Unveiling the Role of Sik1 in Osteoblast Differentiation: Implications for Osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative disease characterized by subchondral osteosclerosis, mainly due to osteoblast activity. This research investigates the function of Sik1, a member of the AMP-activated protein kinase family, in OA. Proteomic analysis was conducted on clinical samples from 30 OA patients, revealing a negative correlation between Sik1 expression and OA. In vitro experiments utilized BMSCs to examine the effect of Sik1 on osteogenic differentiation. BMSCs were cultured and induced toward osteogenesis with specific media. Sik1 overexpression was achieved through lentiviral transfection, followed by analysis of osteogenesis-associated proteins using Western blotting, RT-qPCR, and alkaline phosphate staining. In vivo experiments involved destabilizing the medial meniscus in mice to establish an OA model, assessing the therapeutic potential of Sik1. The CT scans and histological staining were used to analyze subchondral bone alterations and cartilage damage. The findings show that Sik1 downregulation correlates with advanced OA and heightened osteogenic differentiation in BMSCs. Sik1 overexpression inhibits osteogenesis-related markers in vitro and reduces cartilage damage and subchondral osteosclerosis in vivo. Mechanistically, Sik1 modulates osteogenesis and subchondral bone changes through Runx2 activity regulation. The research emphasizes Sik1 as a promising target for treating OA, suggesting its involvement in controlling bone formation and changes in the subchondral osteosclerosis.

Effects of Acremonium terricola Culture on Lactation Performance, Immune Function, Antioxidant Capacity, and Intestinal Flora of Sows.

This study aimed to determine the effects of different doses of Acremonium terricola culture (ATC) on lactation performance, immune function, antioxidant capacity, and intestinal flora of sows. Forty-five Landrace sows (3-6 parity) were randomly assigned to the following three treatments from 85 days of gestation to 21 days after farrowing: a control diet (CON, basal diet), a low-dose Acremonium terricola culture diet (0.2% ATC, basal diet + 0.2% ATC), and a high-dose Acremonium terricola culture diet (0.4% ATC, basal diet + 0.4% ATC). Compared with the CON group, the supplementation of 0.2% ATC increased the average daily milk yield of sows by 4.98%, increased milk fat, total solids, and freezing point depression on day 1 postpartum (p < 0.05), increased serum concentration of Triiodothyronine, Thyroxin, and Estradiol on day 21 postpartum (p < 0.05). Compared with the CON group, the supplementation of 0.4% ATC increased the average daily milk yield of sows by 9.38% (p < 0.05). Furthermore, the supplementation of 0.2% ATC increased serum concentration of IgG, IgM, and IFN-γ, CD4 on day 1 postpartum (p < 0.05) and increased serum concentration of immunoglobulin A ( IgA), immunoglobulin G (IgG), immunoglobulin M ( IgM), complement 3 (C3), cluster of differentiation 4 (CD4), cluster of differentiation 8 (CD8), interferon-γ (IFN-γ) on day 21 postpartum (p < 0.05), while the supplementation of 0.4% ATC reduced serum concentration of IL-2 on day 21 postpartum (p < 0.05). Moreover, the supplementation of 0.4% ATC significantly increased serum concentration of catalase (CAT) (p < 0.05). Additionally, the supplementation of ATC affected the relative abundance of the intestinal flora at different taxonomic levels in sows and increased the abundance of beneficial bacteria such as in the norank_f__Eubacterium_coprostanoligenes group, Eubacterium_coprostanoligenes group, and Lachnospiraceae_XPB1014 group of sows, while reducing the abundance of harmful bacteria such as Phascolarctobacterium and Clostridium_sensu_stricto_1. These data revealed that the supplementation of ATC during late gestation and lactation can improve lactation performance, immune function, antioxidant capacity, and the gut microbiota. Compared with supplementation of 0.4% ATC, 0.2% ATC enhances the levels of thyroid-related hormones, specific antibodies, and cytokines in serum, promotes the diversity of beneficial gut microbiota, beneficial bacteria in the intestine, reduces the population of harmful bacteria, and thereby bolsters the immunity of sows. Hence, 0.2% ATC is deemed a more optimal concentration.

