear. During the 2022 Omicron outbreak in Shanghai, we enrolled 122 infected adults and 50 uninfected controls who had been unvaccinated or vaccinated with two or three doses of COVID-19 inactive vaccines and performed integrative analysis of 41-plex CyTOF, RNA-seq, and Olink on their peripheral blood samples. The frequencies of HLA-DRhi classical monocytes, non-classical monocytes, and Th1-like Tem tended to increase, whereas the frequency of Treg was reduced by booster vaccine, and they influenced symptom occurrence in a vaccine dose-dependent manner. Intercorrelation and mechanistic analysis suggested that the booster vaccination induced monocytic training, which would prime monocytic activation and maturation rather than differentiating into myeloid-derived suppressive cells upon Omicron infections. Overall, our study provides insights into how booster vaccination elaborates protective immunity across SARS-CoV-2 variants.

Lactobacillus gasseri ATCC33323 affects the intestinal mucosal barrier to ameliorate DSS-induced colitis through the NR1I3-mediated regulation of E-cadherin.

Inflammatory bowel disease (IBD) is an immune system disorder primarily characterized by colitis, the exact etiology of which remains unclear. Traditional treatment approaches currently yield limited efficacy and are associated with significant side effects. Extensive research has indicated the potent therapeutic effects of probiotics, particularly Lactobacillus strains, in managing colitis. However, the mechanisms through which Lactobacillus strains ameliorate colitis require further exploration. In our study, we selected Lactobacillus gasseri ATCC33323 from the intestinal microbiota to elucidate the specific mechanisms involved in modulation of colitis. Experimental findings in a DSS-induced colitis mouse model revealed that L. gasseri ATCC33323 significantly improved physiological damage in colitic mice, reduced the severity of colonic inflammation, decreased the production of inflammatory factors, and preserved the integrity of the intestinal epithelial structure and function. It also maintained the expression and localization of adhesive proteins while improving intestinal barrier permeability and restoring dysbiosis in the gut microbiota. E-cadherin, a critical adhesive protein, plays a pivotal role in this protective mechanism. Knocking down E-cadherin expression within the mouse intestinal tract significantly attenuated the ability of L. gasseri ATCC33323 to regulate colitis, thus confirming its protective role through E-cadherin. Finally, transcriptional analysis and in vitro experiments revealed that L. gasseri ATCC33323 regulates CDH1 transcription by affecting NR1I3, thereby promoting E-cadherin expression. These findings contribute to a better understanding of the specific mechanisms by which Lactobacillus strains alleviate colitis, offering new insights for the potential use of L. gasseri as an alternative therapy for IBD, particularly in dietary supplementation.

Nasal delivery of polymeric nanoDisc mobilizes a synergy of central and peripheral amyloid-ß clearance to treat Alzheimer's disease.

The disequilibrium of amyloid ß-peptide (Aß) between the central and peripheral pools has been claimed as an initiating event in Alzheimer's disease (AD). In this study, we employ discoidal high-density lipoproteins (HDL-Disc) mimicking Aß antibody for directional flux of Aß from central to peripheral catabolism, with desirable safety and translation potential. Structurally, HDL-Disc assembly (polyDisc) is prepared with aid of chitosan derivative polymerization. After intranasal administration and response to slightly acidic nasal microenvironment, polyDisc depolymerizes into carrier-free HDL-Disc with chitosan derivatives that adhere to the mucosal layer to reversibly open tight junctions, helping HDL-Disc penetrate the olfactory pathway into brain. Thereafter, HDL-Disc captures Aß into microglia for central clearance or ferries Aß out of the brain for liver-mediated compensatory catabolism. For synergy therapy, intranasal administration of polyDisc can effectively reduce intracerebral Aß burden by 97.3% and vascular Aß burden by 73.5%, ameliorate neurologic damage, and rescue memory deficits in APPswe/PS1dE9 transgenic AD mice with improved safety, especially vascular safety. Collectively, this design provides a proof of concept for developing Aß antibody mimics to mobilize a synergy of central and peripheral Aß clearance for AD treatment.

Exploring the therapeutic potential of urine-derived stem cell exosomes in temporomandibular joint osteoarthritis.

