Thy-1 knockdown promotes the osteogenic differentiation of GMSCs via the Wnt/ß-catenin pathway.

Gingival mesenchymal stem cells (GMSCs) are newly developed seed cells for tissue engineering owing to their easy isolation, abundance and high growth rates. Thy-1 is an important regulatory molecule in the differentiation of mesenchymal stem cells (MSCs). In this study, we investigated the function of Thy-1 in the osteogenic differentiation of GMSCs by reducing the expression of Thy-1 using a lentivirus. The results demonstrated that Thy-1 knockdown promoted the osteogenic differentiation of GMSCs in vitro. Validation by RNA-seq revealed an obvious decrease in Vcam1 and Sox9 gene expression with Thy-1 knockdown. Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that the differentially expressed genes were enriched in the Wnt signalling pathway. We further demonstrated that Thy-1 knockdown promoted osteogenic differentiation of GMSCs by activating the Wnt/ß-catenin signalling pathway. Therefore, Thy-1 has a key regulatory role in the differentiation of GMSCs and maybe a core molecule connecting transcription factors related to the differentiation of MSCs. Our study also highlighted the potential of Thy-1 to modify MSCs, which may help improve their use in tissue engineering.

Insights into N6-methyladenosine and programmed cell death in cancer.

N6-methyladenosine (m6A) methylation, the most common form of internal RNA modification in eukaryotes, has gained increasing attention and become a hot research topic in recent years. M6A plays multifunctional roles in normal and abnormal biological processes, and its role may vary greatly depending on the position of the m6A motif. Programmed cell death (PCD) includes apoptosis, autophagy, pyroptosis, necroptosis and ferroptosis, most of which involve the breakdown of the plasma membrane. Based on the implications of m6A methylation on PCD, the regulators and functional roles of m6A methylation were comprehensively studied and reported. In this review, we focus on the high-complexity links between m6A and different types of PCD pathways, which are then closely associated with the initiation, progression and resistance of cancer. Herein, clarifying the relationship between m6A and PCD is of great significance to provide novel strategies for cancer treatment, and has a great potential prospect of clinical application.

Introduction of long non-coding RNAs to regulate autophagy-associated therapy resistance in cancer.

Autophagy is a lysosomal degradation pathway that depends on various evolutionarily conserved autophagy-related genes (ATGs). Dysregulation of autophagy plays an important role in the occurrence and development of cancer. Chemotherapy, targeted therapy, radiotherapy, and immunotherapy are important treatment options for cancer, which can significantly improve the survival rate of cancer patients. However, the occurrence of therapy resistance results in therapeutic failure and poor prognosis of cancer. Accumulating studies have found that long non-coding RNAs (lncRNAs) are well known as crucial regulators to control autophagy through regulating ATGs and autophagy-associated signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, ultimately mediating chemoresistance and radioresistance. Taken together, this review systematically summarizes and elucidates the pivotal role of lncRNAs in cancer chemoresistance and radioresistance via regulating autophagy. Understanding the specific mechanism of which may provide autophagy-related therapeutic targets for cancer in the future.

Intricate crosstalk between MYB and noncoding RNAs in cancer.

MYB is often overexpressed in malignant tumors and plays a carcinogenic role in the initiation and development of cancer. Deletion of the MYB regulatory C-terminal domain may be a driving mutation leading to tumorigenesis, therefore, different tumor mechanisms produce similar MYB proteins. As MYB is a transcription factor, priority has been given to identifying the genes that it regulates. All previous attention has been focused on protein-coding genes. However, an increasing number of studies have suggested that MYB can affect the complexity of cancer progression by regulating tumor-associated noncoding RNAs (ncRNAs), such as microRNAs, long-non-coding RNAs and circular RNAs. ncRNAs can regulate the expression of numerous downstream genes at the transcription, RNA processing and translation levels, thereby having various biological functions. Additionally, ncRNAs play important roles in regulating MYB expression. This review focuses on the intricate crosstalk between oncogenic MYB and ncRNAs, which play a pivotal role in tumorigenesis, including proliferation, apoptosis, angiogenesis, metastasis, senescence and drug resistance. In addition, we discuss therapeutic strategies for crosstalk between MYB and ncRNAs to prevent the occurrence and development of cancer.