Unveiling the role of RhoA and ferroptosis in vascular permeability: Implications for osteoarthritis.

Abnormal angiogenesis and increased vascular permeability of subchondral bone are key mechanisms related to osteoarthritis (OA). However, the precise mechanisms responsible for heightened vascular permeability in OA remain unclear. The present study used proteomics to identify protein expression in damaged subchondral bone compared with normal subchondral bone. The results suggest that Ras homolog family member A (RhoA) may be associated with the vascular permeability of subchondral bone and ferroptosis in OA. The results of analysis of clinical samples indicated a significant increase in expression of RhoA in the subchondral bone of OA. This were consistent with the proteomics findings. We found through western blotting, RT­PCR, and immunofluorescence that RhoA significantly increased the permeability of endothelial cells (ECs) by inhibiting inter­EC adhesion proteins (zona occludens­1, connexin 43 and Vascular endothelial­Cadherin) and actin filaments. Furthermore, RhoA induced ferroptosis core proteins (glutathione peroxidase 4,  solute carrier family 7 member 11 and acyl­CoA synthase long­chain family member 4, ACSL4) by influencing lipid peroxidation and mitochondrial function, leading to ferroptosis of ECs. This suggested an association between RhoA, ferroptosis and vascular permeability. Ferroptosis significantly increased permeability of ECs by inhibiting inter­EC adhesion proteins. RhoA increased vascular permeability by inducing ferroptosis of ECs. In vivo, inhibition of RhoA and ferroptosis significantly mitigated progression of OA by alleviating cartilage degeneration and subchondral bone remodeling in mice with destabilization of the medial meniscus. In conclusion, the present findings indicated that RhoA enhanced vascular permeability in OA by inducing ferroptosis. This may serve as a novel strategy for the early prevention and treatment of OA.

Catalytic Promiscuity of Fatty Acid Photodecarboxylase Enables Stereoselective Synthesis of Chiral α-Tetralones.

In the field of biocatalysis, discovering novel reactivity from known enzymes has been a longstanding challenge. Fatty acid photo-decarboxylase from Chlorella variabilis (CvFAP) has drawn considerable attention as a promising photoenzyme with potential green chemistry applications; however, its non-natural reactivity has rarely been exploited to date. Herein we report a non-natural reductive dehalogenation (deacetoxylation) reactivity of CvFAP inspired by its natural oxidative decarboxylation process, enabling the  stereoselective synthesis of a series of chiral α-substituted tetralones with high yields (up to 99%) and e.r. values (up to 99:1). Mechanistic studies demonstrated that the native photoenzyme catalyzed the reductive dehalogenation via a novel mechanism involving oxidized state (FADox) / semiquinone state (FADsq) redox pair and an electron transfer (ET)/proton transfer (PT) process of radical termination, distinct from the previous reports. To our knowledge, this study represents a new example of CvFAP promiscuity, and thus expands the reactivity repertoire of CvFAP and highlights the versatility of CvFAP in asymmetric synthesis.

Response Characteristics and Community Assembly Mechanisms of nirS-Type Denitrifiers in the Alpine Wetland under Simulated Precipitation Conditions.

The nitrogen cycling process in alpine wetlands is profoundly affected by precipitation changes, yet the dynamic response mechanism of denitrifiers to long-term precipitation shifts in the alpine wetland of the Qinghai-Tibet Plateau remains enigmatic. Utilizing high-throughput sequencing analysis of nirS-type functional genes, this study delved into the dynamic response mechanism of nirS-type denitrifiers to precipitation changes in the alpine wetland of Qinghai Lake. The findings revealed that nirS-type denitrifiers in the alpine wetland of Qinghai Lake were primarily Proteobacteria, and Alpha diversity exhibited a negative correlation with the precipitation gradient, with deterministic processes predominating in the community assembly of denitrifying microbes. A 50% increase in rainfall shifted the community assembly process of denitrifiers from deterministic to stochastic. Dominant microflora at the genus level responded significantly to precipitation changes, with aerobic bacteria comprising the majority of differentially abundant taxa (55.56%). As precipitation increased, the complexity of the microbial interaction network decreased, and a 25% reduction in precipitation notably elevated the relative abundance of three key functional groups: chemoheterotrophic, aerobic chemoheterotrophic, and nitrogen fixation. Precipitation notably emerged as the primary regulator of nirS-type denitrifiers in the alpine wetland of Qinghai Lake, accounting for 51% of the variation in community composition. In summary, this study offers a fresh perspective for investigating the ecological processes of nitrogen cycling in alpine ecosystems by examining the diversity and community composition of nirS-type denitrifiers in response to precipitation changes.