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative ailment that causes slow cartilage degeneration, aberrant bone remodeling, and persistent discomfort, leading to a considerable reduction in the patient's life quality. Current treatment options for TMJOA have limited efficacy. This investigation aimed to explore a potential strategy for halting or reversing the progression of TMJOA through the utilization of exosomes (EXOs) derived from urine-derived stem cells (USCs). The USC-EXOs were obtained through microfiltration and ultrafiltration techniques, followed by their characterization using particle size analysis, electron microscopy, and immunoblotting. Subsequently, an in vivo model of TMJOA induced by mechanical force was established. To assess the changes in the cartilage of TMJOA treated with USC-EXOs, we performed histology analysis using hematoxylin-eosin staining, immunohistochemistry, and histological scoring. Our findings indicate that the utilization of USC-EXOs yields substantial reductions in TMJOA, while concurrently enhancing the structural integrity and smoothness of the compromised condylar cartilage surface. Additionally, USC-EXOs exhibit inhibitory effects on osteoclastogenic activity within the subchondral bone layer of the condylar cartilage, as well as attenuated apoptosis in the rat TMJ in response to mechanical injury. In conclusion, USC-EXOs hold considerable promise as a potential therapeutic intervention for TMJOA.

Temperature Self-Limited Intelligent Thermo-chemotherapeutic Lipid Nanosystem for P-gp Reversal Time Window Matched Pulse Treatment of MDR Tumor.

Mild photothermal therapy (PTT) shows the potential for chemosensitization by tumor-localized P-glycoprotein (P-gp) modulation. However, conventional mild PTT struggles with real-time uniform temperature control, obscuring the temperature-performance relationship and resulting in thermal damage. Besides, the time-performance relationship and the underlying mechanism of mild PTT-mediated P-gp reversal remains elusive. Herein, we developed a temperature self-limiting lipid nanosystem (RFE@PD) that integrated a reversible organic heat generator (metal-phenolic complexes) and metal chelator (deferiprone, DFP) encapsulated phase change material. Upon NIR irradiation, RFE@PD released DFP for blocking ligand-metal charge transfer to self-limit temperature below 45 °C, and rapidly reduced P-gp within 3 h via Ubiquitin-proteasome degradation. Consequently, the DOX·HCl-loaded thermo-chemotherapeutic lipid nanosystem (RFE@PD-DOX) led to dramatically improved drug accumulation and 5-fold chemosensitization in MCF-7/ADR tumor models by synchronizing P-gp reversal and drug pulse liberation, achieving a tumor inhibition ratio of 82.42%. This lipid nanosystem integrated with "intrinsic temperature-control" and "temperature-responsive pulse release" casts new light on MDR tumor therapy.

Excessive load promotes temporomandibular joint chondrocyte apoptosis via Piezo1/endoplasmic reticulum stress pathway.

Excessive load on the temporomandibular joint (TMJ) is a significant factor in the development of TMJ osteoarthritis, contributing to cartilage degeneration. The specific mechanism through which excessive load induces TMJ osteoarthritis is not fully understood; however, mechanically-activated (MA) ion channels play a crucial role. Among these channels, Piezo1 has been identified as a mediator of chondrocyte catabolic responses and is markedly increased in osteoarthritis. Our observations indicate that, under excessive load conditions, endoplasmic reticulum stress in chondrocytes results in apoptosis of the TMJ chondrocytes. Importantly, using the Piezo1 inhibitor GsMTx4 demonstrates its potential to alleviate this condition. Furthermore, Piezo1 mediates endoplasmic reticulum stress in chondrocytes by inducing calcium ion influx. Our research substantiates the role of Piezo1 as a pivotal ion channel in mediating chondrocyte overload. It elucidates the link between excessive load, cell apoptosis, and calcium ion influx through Piezo1. The findings underscore Piezo1 as a key player in the pathogenesis of TMJ osteoarthritis, shedding light on potential therapeutic interventions for this condition.

Magnetic Micromotors with Spiky Gold Nanoshells as SERS Sensors for Thiram and Bacteria Detection.