Exosomes derived from ADSCs containing miR-378 promotes wound healing by targeting caspase-3.

Pathological scars and chronic wounds caused by injury, aging, or surgery have always been important public health problems, and there is an urgent need to study the driving forces to find more effective treatments. In this study, we extracted and identified ADSCs exosomes and found that they have the ability to protect HaCat cells from oxidative damage, including promoting proliferation and migration and reducing apoptosis. Further studies determined that the expression of miR-378 was significantly enriched in exosomes. Studies have found that miR-378 mimic can produce protection similar to ADSCs-exo. However, when miR-378 inhibitors are used on ADSCs, the damage protection of the secreted exosomes disappears. This proves that miR-378 enriched in exosomes can improve HaCat's oxidative stress damage. Luciferase experiments show that this effect is achieved by targeting caspase-3. These results indicate that ADSCs play a protective role in wound healing by secreting miR-378-rich exosomes.

Growth of Salmonella spp. and Escherichia coli O157:H7 on Fresh-Cut Fruits Stored at Different Temperatures.

The objective of this work was to determine the growth potential of Salmonella spp. and Escherichia coli O157:H7 on fresh-cut honeydew melon, cantaloupe, watermelon, pitaya, mango, papaya, and pineapple stored at 5°C, 13°C, and 25°C. The results showed that both pathogens were able to grow on fresh-cut fruits except fresh-cut pineapple at 13°C and 25°C. Salmonella spp. grew more rapidly on fresh-cut honeydew melon, cantaloupe, watermelon, and mango than did E. coli O157:H7 at 13°C. The growth of both species was inhibited on fresh-cut pineapple, with that of Salmonella spp. being particularly pronounced. Naturally occurring microbiota populations on fresh-cut fruits increased significantly at 13°C and 25°C, but no significant changes in growth were observed for Salmonella spp., E. coli O157:H7, or natural microbiota species at 5°C. The study therefore emphasizes the importance of strict temperature control from processing to consumption, including transportation, distribution, storage, and handling in supermarkets and by consumers.

Towards an informative mutant phenotype for every bacterial gene.

Mutant phenotypes provide strong clues to the functions of the underlying genes and could allow annotation of the millions of sequenced yet uncharacterized bacterial genes. However, it is not known how many genes have a phenotype under laboratory conditions, how many phenotypes are biologically interpretable for predicting gene function, and what experimental conditions are optimal to maximize the number of genes with a phenotype. To address these issues, we measured the mutant fitness of 1,586 genes of the ethanol-producing bacterium Zymomonas mobilis ZM4 across 492 diverse experiments and found statistically significant phenotypes for 89% of all assayed genes. Thus, in Z. mobilis, most genes have a functional consequence under laboratory conditions. We demonstrate that 41% of Z. mobilis genes have both a strong phenotype and a similar fitness pattern (cofitness) to another gene, and are therefore good candidates for functional annotation using mutant fitness. Among 502 poorly characterized Z. mobilis genes, we identified a significant cofitness relationship for 174. For 57 of these genes without a specific functional annotation, we found additional evidence to support the biological significance of these gene-gene associations, and in 33 instances, we were able to predict specific physiological or biochemical roles for the poorly characterized genes. Last, we identified a set of 79 diverse mutant fitness experiments in Z. mobilis that are nearly as biologically informative as the entire set of 492 experiments. Therefore, our work provides a blueprint for the functional annotation of diverse bacteria using mutant fitness.

Indirect and suboptimal control of gene expression is widespread in bacteria.