Exosomes-based dual drug-loaded nanocarrier for targeted and multiple proliferative vitreoretinopathy therapy.

Proliferative vitreoretinopathy (PVR) is a common cause of vision loss after retinal reattachment surgery and ocular trauma. The key pathogenic mechanisms of PVR development include the proliferation, migration and epithelial-mesenchymal transition (EMT) of retinal pigment epithelial cells (RPEs) activated by the growth factors and cytokines after surgery. Although some drugs have been tried in PVR treatments as basic investigations, the limited efficacy remains an obstacle, which may be due to the single pharmacological action and lack of targeting. Herein, the anti-proliferative Daunorubicin and anti-inflammatory Dexamethasone were co-loaded in the RPEs-derived exosomes (Exos), obtaining an Exos-based dual drug-loaded nanocarrier (Exos@D-D), and used for multiple PVR therapy. Owing to the advantages of homologous Exos and the dual drug loading, Exos@D-D showed good RPEs targeting as well as improved uptake efficiency, and could inhibit the proliferation, migration, as well as EMT of RPEs effectively. The animal studies have also demonstrated that Exos@D-D effectively inhibits the production of proliferative membranes and prevents the further development of inflammation, shows significant therapeutic effects on PVR and good biocompatibility. Such Exos-based dual drug-loaded nanocarrier investigation not only provides a promising approach for multifunctional exosome drug delivery systems construction, but also has great potential in PVR clinical therapy application.

Paper substrate designed with TEMPO-oxidized cellulose nanofibers/cationic guar gum hydrogel and its application in a colorimetric biosensor for rapid bacteria detection.

The monitoring of foodborne bacterial contamination requires simple and convenient biosensors. This work describes a novel paper-based colorimetric biosensor for the rapid and sensitive bacteria detection. The biosensor was constructed via the encapsulation of D-alanyl-D-alanine capped gold nanoparticles (DADA-AuNPs) in a modified paper that was fabricated by the freeze-drying of TEMPO-oxidized cellulose nanofibers/cationic guar gum composite hydrogel-modified filter paper. The results indicated that the size of DADA-AuNPs largely determined the color of their aqueous system and they exhibited light red to dark red as their size increased from around 6 to 36 nm. All these different sized DADA-AuNPs turned into colorless when encountered with either S. aureus or E. coli. In particular, the smaller the DADA-AuNPs size, the faster the discoloration. The encapsulation of DADA-AuNPs into modified paper negligibly changed their responsiveness towards bacteria. In comparison to the original filter paper and oven-dried hydrogel-modified filter paper, the freeze-dried hydrogel-modified paper was demonstrated to be a better substrate for the encapsulation of DADA-AuNPs since they could be loaded with a larger amount of DADA-AuNPs in a faster way and showed a better perceivable color. This work demonstrated a promising paper-based colorimetric biosensor for the facile and rapid detection of bacteria.

Effects of steaming on physicochemical and emulsification properties of gum arabic.

Gum arabic finds extensive application and typically undergoes sterilization prior to utilization in the food industry. This study explored the impact of steam sterilization temperature and duration on the physicochemical and emulsification characteristics of gum arabic, accompanied by proposed mechanisms elucidating observed effects. The results showed that when gum arabic was treated with high temperature sterilization (110 °C âˆ¼ 140 °C), the emulsion prepared turned unstable. The interfacial tension decreased from 8.26 mN/m to 6.77 mN/m after sterilization, while the elastic modulus decreased from 23.65 mN/m to 16.16 mN/m. Moreover, the circular dichroic chromatographic results indicated that the arabinogalactan protein (AGP) structure of gum arabic was more relaxed after high temperature treatment with ß-sheets content decreased from 36.2 % to 29.8 % and random coil content increased from 41.3 % to 51.8 %. Quartz crystal microbalance with dissipation (QCM-D) results demonstrated that emulsion surface film thickness and toughness decreased after sterilization treatment of gum arabic. The study indicates that high temperature sterilization may change protein structure in gum arabic and reduce the stability of prepared emulsions.