Surface-enhanced Raman scattering (SERS) is widely used in all kinds of detection due to its ultrahigh sensitivity and selectivity. Micromotors, when used as SERS sensors, or the so-called "hotspots on the fly", can combine both controlled mobility and SERS sensing capacity, and are ideal for versatile in situ detection. In this work, mobile SERS sensors are successfully fabricated by growing gold nanospikes onto magnetic microsphere surfaces. These mobile micromotors can act as normal SERS sensors, characterized by the trace detection of thiram, a highly toxic fungicide. The detection limit can reach 0.1 nM, as good as most other noble metal deposited substrates. With significant magnetic gradient forces, separation of pathogenic bacteria from bulk solution is achieved once these magnetic micromotors bind with bacterial cells. Manipulated propulsion of micromotors, on the other hand, enables them to approach and contact pathogenic bacterial cells on command and further acquire Raman spectra under a controlled degree of contact, a capability never seen with passive sensors. The robotic SERS sensors have demonstrated unique sensing characteristics with controlled manipulations along with discriminative detection between bacterial species.

An efficient CRISPR-Cas12a-mediated MicroRNA knockout strategy in plants.

In recent years, the CRISPR-Cas9 nuclease has been used to knock out MicroRNA (miRNA) genes in plants, greatly promoting the study of miRNA function. However, due to its propensity for generating small insertions and deletions, Cas9 is not well-suited for achieving a complete knockout of miRNA genes. By contrast, CRISPR-Cas12a nuclease generates larger deletions, which could significantly disrupt the secondary structure of pre-miRNA and prevent the production of mature miRNAs. Through the case study of OsMIR390 in rice, we confirmed that Cas12a is a more efficient tool than Cas9 in generating knockout mutants of a miRNA gene. To further demonstrate CRISPR-Cas12a-mediated knockout of miRNA genes in rice, we targeted nine OsMIRNA genes that have different spaciotemporal expression and have not been previously investigated via genetic knockout approaches. With CRISPR-Cas12a, up to 100% genome editing efficiency was observed at these miRNA loci. The resulting larger deletions suggest Cas12a robustly generated null alleles of miRNA genes. Transcriptome profiling of the miRNA mutants, as well as phenotypic analysis of the rice grains revealed the function of these miRNAs in controlling gene expression and regulating grain quality and seed development. This study established CRISPR-Cas12a as an efficient tool for genetic knockout of miRNA genes in plants.

PAM-relaxed and temperature-tolerant CRISPR-Mb3Cas12a single transcript unit systems for efficient singular and multiplexed genome editing in rice, maize, and tomato.

Class 2 Type V-A CRISPR-Cas (Cas12a) nucleases are powerful genome editing tools, particularly effective in A/T-rich genomic regions, complementing the widely used CRISPR-Cas9 in plants. To enhance the utility of Cas12a, we investigate three Cas12a orthologs-Mb3Cas12a, PrCas12a, and HkCas12a-in plants. Protospacer adjacent motif (PAM) requirements, editing efficiencies, and editing profiles are compared in rice. Among these orthologs, Mb3Cas12a exhibits high editing efficiency at target sites with a simpler, relaxed TTV PAM which is less restrictive than the canonical TTTV PAM of LbCas12a and AsCas12a. To optimize Mb3Cas12a, we develop an efficient single transcription unit (STU) system by refining the linker between Mb3Cas12a and CRISPR RNA (crRNA), nuclear localization signal (NLS), and direct repeat (DR). This optimized system enables precise genome editing in rice, particularly for fine-tuning target gene expression by editing promoter regions. Further, we introduced Arginine (R) substitutions at Aspartic acid (D) 172, Asparagine (N) 573, and Lysine (K) 579 of Mb3Cas12a, creating two temperature-tolerant variants: Mb3Cas12a-R (D172R) and Mb3Cas12a-RRR (D172R/N573R/K579R). These variants demonstrate significantly improved editing efficiency at lower temperatures (22 °C and 28 °C) in rice cells, with Mb3Cas12a-RRR showing the best performance. We extend this approach by developing efficient Mb3Cas12a-RRR STU systems in maize and tomato, achieving biallelic mutants targeting single or multiple genes in T0 lines cultivated at 28 °C and 25 °C, respectively. This study significantly expands Cas12a's targeting capabilities in plant genome editing, providing valuable tools for future research and practical applications.

MicroRNA-34 and gastrointestinal cancers: a player with big functions.