Gene regulation in bacteria is usually described as an adaptive response to an environmental change so that genes are expressed when they are required. We instead propose that most genes are under indirect control: their expression responds to signal(s) that are not directly related to the genes' function. Indirect control should perform poorly in artificial conditions, and we show that gene regulation is often maladaptive in the laboratory. In Shewanella oneidensis MR-1, 24% of genes are detrimental to fitness in some conditions, and detrimental genes tend to be highly expressed instead of being repressed when not needed. In diverse bacteria, there is little correlation between when genes are important for optimal growth or fitness and when those genes are upregulated. Two common types of indirect control are constitutive expression and regulation by growth rate; these occur for genes with diverse functions and often seem to be suboptimal. Because genes that have closely related functions can have dissimilar expression patterns, regulation may be suboptimal in the wild as well as in the laboratory.

Evidence-based annotation of gene function in Shewanella oneidensis MR-1 using genome-wide fitness profiling across 121 conditions.

Most genes in bacteria are experimentally uncharacterized and cannot be annotated with a specific function. Given the great diversity of bacteria and the ease of genome sequencing, high-throughput approaches to identify gene function experimentally are needed. Here, we use pools of tagged transposon mutants in the metal-reducing bacterium Shewanella oneidensis MR-1 to probe the mutant fitness of 3,355 genes in 121 diverse conditions including different growth substrates, alternative electron acceptors, stresses, and motility. We find that 2,350 genes have a pattern of fitness that is significantly different from random and 1,230 of these genes (37% of our total assayed genes) have enough signal to show strong biological correlations. We find that genes in all functional categories have phenotypes, including hundreds of hypotheticals, and that potentially redundant genes (over 50% amino acid identity to another gene in the genome) are also likely to have distinct phenotypes. Using fitness patterns, we were able to propose specific molecular functions for 40 genes or operons that lacked specific annotations or had incomplete annotations. In one example, we demonstrate that the previously hypothetical gene SO_3749 encodes a functional acetylornithine deacetylase, thus filling a missing step in S. oneidensis metabolism. Additionally, we demonstrate that the orphan histidine kinase SO_2742 and orphan response regulator SO_2648 form a signal transduction pathway that activates expression of acetyl-CoA synthase and is required for S. oneidensis to grow on acetate as a carbon source. Lastly, we demonstrate that gene expression and mutant fitness are poorly correlated and that mutant fitness generates more confident predictions of gene function than does gene expression. The approach described here can be applied generally to create large-scale gene-phenotype maps for evidence-based annotation of gene function in prokaryotes.

Bone block from lateral window - correcting vertical and horizontal bone deficiency in maxilla posterior site: A case report.

BACKGROUND: Lateral window approach for sinus floor lift is commonly used for vertical bone augmentation in cases when the residual bone height is less than 5 mm. However, managing cases becomes more challenging when a maxillary sinus pseudocyst is present or when there is insufficient bone width. In this case, we utilized the bone window prepared during the lateral window sinus lift as a shell for horizontal bone augmentation. This allowed for simultaneous horizontal and vertical bone augmentation immediately after the removal of the maxillary sinus pseudocyst. CASE SUMMARY: A 28-year-old female presented to our clinic with the chief complaint of missing upper left posterior teeth. Intraoral examination showed a horizontal deficiency of the alveolar ridge contour. The height of the alveolar bone was approximately 3.6 mm on cone beam computed tomography (CBCT). And a typical well-defined 'dome-shaped' lesion in maxillary sinus was observed on CBCT imaging. The lateral bony window was prepared using a piezo-ultrasonic device, then the bony window was fixed to the buccal side of the 26 alveolar ridge using a titanium screw with a length of 10 mm and a diameter of 1.5 mm. The space between the bony window and the alveolar ridge was filled with Bio-Oss, covered with a Bio-Gide collagen membrane, and subsequently sutured. Nine months later, the patient's bone width increased from 4.8 to 10.5 mm, and the bone height increased from 3.6 to 15.6 mm. Subsequently, a Straumann® 4.1 mm × 10 mm implant was placed. The final all-ceramic crown restoration was completed four months later, and both clinical and radiographic examinations showed that the implant was successful, and the patient was satisfied with the results. CONCLUSION: The bone block harvested from the lateral window sinus lift can be used for simultaneous horizontal bone augmentation acting as a shell for good two-dimensional bone augmentation.