Vertical differentiation drives the changes in the main microflora and metabolites of carbon and nitrogen cycling in the early freeze-thaw period in the Qinghai Lake Basin.

Global climate change has altered the frequency of soil freeze-thaw cycles, but the response of soil microorganisms to different elevation gradients during the early freeze-thaw period remains unclear. So far, the influence of the altitudinal gradient on the microbial community and metabolic characteristics in the early freeze-thaw period of the Qinghai Lake Basin remains unclear. To this end, we collected soil at different elevations in the early freeze-thaw period of the Qinghai Lake Basin and investigated the influence of the elevation gradient on soil microbial community characteristics and soil metabolic processes as well as the corresponding environmental driving mechanism by high-throughput sequencing and LC-MS (Liquid Chromatograph-Mass Spectrometer) nontargeted metabolite determination. The results showed that Proteobacteria were the dominant microflora in the Qinghai Lake Basin. The dominant phyla associated with carbon and nitrogen are Proteobacteria and Firmicutes, both of which are significantly affected by elevation. The soil physicochemical factors jointly affected the soil microbial communities and metabolism. Total phosphorus nitrate nitrogen and pH were the main driving factors of the microbial community, and metabolites were sensitive to changes in chemical factors. In short, the microbial community structure and function, soil physicochemical factors and soil metabolic processes were significantly affected by the altitudinal gradient in the early freeze-thaw period, while the microbial community diversity showed no significant response to the altitudinal gradient. Additionally, a high potassium content in the soil may promote the growth and reproduction of bacteria associated with carbon and nitrogen cycling, as well as the production of metabolites.

Urolithin A exerts anti-tumor effects on gastric cancer via activating autophagy-Hippo axis and modulating the gut microbiota.

Gastric cancer (GC) treatment regimens are still unsatisfactory. Recently, Urolithin A (UroA) has gained tremendous momentum due to its anti-tumor properties. However, the therapeutic effect and underlying mechanisms of UroA in GC are unclear. We explored the effects and related mechanisms of UroA on GC both in vivo and in vitro. A Cell Counting Kit-8 was used to determine the influence of UroA on the proliferation of GC cell lines. The Autophagy inhibitor 3-methyladenine (3MA) was employed to clarify the role of autophagy in the anti-tumor effect of UroA. Simultaneously, we detected the core-component proteins involved in autophagy and its downstream pathways. Subsequently, the in vivo anti-tumor effect of UroA was determined using a xenograft mouse model. Western blotting was used to detect the core protein components of the anti-tumor pathways, and 16S rDNA sequencing was used to detect the effect of UroA on the gut microbiota. We found that UroA suppressed tumor progression. The use of 3MA undermined the majority of the inhibitory effect of UroA on tumor cell proliferation, further confirming the importance of autophagy in the anti-tumor effect of UroA. Invigorating of autophagy activated the downstream Hippo pathway, thereby inhibiting the Warburg effect and promoting cell apoptosis. In addition, UroA modulated the composition of the gut microbiota, as indicated by the increase of probiotics and the decrease of pathogenic bacteria. Our research revealed new anti-tumor mechanisms of UroA, which may be a promising candidate for GC treatment.

Carrimycin ameliorates lipopolysaccharide and cecal ligation and puncture-induced sepsis in mice.