It is commonly assumed that gastrointestinal cancer is the most common form of cancer across the globe and is the leading contributor to cancer-related death. The intricate mechanisms underlying the growth of GI cancers have been identified. It is worth mentioning that both non-coding RNAs (ncRNAs) and certain types of RNA, such as circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), can have considerable impact on the development of gastrointestinal (GI) cancers. As a tumour suppressor, in the group of short non-coding regulatory RNAs is miR-34a. miR-34a silences multiple proto-oncogenes at the post-transcriptional stage by targeting them, which inhibits all physiologically relevant cell proliferation pathways. However, it has been discovered that deregulation of miR-34a plays important roles in the growth of tumors and the development of cancer, including invasion, metastasis, and the tumor-associated epithelial-mesenchymal transition (EMT). Further understanding of miR-34a's molecular pathways in cancer is also necessary for the development of precise diagnoses and effective treatments. We outlined the most recent research on miR-34a functions in GI cancers in this review. Additionally, we emphasize the significance of exosomal miR-34 in gastrointestinal cancers.

PPP2R1B abolishes colorectal cancer liver metastasis and sensitizes Oxaliplatin by inhibiting MAPK/ERK signaling pathway.

BACKGROUND: Patients with colorectal cancer (CRC) with liver metastasis or drug resistance have a poor prognosis. Previous research has demonstrated that PPP2R1B inactivation results in the development of CRC. However, the role of PPP2R1B in CRC metastasis and drug resistance is unclear. METHODS: Venny 2.1 was used to determine the intersection between survival-related differentially expressed genes (DEGs) and liver metastasis-related DEGs according to RNA-seq data from The Cancer Genome Atlas (TCGA) and the GEO database (GSE179979). LC‒MS/MS and coimmunoprecipitation were performed to predict and verify the substrate protein of PPP2R1B. Gene Set Variation Analysis (GSVA) was subsequently utilized to assess pathway enrichment levels. The predictive performance of PPP2R1B was assessed by regression analysis, Kaplan-Meier (KM) survival analysis and drug sensitivity analysis. Immunohistochemistry (IHC), qRT-PCR and western blotting were performed to measure the expression levels of related mRNAs or proteins. Biological features were evaluated by wound healing, cell migration and invasion assays and CCK-8 assays. A mouse spleen infection liver metastasis model was generated to confirm the role of PPP2R1B in the progression of liver metastasis in vivo. RESULTS: According to bioinformatics analysis, PPP2R1B is significantly associated with liver metastasis and survival in CRC patients, and these findings were further verified via immunohistochemistry (IHC), qPCR and Western blotting. Pathway enrichment and LC‒MS/MS analysis revealed that PPP2R1B is negatively associated with the MAPK/ERK signalling pathway. Additionally, PD98059, a MAPK/ERK pathway inhibitor, inhibited EMT in vitro by reversing the changes in key proteins involved in EMT signalling (ZEB1, E-cadherin and Snail) and ERK/MAPK signalling (p-ERK) mediated by PPP2R1B. Oxaliplatin sensitivity prediction and validation revealed that PPP2R1B silencing decreased Oxaliplatin chemosensitivity, and these effects were reversed by PD98059 treatment. Moreover, PPP2R1B was coimmunoprecipitated with p-ERK in vitro. A negative correlation between PPP2R1B and p-ERK expression was also observed in clinical CRC samples, and the low PPP2R1B/high p-ERK coexpression pattern indicated a poor prognosis in CRC patients. In vivo, PPP2R1B silencing significantly promoted liver metastasis. CONCLUSIONS: This study revealed that PPP2R1B induces dephosphorylation of the p-ERK protein, inhibits liver metastasis and increases Oxaliplatin sensitivity in CRC patients and could be a potential candidate for therapeutic application in CRC.

C6orf15 promotes liver metastasis via WNT/ß-catenin signalling in colorectal cancer.