Co-delivery of drugs by adhesive transdermal patches equipped with dissolving microneedles for the treatment of rheumatoid arthritis.

In this study, a dosage form consisting of dissolving (D) microneedles (M) and an adhesive (A) transdermal patch (P; DMAP) was designed and pre-clinically evaluated for the treatment of rheumatoid arthritis (RA). The tip of the dissolving microneedles (DMNs) was loaded with the macromolecular drug melittin (Mel@DMNs), this to treat joint inflammation and bone damage, while the adhesive transdermal patches contained the low molecular weight drug diclofenac sodium (DS; DS@AP) for pain relief. Mel@DMNs and DS@AP were ingeniously connected through an isolation layer for compounding Mel-DS@DMAP for the simultaneous delivery of the drugs. In vitro and in vivo experiments showed that DS@AP did not affect the mechanical properties and dissolution process of Mel@DMNs while the pores formed by the microneedles promoted the skin penetration of DS. Treatment of rats suffering from RA with Mel-DS@DMAP reduced paw swelling and damage of the synovium, joint and cartilage, suggesting that the 'patch-microneedle' dosage form might be promising for the treatment and management of RA.

Characteristics of cerebrospinal fluid oligoclonal band in anti-myelin oligodendrocyte glycoprotein (MOG) antibody associated disease.

Objective: To analyze the immune parameters of cerebrospinal fluid (CSF) and oligoclonal band (OCB) type in patients with anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases (MOGAD). Methods: Patients who were seropositive for MOG-IgG and diagnosed with MOGAD according to the diagnosis criteria in the Department of Neurology, Huashan Hospital, Fudan University from December 2020 to June 2022 were retrospectively included in this study. Complete clinical data, blood and cerebrospinal fluid samples were collected from all the participants. Paired serum and CSF MOG-IgG and autoimmune encephalitis antibody were assayed by Cell Based Assay (CBA) based on transfected target antigens. Paired serum and CSF albumin and IgG were detected by turbidimetric scattering method, and OCB was detected by standard operation procedure as described. Results: A total of 86 patients (44 males and 42 females) with MOGAD were included in this study, with a median age of 30 years (range: 5-82 years). Among all the patients, 73 patients showed OCB type I, 12 patients showed OCB type II, and one patient showed OCB type III. The overall positive rate of CSF-OCB in MOGAD patients was 15.1 %. The 24-h intrathecal synthesis rate of CSF in the OCB-positive group (n = 13) was higher than that in the OCB-negative group [n = 73, 0.62 (0.26) vs 5.11 (13.67), P = 0.003]. Subgroup analysis revealed that the positive rates of CSF-OCB in the single MOG group (n = 61) and the group combined with other antibodies (n = 25) were 14.8 % and 16.0 %, respectively. The incidence of meningoencephalitis (13/61 vs 13/25, P = 0.011) was significantly different between the two groups. The proportion of patients with high (≥1:32) or low (≤1:10) CSF MOG-IgG also showed significant difference in the group combined with other antibodies (P = 0.032). Optic neuritis was more common in the relapse course group (n = 49) than the monophasic course group (n = 37, P < 0.001) No significant diferences of CSF immune parameters were found in the MOG-IgGserum+/CSF- group and the MOG-IgGserum+/CSF + group, and the titer of MOG-IgG in the serum or CSF did not influence CSF immune parameters in different subgroups. Conclusion: The overall positive rate of CSF-OCB in MOGAD patients was 15.1 %. The 24-h intrathecal synthesis rate of cerebrospinal fluid in the OCB-positive group was higher than that in the OCB-negative group. This study illustrated OCB characterization in MOGAD patients, and will shed light on the standardization of OCB test in the study of immune diseases.