Carrimycin (CA), sanctioned by China's National Medical Products Administration (NMPA) in 2019 for treating acute bronchitis and sinusitis, has recently been observed to exhibit multifaceted biological activities, encompassing anti-inflammatory, antiviral, and anti-tumor properties. Despite these applications, its efficacy in sepsis treatment remains unexplored. This study introduces a novel function of CA, demonstrating its capacity to mitigate sepsis induced by lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) in mice models. Our research employed in vitro assays, real-time quantitative polymerase chain reaction (RT-qPCR), and RNA-seq analysis to establish that CA significantly reduces the levels of pro-inflammatory cytokines, namely tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6), in response to LPS stimulation. Additionally, Western blotting and immunofluorescence assays revealed that CA impedes Nuclear Factor Kappa B (NF-κB) activation in LPS-stimulated RAW264.7 cells. Complementing these findings, in vivo experiments demonstrated that CA effectively alleviates LPS- and CLP-triggered organ inflammation in C57BL/6 mice. Further insights were gained through 16S sequencing, highlighting CA's pivotal role in enhancing gut microbiota diversity and modulating metabolic pathways, particularly by augmenting the production of short-chain fatty acids in mice subjected to CLP. Notably, a comparative analysis revealed that CA's anti-inflammatory efficacy surpasses that of equivalent doses of aspirin (ASP) and TIENAM. Collectively, these findings suggest that CA exhibits significant therapeutic potential in sepsis treatment. This discovery provides a foundational theoretical basis for the clinical application of CA in sepsis management.

[Corrigendum] PRIMA­1met induces autophagy in colorectal cancer cells through upregulation of the mTOR/AMPK­ULK1­Vps34 signaling cascade.

Following the publication of the above article, the authors contacted the Editorial Office to explain that the strips of ß­actin, LC3 and p62 proteins of the RKO cell line shown in Fig. 2A and B, and those of the SW620 cell line shown in Fig. 3A and B, were assembled in these figures incorrectly. To rectify the presentation of these two figures, the authors proposed that they replace the strips of ß­actin and p62 proteins in the original Figs. 2B and 3B with the ß­actin bands from one of the repeated western blotting experiments.  The revised and corrected versions of Figs. 2 and 3 are shown on the next page. The authors wish to emphasize that these corrections do not grossly affect either the results or the conclusions reported in this work. The authors all agree to the publication of this Corrigendum, and are grateful to the Editor of Oncology Reports for granting them the opportunity to correct the errors that were made during the assembly of these figures. Lastly, the authors apologize to the readership for any inconvenience these errors may have caused. [Oncology Reports 45: 86, 2021; DOI: 10.3892/or.2021.8037].

Transcriptomic analysis of the longissimus thoracis muscle in pigs has identified molecular regulatory patterns associated with meat quality.

Meat quality is a critical aspect of pig breeding. In addition to genetics, meat quality is also influenced by nutritional and environmental factors. In this study, three pig breeds, Shengxianhua, Jiaxing, and Qinglian Black (SXH, JXB and QLB), were used as experimental animals. Transcriptional analysis was performed on the longissimus thoracis (LT) muscle to investigate variations in intramuscular fat (IMF), inosine monophosphate (IMP), amino acids, and muscle fiber morphology across different breeds. Ingenuity canonical pathway analysis (IPA) identified biological processes and key driver genes related to metabolism and muscle development. Additionally, weighted gene co-expression network analysis (WGCNA) revealed gene modules associated with IMP. KEGG and GO analyses identified specific biological processes and signaling pathways related to IMP, including the Oxidative Phosphorylation pathway and rRNA Metabolic Processes. These findings provide novel insights into the molecular regulatory mechanisms underlying meat quality variations among pig breeds.

RMBase v3.0: decode the landscape, mechanisms and functions of RNA modifications.

Although over 170 chemical modifications have been identified, their prevalence, mechanism and function remain largely unknown. To enable integrated analysis of diverse RNA modification profiles, we have developed RMBase v3.0 (http://bioinformaticsscience.cn/rmbase/), a comprehensive platform consisting of eight modules. These modules facilitate the exploration of transcriptome-wide landscape, biogenesis, interactome and functions of RNA modifications. By mining thousands of epitranscriptome datasets with novel pipelines, the 'RNA Modifications' module reveals the map of 73 RNA modifications of 62 species. the 'Genes' module allows to retrieve RNA modification profiles and clusters by gene and transcript. The 'Mechanisms' module explores 23 382 enzyme-catalyzed or snoRNA-guided modified sites to elucidate their biogenesis mechanisms. The 'Co-localization' module systematically formulates potential correlations between 14 histone modifications and 6 RNA modifications in various cell-lines. The 'RMP' module investigates the differential expression profiles of 146 RNA-modifying proteins (RMPs) in 18 types of cancers. The 'Interactome' integrates the interactional relationships between 73 RNA modifications with RBP binding events, miRNA targets and SNPs. The 'Motif' illuminates the enriched motifs for 11 types of RNA modifications identified from epitranscriptome datasets. The 'Tools' introduces a novel web-based 'modGeneTool' for annotating modifications. Overall, RMBase v3.0 provides various resources and tools for studying RNA modifications.