BACKGROUND: Colon cancer ranks third among global tumours and second in cancer-related mortality, prompting an urgent need to explore new therapeutic targets. C6orf15 is a novel gene that has been reported only in Sjogren's syndrome and systemic lupus erythematosus patients. We found a close correlation between increased C6orf15 expression and the occurrence of colon cancer. The aim of this study was to explore the potential of C6orf15 as a therapeutic target for colorectal cancer. METHOD: RNA-seq differential expression analysis of the TCGA database was performed using the R package 'limma.' The correlation between target genes and survival as well as tumour analysis was analysed using GEPIA. Western blot and PCR were used to assess C6orf15 expression in colorectal cancer tissue samples. Immunofluorescence and immunohistochemistry were used to assess C6orf15 subcellular localization and tissue expression. The role of C6orf15 in liver metastasis progression was investigated via a mouse spleen infection liver metastasis model. The association of C6orf15 with signalling pathways was assessed using the GSEA-Hallmark database. Immunohistochemistry (IHC), qPCR and western blotting were performed to assess the expression of related mRNAs or proteins. Biological characteristics were evaluated through cell migration assays, MTT assays, and Seahorse XF96 analysis to monitor fatty acid metabolism. RESULTS: C6orf15 was significantly associated with liver metastasis and survival in CRC patients as determined by the bioinformatic analysis and further verified by immunohistochemistry (IHC), qPCR and western blot results. The upregulation of C6orf15 expression in CRC cells can promote the nuclear translocation of ß-catenin and cause an increase in downstream transcription. This leads to changes in the epithelial-mesenchymal transition (EMT) and alterations in fatty acid metabolism, which together promote liver metastasis of CRC. CONCLUSION: Our study identified C6orf15 as a marker of liver metastasis in CRC. C6orf15 can activate the WNT/ß-catenin signalling pathway to promote EMT and fatty acid metabolism in CRC.

Morphological and phylogenetic analyses reveal a new species of Anthracophyllum (Omphalotaceae, Agaricales) in Zhejiang Province, China.

During the investigations of macrofungi resources in Zhejiang Province, China, an interesting wood rot fungus was collected. Based on morphological and molecular phylogenetic studies, it is described as a new species, Anthracophyllum sinense. A. sinense is characterized by its sessile, charcoal black and pleurotoid pileus, sparse lamellae occasionally branching, clavate basidia with long sterigmata [(3-)6-7(-8) µm], and non-heteromorphous cystidia. A. sinense establishes a separate lineage close to A. archeri and A. lateritium in the phylogenetic tree.

Carbon Nanotube Loading Strategies for Peptide Drugs: Insights from Molecular Dynamics Simulations.

Carbon nanotubes (CNTs) can be regarded as a potential platform for transmembrane drug delivery as many experimental works have demonstrated their capability to effectively transport bioactive molecules into living cells. Within this framework, the loading of a peptide drug onto either the interior or exterior of CNTs has gained considerable interest. This study aims to conduct a comprehensive comparison of these two loading methods. To this end, we performed molecular dynamics simulations and the umbrella sampling technique to investigate the interaction energy, conformational changes, and free energy changes of a model peptide drug containing α-helical structure interacting with the inner or outer walls of a 14.7-nm-long (20,20) CNT. Our finding reveals that, for a tube of such dimensions, it is thermodynamically more favorable for the peptide to be loaded onto the inner tube wall than the outer tube wall, primarily due to a larger free energy change for the former strategy. Conversely, unloading the drug from the tube interior poses greater challenges. Moreover, the tube's curvature plays an essential role in influencing the conformation of the adsorbed peptide. Despite the relatively weaker van der Waals interaction between the CNT exterior and the peptide, loading the peptide onto the exterior may induce significant conformational changes, particularly affecting the peptide's α-helix structure. In contrast, loading of the peptide on the CNT interior could maintain most of the α-helical content. CNTs do not typically attract specific peptide residues, with adsorbed groups primarily determined by the peptide's configurations and orientations. Finally, we offer a guideline for selecting an optimal loading strategy for CNT-based drug delivery.

Research progress on pretreatment technology for the analysis of amphetamine biological samples.