ROS-Induced Gingival Fibroblast Senescence: Implications in Exacerbating Inflammatory Responses in Periodontal Disease.

Periodontal disease is the pathological outcome of the overwhelming inflammation in periodontal tissue. Cellular senescence has been associated with chronic inflammation in several diseases. However, the role of cellular senescence in the pathogenesis of periodontal disease remained unclear. This study aimed to investigate the role and the mechanism of cellular senescence in periodontal disease. Using single-cell RNA sequencing, we first found the upregulated level of cellular senescence in fibroblasts and endothelial cells from inflamed gingival tissue. Subsequently, human gingival fibroblasts isolated from healthy and inflamed gingival tissues were labeled as H-GFs and I-GFs, respectively. Compared to H-GFs, I-GFs exhibited a distinct cellular senescence phenotype, including an increased proportion of senescence-associated ß-galactosidase (SA-ß-gal) positive cells, enlarged cell morphology, and significant upregulation of p16INK4A expression. We further observed increased cellular reactive oxygen species (ROS) activity, mitochondrial ROS, and DNA damage of I-GFs. These phenotypes could be reversed by ROS scavenger NAC, which suggested the cause of cellular senescence in I-GFs. The migration and proliferation assay showed the decreased activity of I-GFs while the gene expression of senescence-associated secretory phenotype (SASP) factors such as IL-1ß, IL-6, TGF-ß, and IL-8 was all significantly increased. Finally, we found that supernatants of I-GF culture induced more neutrophil extracellular trap (NET) formation and drove macrophage polarization toward the CD86-positive M1 pro-inflammatory phenotype. Altogether, our findings implicate that, in the inflamed gingiva, human gingival fibroblasts acquire a senescent phenotype due to oxidative stress-induced DNA and mitochondrial damage, which in turn activate neutrophils and macrophages through the secretion of SASP factors.

Third-generation D-lactic acid production using red macroalgae Gelidium amansii by co-fermentation of galactose, glucose and xylose.

Macroalgae biomass has been considered as a promising renewable feedstock for lactic acid production owing to its lignin-free, high carbohydrate content and high productivity. Herein, the D-lactic acid production from red macroalgae Gelidium amansii by Pediococcus acidilactici was investigated. The fermentable sugars in G. amansii acid-prehydrolysate were mainly galactose and glucose with a small amounts of xylose. P. acidilactici could simultaneously ferment the mixed sugars of galactose, glucose and xylose into D-lactic acid at high yield (0.90 g/g), without carbon catabolite repression (CCR). The assimilating pathways of these sugars in P. acidilactici were proposed based on the whole genome sequences. Simultaneous saccharification and co-fermentation (SSCF) of the pretreated and biodetoxified G. amansii was also conducted, a record high of D-lactic acid (41.4 g/L) from macroalgae biomass with the yield of 0.34 g/g dry feedstock was achieved. This study provided an important biorefinery strain for D-lactic acid production from macroalgae biomass.

Expression of fibrinogen-like protein 2 (Fgl2) on Toll-like receptor 9 (TLR9) expression in autoimmune myelitis.