Implementation of Thermal-Triggered Binary-Ternary Switchable Memory Performance in Zn/polysulfide/organic Complex-Based Memorizers by Finely Modulating the S62- Relaxation.

Polysulfide-based multilevel memorizers are promising as novel memorizers, in which the occurrence of Sn2- relaxation is key for their multilevel memory. However, the effects of crystal packing and the side group of organic ligands on Sn2- relaxation are still ambiguous. In this work, ionic [Zn(S6)2·Zn2(Bipy)2SO4 (1), Zn(S6)2·Zn(Pmbipy)3 (2)] and neutral [ZnS6(Ombipy) (3), ZnS6(Phen)2 (4)] Zn/polysulfide/organic complexes with different packing modes and structures of organic ligands have been synthesized and were fabricated as memory devices. In both ionic and neutral Zn complexes, the S62- relaxation will be blocked by steric hindrances due to the packing of counter-cations and hydrogen-bond restrictions. Consequently, only the binary memory performances can be seen in FTO/1/Ag, FTO/2/Ag, and FTO/4/Ag, which originate from the more condensed packing of conjugated ligands upon electrical stimulus. Interestingly, FTO/3/Ag illustrates the unique thermally triggered reversible binary-ternary switchable memory performance. In detail, after introducing a methyl group on the 6'-position of bipyridine in ZnS6(Ombipy) (3), the ring-to-chain relaxation of S62- anions at room temperature will be inhibited, but it can happen at a higher temperature of 120 °C, which has been verified by elongated S-S lengths and the strengthened C-H···S hydrogen bond upon heating. The rules drawn in this work will provide a useful guide for the design of stimulus-responsive memorizers that can be applied in special industries such as automobile, oil, and gas industries.

CFD-PBM Simulation of Sauter Mean Diameter in a Stirred Sieve-Plate Extraction Column.

A computational fluid dynamics-population balance model (CFD-PBM)-coupled simulation method was established to simulate the Sauter mean diameter (d32) in a stirred sieve-plate extraction column with Ansys Fluent 19.2. The droplet breakage and coalescence were considered, and the kernel functions were loaded into Fluent as a user-defined function (UDF). The simulated d32 by different kernels was compared with the experimental values, and the results showed that the modified model considering the dispersed phase viscosity has better simulation accuracy and good applicability. In addition, the effects of different operating conditions on d32 were investigated. When the stirring speed is increased, d32 decreases. As the dispersed phase flow rate increases, d32 increases, while the change in the continuous phase flow rate does not have a significant impact on d32.

Right paraduodenal hernia, classification, and selection of surgical methods: a case report and review of the literature.

BACKGROUND: Considering that right paraduodenal hernia is a rare internal hernia with abnormal anatomy and is often encountered during an emergency, surgeons may lack knowledge about it and choose incorrect treatment. Thus, this case report is a helpful complement to the few previously reported cases of right paraduodenal hernia. Additionally, we reviewed all the reported right paraduodenal hernia cases and proposed appropriate surgical strategies according to different anatomical features. CASE PRESENTATION: The case involved a 33-year-old Chinese male patient who was admitted to the hospital due to abdominal pain. The patient was initially diagnosed with small bowel obstruction, and conservative treatment failed. An emergency operation was arranged, during which a diagnosis of right paraduodenal hernia was made instead. After surgery, the patient recovered well without abdominal pain for 2 years. CONCLUSION: Although right paraduodenal hernia accounts only for a small proportion of paraduodenal hernia, its anatomical characteristics can vary considerably. We divided right paraduodenal hernia into three types, with each type requiring a different surgical strategy.