Sample pretreatment technology is crucial for drug analysis and detection, because the effect of sample pretreatment directly determinates the final analysis results. In recent years, with the continuous innovation of microextraction and other technologies like material preparation technologies and assistant technologies for extraction, the sample pretreatment techniques in the process of drug analysis have become more and more mature and diverse. This article takes amphetamine (AM) or methamphetamine as an example to review the recent development of pretreatment methods for AM-containing biological samples from the perspectives of extraction techniques, extraction media and auxiliary technologies. Extraction techniques are summarized with the categories of contact microextraction, separate microextraction and membrane-based microextraction for better guidance of application according to their features. Prevailing and innovative extraction media including carbon-based material, silicon-based material, metal organic framework, molecularly selective materials, supramolecular solvents and ionic liquids are reviewed. Auxiliary technologies like magnetic field, electric field, microwave, ultrasound and so on which can enhance extraction efficiency and accuracy are also reviewed. In the last, prospects of the future development of pretreatment technology for the analysis of AM biological samples are provided.

Multivariate analysis of alveolar bone dehiscence and fenestration in anterior teeth after orthodontic treatment: A retrospective study.

OBJECTIVE: To compare the prevalence of fenestration and dehiscence between pre- and post-orthodontic treatment and to explore the factors related to fenestration and dehiscence in the anterior teeth after treatment. METHODS: This study included 1000 cone-beam computed tomography (CBCT) scans of 500 patients before (T1) and after (T2) orthodontic treatment. These images were imported into Dolphin 11.9 software to detect alveolar fenestration and dehiscence in the anterior teeth area. The chi-square test and Fisher's exact test were performed to compare the prevalence of alveolar bone defects between time points T1 and T2. A total of 499 patients were selected for logistic regression analysis to examine the correlation among age, sex, crowding, sagittal facial type, extraction, miniscrew use and fenestration or dehiscence post-treatment. RESULTS: Except for the maxillary lingual fenestration and labial fenestration of mandibular canines, a significant change in the prevalence of fenestration and dehiscence was noted between time points T1 and T2 (P < .025). Multinomial logistic regression showed that age, miniscrew use and extraction highly influenced the prevalence of anterior lingual dehiscence (P < .05). Dehiscence of the mandibular labial side (skeletal Class III vs. I, OR = 2.368, P = .000) and fenestration of the mandibular lingual side (skeletal Class II vs. I, OR = 2.344, P = .044) were strongly correlated with the sagittal facial type. Dehiscence of the maxillary labial side (moderate vs. mild, OR = 1.468, P = .017) was significantly associated with crowding. CONCLUSIONS: Older age, maxillary moderate crowding, skeletal Class III, extraction and miniscrew potentially significantly affect the prevalence of anterior teeth dehiscence. Adult females, skeletal Class III patients on the mandibular labial side and skeletal Class II patients on the mandibular lingual side should be monitored for anterior teeth fenestration.

The short- and long-term effects of congenital occlusion loss of the unilateral first permanent molar on the temporomandibular joint morphology and position: A retrospective study based on cone-beam computed tomography.

OBJECTIVE: To investigate the effects of congenital unilateral first permanent molar occlusal loss (CUMOL) on the morphology and position of temporomandibular joint (TMJ). MATERIALS AND METHODS: Cone-beam computed tomography (CBCT) images of 37 patients with CUMOL (18 males and 19 females, mean age: 13.60 ± 4.38 years) were divided into two subgroups according to the status of second molar (G1: the second molar not erupted, n = 18, G2: second molar erupted, n = 19). The control group consisted of 33 normal occlusion patients (9 males and 24 females, mean age: 16.15 ± 5.44 years) and was divided into 2 subgroups accordingly (G3: the second molar had not erupted, n = 18, G4: the second molar had erupted and made contact with the opposing tooth, n = 15). Linear and angular measurements were used to determine the characteristics of TMJ. RESULTS: In G1, the condyle on the side of the CUMOL shifts posteriorly, with significant side differences observed in Anterior space (AS, P < .05) and Posterior space (PS, P < .05). However, with the eruption of the second permanent molars, in G2, the condyle on the CUMOL side moves posteriorly and inferiorly. This results in significant lateral differences in the AS (P < .05), PS (P < .05), and Superior space (SS, P < .05). Additionally, there is an increase in the thickness of the roof of the glenoid fossa (TRF) on the CUMOL side (P < .05), and a decrease in the inclination of the bilateral articular eminences (P < .05). CONCLUSIONS: CUMOL can affect the position and the morphology of the condyle and was associated with the eruption of the second permanent molars. Before the eruption of the second permanent molars, CUMOL primarily affects the position of the condyle. After the emergence of the second permanent molars, CUMOL leads to changes in both the condyle's position and the morphology of the glenoid fossa.