Toll-like receptor 9 (TLR9) can participate in the signal transduction of activated immune cells and induce myelitis and other autoimmune diseases. The effector molecule fibrin-like protein 2 (Fgl2) plays a role in regulating the body's autoimmune signaling pathway. They both have the conditions for the treatment of this disease target. The objective of this work was to investigate the effect of Fgl2 on the expression of DNA receptor TLR9 in autoimmune myelitis. 140 rats were randomly divided into a normal control group, an autoimmune myelitis group, a low-dose Fgl2 group, a middle-dose Fgl2 group, a higher-dose Fgl2 group, a high-dose Fgl2 group, and a methylprednisolone group. Different injection methods were used in each group. The changes of rat behavior and disease were recorded, and brain and spinal cord tissue slices were made for observation. The results showed that in the high dose Fgl2 group, the incidence of disease was 15 %, the nerve injury score was 1.0 ± 0.15, the body weight change was -5.8 ± 1.24 g, the number of spinal cord tissue injury was 1.82 ± 0.44, the number of TLR9 positive cells in the brain tissue was 7.53 ± 1.84, and the number of TLR9 positive cells in spinal cord tissue was 5.02 ± 1.81. These indexes were lower than those in other Fgl2 groups and significantly lower than those in autoimmune myelitis group (P < 0.05). The average incubation period of the disease was 13.66 ± 0.41 days, which was significantly higher than that of the autoimmune myelitis group (P < 0.05). It can be observed that TLR9 signaling pathway played an important role in the occurrence and development of autoimmune myelitis. With the increase of Fgl2 dose, the number of TLR9 positive cells decreased gradually. Fgl2 treatment can reduce the expression of inflammatory factors and the severity of dysfunction in autoimmune myelitis, inhibit the expression of TLR9, and improve the condition of autoimmune myelitis.

The role of m6A-mediated PD-1/PD-L1 in antitumor immunity.

N6-methyladenosine (m6A) is the most prevalent, abundant and conserved type of internal posttranscriptional RNA modification in eukaryotic cells. Emerging evidence suggests that m6A modifications perform important functions that affect antitumor immunity. Programmed death 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) are the two most well-studied immune checkpoint pathways. The interaction of PD-L1 with its receptor PD-1 inhibits cytotoxic T-cell-mediated tumor responses, and blockade of this interaction has proven to be an effective immunotherapy strategy in various cancers. Unfortunately, few cancer patients benefit from the two tools due to uncertain resistance. m6A plays an important role in affecting RNA biogenesis and process in various cancers. Understanding the molecular mechanism of drug resistance will promote the development of personalized clinical management. In this review, we systematically discussed the mechanisms by which m6A regulates PD-1 and PD-L1 expression and further their functions in the process of tumor immunotherapy and the potential application prospects of m6A-associated molecules. Moreover, mounting m6Ascore is established to evaluate the prognosis of cancer.

Black phosphorus-enhanced injectable hydrogel for infected soft tissue healing.

The misuse of antibiotics makes clinical treatment of soft tissue infection a huge challenge in prosthesis replacement. In this study, a black phosphorus (BP)-enhanced antibacterial injectable hydrogel (HAABP) was developed by the dynamic coordinative cross-linking among thiolated hyaluronic acid, silver ion (Ag+), and BP. HAABP has been proven to possess typical porous structures, excellent injectability, and rapid self-healing properties. In addition, the shear modulus was positive correlative to the concentration of BP. In vitro, HAABP maintained good cytocompatibility and showed a highly efficient synergistic inhibitory effect on Staphylococcus aureus through the irradiation of near infrared light and the release of Ag+. In vivo, HAABP not only inhibited the persistent infection but also accelerated the deposition of collagen fibers and angiogenesis by down-regulating the inflammatory factor TNF-α in the infectious wound defect, thereby repairing the natural barrier of tissue. This study developed a BP-enhanced injectable hydrogel that provided a simple and efficient synergistic antibacterial strategy to treat soft tissue infections around prostheses.

Investigation of Crystallization, Morphology, and Mechanical Properties of Polypropylene/Polypropylene-Polyethylene Block Copolymer Blends.

Polyethylene (PE)-based elastomers are the ideal choice for enhancing the compatibility of polypropylene/polyethylene (PP/PE) blends and improving the mechanical properties of PP-based materials. However, the issue of blend systems lies in the interplay between the crystallization processes. Therefore, we investigated the crystallization behavior during the cooling process of a new generation of PP/PE block copolymers (PP-b-PE) and random polypropylene (PPR, a copolymer of propylene and a small amount of ethylene or an alpha-olefin) blends using in-situ X-ray diffraction/scattering and differential scanning calorimetry (DSC) techniques. We also conducted mechanical performance tests on PPR/PP-b-PE blends at room temperature and low temperature (-5 °C). The results indicate that during the cooling process, the PP phase of PP-b-PE will follow the PPR to crystallize in advance and form a eutectic mixture, thereby enhancing the compatibility of PP/PE. Moreover, the PPR/PP-b-PE blend will form stable ß-(300) crystals with excellent mechanical properties. Due to the improved compatibility of PP/PE with PP-b-PE, PE crystals are dispersed within PP crystals, providing bonding that improves the toughness of PPR under the low stiffness failure conditions of PPR/PP-b-PE blends, thereby enhancing their impact performance at low and room temperatures. This research has great significance for both recycling waste plastics and enhancing the low-temperature toughness of PPR.