A drug-delivery depot for epigenetic modulation and enhanced cancer immunotherapy.

DNA methyltransferase inhibitors (DNMTis) have found widespread application in the management of cancer. Zebularine (Zeb), functioning as a demethylating agent, has exhibited notable advantages and enhanced therapeutic efficacy in the realm of tumour immunotherapy. Nevertheless, due to its lack of targeted functionality, standalone Zeb therapy necessitates the administration of a substantially higher dosage. In this investigation, we have devised an innovative nanodrug formulation, comprising the DNA methyltransferase inhibitor Zeb and pH-responsive chitosan (CS), hereinafter referred to as CS-Zeb nanoparticles (NPs). Our findings have unveiled that CS-Zeb NPs manifest heightened drug release within an acidic milieu (pH 5.5) in comparison to a neutral environment (pH 7.4). Furthermore, in vivo studies have conclusively affirmed that, in contrast to equivalent quantities of Zeb in isolation, the nanocomplex significantly curtailed tumour burden and protracted the survival duration of the B16F10 tumour-bearing murine model. Additionally, CS-Zeb NPs elicited an augmentation of CD8+ T cells within the peripheral circulation of mice and tumour-infiltrating lymphocytes (TILs). Notably, the dosage of CS-Zeb NPs was reduced by a remarkable 70-fold when juxtaposed with Zeb administered in isolation. To summarise, our study underscores the potential of CS-Zeb NPs as an alternative chemotherapeutic agent for cancer treatment.

Nintedanib ameliorates osteoarthritis in mice by inhibiting synovial inflammation and fibrosis caused by M1 polarization of synovial macrophages via the MAPK/PI3K-AKT pathway.

Synovial inflammation and fibrosis are important pathological changes associated with osteoarthritis (OA). Herein, we investigated if nintedanib, a drug specific for pulmonary fibrosis, plays a positive role in osteoarthritic synovial inflammation and fibrosis. We assessed the effect of nintedanib on osteoarthritic synovial inflammation and fibrosis in a mouse model of OA created by destabilization of the medial meniscus and a macrophage M1 polarization model created by stimulating RAW264.7 cells with lipopolysaccharide. Histological staining showed that daily gavage administration of nintedanib significantly alleviated articular cartilage degeneration, reduced the OARSI score, upregulated matrix metalloproteinase-13 and downregulated collagen II expression, and significantly reduced the synovial score and synovial fibrosis in a mouse OA model. In addition, immunofluorescence staining showed that nintedanib significantly decreased the number of M1 macrophages in the synovium of a mouse model of OA. In vitro results showed that nintedanib downregulated the phosphorylation levels of ERK, JNK, p38, PI3K, and AKT while inhibiting the expression of macrophage M1 polarization marker proteins (CD86, CD80, and iNOS). In conclusion, this study suggests that nintedanib is a potential candidate for OA treatment. The mechanisms of action of nintedanib include the inhibition of M1 polarization in OA synovial macrophages via the MAPK/PI3K-AKT pathway, inhibition of synovial inflammation and fibrosis, and reduction of articular cartilage degeneration.

Regulation of IFNß expression: focusing on the role of its promoter and transcription regulators.

IFNß is a single-copy gene without an intron. Under normal circumstances, it shows low or no expression in cells. It is upregulated only when the body needs it or is stimulated. Stimuli bind to the pattern recognition receptors (PRRs) and pass via various signaling pathways to several basic transcriptional regulators, such as IRFs, NF-кB, and AP-1. Subsequently, the transcriptional regulators enter the nucleus and bind to regulatory elements of the IFNß promoter. After various modifications, the position of the nucleosome is altered and the complex is assembled to activate the IFNß expression. However, IFNß regulation involves a complex network. For the study of immunity and diseases, it is important to understand how transcription factors bind to regulatory elements through specific forms, which elements in cells are involved in regulation, what regulation occurs during the assembly of enhancers and transcription complexes, and the possible regulatory mechanisms after transcription. Thus, this review focuses on the various regulatory mechanisms and elements involved in the activation of IFNß expression. In addition, we discuss the impact of this regulation in biology.