Anti-oxidant effects of herbal residue from Shengxuebao mixture on heat-stressed New Zealand rabbits.

Heat stress can lead to hormonal imbalances, weakened immune system, increased metabolic pressure on the liver, and ultimately higher animal mortality rates. This not only seriously impairs the welfare status of animals, but also causes significant economic losses to the livestock industry. Due to its rich residual bioactive components and good safety characteristics, traditional Chinese medicine (TCM) residue is expected to become a high-quality feed additive with anti-oxidative stress alleviating function. This study focuses on the potential of Shengxuebao mixture herbal residue (SXBR) as an anti-heat stress feed additive. Through the UPLC (ultra performance liquid chromatography) technology, the average residue rate of main active ingredients from SXBR were found to be 25.39%. SXBR were then added into the basal diet of heat stressed New Zealand rabbits at the rates of 5% (SXBRl), 10% (SXBRm) and 20% (SXBRh). Heat stress significantly decreased the weight gain, as well as increased neck and ear temperature, drip loss in meat, inflammation and oxidative stress. Also, the hormone levels were disrupted, with a significant increase in serum levels of CA, COR and INS. After the consumption of SXBR in the basal diet for 3 weeks, the weight of New Zealand rabbits increased significantly, and the SXBRh group restored the redness value of the meat to a similar level as the control group. Furthermore, the serum levels T3 thyroid hormone in the SXBRh group and T4 thyroid hormone in the SXBRm group increased significantly, the SXBRh group showed a significant restoration in inflammation markers (IL-1ß, IL-6, and TNF-α) and oxidative stress markers (total antioxidant capacity, HSP-70, MDA, and ROS) levels. Moreover, the real-time fluorescence quantitative PCR analysis found that, the expression levels of antioxidant genes such as Nrf2, HO-1, NQO1, and GPX1 were significantly upregulated in the SXBRh group, and the expression level of the Keap1 gene was significantly downregulated. Additionally, the SXBRm group showed significant upregulation in the expression levels of HO-1 and NQO1 genes. Western blot experiments further confirmed the up-regulation of Nrf2, Ho-1 and NQO1 proteins. This study provides a strategy for the utilization of SXBR and is of great significance for the green recycling of the TCM residues, improving the development of animal husbandry and animal welfare.

NLRP3 Inflammasome Inhibitors for Antiepileptogenic Drug Discovery and Development.

Epilepsy is one of the most prevalent and serious brain disorders and affects over 70 million people globally. Antiseizure medications (ASMs) relieve symptoms and prevent the occurrence of future seizures in epileptic patients but have a limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms of these medications for the development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made, and challenges faced in the development of NLRP3 inhibitors for the treatment of epilepsy.

Alleviation of temporomandibular joint osteoarthritis by targeting RIPK1-mediated inflammatory signalling.

Temporomandibular joint osteoarthritis (TMJOA), prevalent in adolescents and the elderly, has serious physical and psychological consequences. TMJOA is a degenerative disease of the cartilage and bone, mostly driven by inflammation, and synoviocytes are the first and most important inflammatory factor releasers. Receptor-interacting serine/threonine-protein kinase (RIPK1) promotes inflammatory response and cell death during an array of illnesses. This research aimed to explore the impacts of RIPK1 inhibitor therapy in TMJOA and the mechanism of RIPK1 in inducing inflammation during TMJOA. Herein, inhibition of RIPK1 suppressed the elevated levels of inflammatory factors, nuclear factor kappa B (NF-κB), along with markers of apoptosis and necroptosis after tumour necrosis factor (TNF)-α/cycloheximide (CHX) treatment in synoviocytes. Moreover, inflammation models were constructed in vivo through complete Freund's adjuvant (CFA) induction and disc perforation, and the findings supported that RIPK1 inhibition protected TMJ articular cartilage against progressive degradation. RIPK1 regulates NF-κB activation via cellular inhibitor of apoptosis proteins (cIAP), apoptosis via caspase-8, and necroptosis via RIPK3/mixed lineage kinase domain-like (MLKL) in synoviocytes, which in turn facilitates TMJOA inflammation progression.