FRMD3 inhibits the growth and metastasis of breast cancer through the ubiquitination-mediated degradation of vimentin and subsequent impairment of focal adhesion.

Recurrence and metastasis are the main causes of breast cancer (BRCA)-related death and remain a challenge for treatment. In-depth research on the molecular mechanisms underlying BRCA progression has been an important basis for developing precise biomarkers and therapy targets for early prediction and treatment of progressed BRCA. Herein, we identified FERM domain-containing protein 3 (FRMD3) as a novel potent BRCA tumor suppressor which is significantly downregulated in BRCA clinical tissue and cell lines, and low FRMD3 expression has been closely associated with progressive BRCA and shortened survival time in BRCA patients. Overexpression and knockdown experiments have revealed that FRMD3 significantly inhibits BRCA cell proliferation, migration, and invasion in vitro and suppresses BRCA xenograft growth and metastasis in vivo as well. Mechanistically, FRMD3 can interact with vimentin and ubiquitin protein ligase E3A(UBE3A) to induce the polyubiquitin-mediated proteasomal degradation of vimentin, which subsequently downregulates focal adhesion complex proteins and pro-cancerous signaling activation, thereby resulting in cytoskeletal rearrangement and defects in cell morphology and focal adhesion. Further evidence has confirmed that FRMD3-mediated vimentin degradation accounts for the anti-proliferation and anti-metastasis effects of FRMD3 on BRCA. Moreover, the N-terminal ubiquitin-like domain of FRMD3 has been identified as responsible for FRMD3-vimentin interaction through binding the head domain of vimentin and the truncated FRMD3 with the deletion of ubiquitin-like domain almost completely loses the anti-BRCA effects. Taken together, our study indicates significant potential for the use of FRMD3 as a novel prognosis biomarker and a therapeutic target of BRCA and provides an additional mechanism underlying the degradation of vimentin and BRCA progression.

Tectorigenin targets PKACα to promote GLUT4 expression in skeletal muscle and improve insulin resistance in vitro and in vivo.

The decreased expression and dysfunction of glucose transporter 4 (GLUT4), the insulin-responsive glucose transporter, are closely related to the occurrence of insulin resistance (IR). To improve the expression of GLUT4 may represent a promising strategy to prevent and treat IR and type 2 diabetes (T2DM). Here, we demonstrate that the natural compound tectorigenin (TG) enhances GLUT4 expression, glucose uptake and insulin responsiveness via activating AMP-activated protein kinase (AMPK)/myocyte enhancer factor 2 (MEF2) signaling in both normal and IR skeletal muscle cells and tissues. Accordingly, prophylactic and therapeutic uses of TG can significantly ameliorate IR and hyperglycemia in T2DM mice. Mechanistically, we identify protein kinase A catalytic subunit α (PKACα) as the target of TG to increase GLUT4 expression and TG-PKACα binding promotes the dissociation of PKACα from the regulatory subunits, leading to the activation of PKA/AMPK signaling. PKACα knockdown in local quadriceps muscles almost completely abolished the therapeutic effects of TG on IR and T2DM, as well as the enhancement on AMPK signaling and GLUT4 expression in skeletal muscle. This study supports TG as a new drug candidate to treat IR and its related diseases, but also enriches our knowledge of PKA signaling in glucose metabolism in skeletal muscle.