BACKGROUND Diabetic foot ulcers (DFU), as severe complications of diabetes mellitus (DM), significantly compromise patient health and carry risks of amputation and mortality. AIM To offer new insights into the occurrence and development of DFU, focusing on the therapeutic mechanisms of X-Paste (XP) of wound healing in diabetic mice. METHODS Employing traditional Chinese medicine ointment preparation methods, XP combines various medicinal ingredients. High-performance liquid chromatography (HPLC) identified XP’s main components. Using streptozotocin (STZ)-induced diabetic, we aimed to investigate whether XP participated in the process of diabetic wound healing. RNA-sequencing analyzed gene expression differences between XP-treated and control groups. Molecular docking clarified XP’s treatment mechanisms for diabetic wound healing. Human umbilical vein endothelial cells (HUVECs) were used to investigate the effects of Andrographolide (Andro) on cell viability, reactive oxygen species generation, apoptosis, proliferation, and metastasis in vitro following exposure to high glucose (HG), while NF-E2-related factor-2 (Nrf2 ) knockdown elucidated Andro’s molecular mechanisms. RESULTS XP notably enhanced wound healing in mice, expediting the healing process. RNA-sequencing revealed Nrf2 upregulation in DM tissues following XP treatment. HPLC identified 21 primary XP components, with Andro exhibiting strong Nrf2 binding. Andro mitigated HG-induced HUVECs proliferation, metastasis, angiogenic injury, and inflammation inhibition. Andro alleviates HG-induced HUVECs damage through Nrf2 /HO-1 pathway activation, with Nrf2 knockdown reducing Andro’s proliferative and endothelial protective effects. CONCLUSION XP significantly promotes wound healing in STZ-induced diabetic models. As XP’s key component, Andro activates the Nrf2 /HO-1 signaling pathway, enhancing cell proliferation, tubule formation, and inflammation reduction.

BACKGROUND Aplastic anemia (AA) presents a significant clinical challenge as a life-threatening condition due to failure to produce essential blood cells, with the current therapeutic options being notably limited. AIM To assess the therapeutic potential of ginsenoside Rg1 on AA, specifically its protective effects, while elucidating the mechanism at play. METHODS We employed a model of myelosuppression induced by cyclophosphamide (CTX) in C57 mice, followed by administration of ginsenoside Rg1 over 13 d. The investigation included examining the bone marrow, thymus and spleen for pathological changes via hematoxylin-eosin staining. Moreover, orbital blood of mice was collected for blood routine examinations. Flow cytometry was employed to identify the impact of ginsenoside Rg1 on cell apoptosis and cycle in the bone marrow of AA mice. Additionally, the study further evaluated cytokine levels with enzyme-linked immunosorbent assay and analyzed the expression of key proteins in the MAPK signaling pathway via western blot. RESULTS Administration of CTX led to significant damage to the bone marrow’s structural integrity and a reduction in hematopoietic cells, establishing a model of AA. Ginsenoside Rg1 successfully reversed hematopoietic dysfunction in AA mice. In comparison to the AA group, ginsenoside Rg1 provided relief by reducing the induction of cell apoptosis and inflammation factors caused by CTX. Furthermore, it helped alleviate the blockade in the cell cycle. Treatment with ginsenoside Rg1 significantly alleviated myelosuppression in mice by inhibiting the MAPK signaling pathway. CONCLUSION This study suggested that ginsenoside Rg1 addresses AA by alleviating myelosuppression, primarily through modulating the MAPK signaling pathway, which paves the way for a novel therapeutic strategy in treating AA, highlighting the potential of ginsenoside Rg1 as a beneficial intervention.

BACKGROUND:The immunoglobulin superfamily protein Trem2 (triggering receptor expressed on myeloid cells 2) is primarily expressed on myeloid cells where it functions to regulate macrophage-related immune response induction. While macrophages are essential mediators of diabetic wound healing, the specific regulatory role that Trem2 plays in this setting remains to be established. OBJECTIVE:This study was developed to explore the potential importance of Trem2 signalling in diabetic wound healing and to clarify the underlying mechanisms through which it functions. METHODS AND RESULTS:Following wound induction, diabetic model mice exhibited pronounced upregulation of Trem2 expression, which was primarily evident in macrophages. No cutaneous defects were evident in mice bearing a macrophage-specific knockout of Trem2 (T2-cKO), but they induced more pronounced inflammatory responses and failed to effectively repair cutaneous wounds, with lower levels of neovascularization, slower rates of wound closure, decreased collagen deposition following wounding. Mechanistically, we showed that interleukin (IL)-4 binds directly to Trem2, inactivating MAPK/AP-1 signalling to suppress the expression of inflammatory and chemoattractant factors. Co-culture of fibroblasts and macrophages showed that macrophages from T2-cKO mice suppressed the in vitro activation and proliferation of dermal fibroblasts through upregulation of leukaemia inhibitory factor (Lif). Injecting soluble Trem2 in vivo was also sufficient to significantly curtail inflammatory responses and to promote diabetic wound healing. CONCLUSIONS:These analyses offer novel insight into the role of IL-4/Trem2 signalling as a mediator of myeloid cell-fibroblast crosstalk that may represent a viable therapeutic target for efforts to enhance diabetic wound healing.

In recent years, chimeric antigen receptor (CAR)-T cell therapy has been highly successful in treating hematological malignancies, leading to significant advancements in the cancer immunotherapy field. However, the typical CAR-T therapy necessitates the enrichment of patients' own leukocytes for ex vivo production of CAR-T cells, this customized pattern requires a complicated and time-consuming manufacturing procedure, making it costly and less accessible. The off-the-shelf universal CAR-T strategy could reduce manufacturing costs and realize timely drug administration, presenting as an ideal substitute for typical CAR-T therapy. Utilizing nanocarriers for targeted gene delivery is one of the approaches for the realization of universal CAR-T therapy, as biocompatible and versatile nanoparticles could deliver CAR genes to generate CAR-T cells in vivo. Nanoparticle-mediated in situ generation of CAR-T cells possesses multiple advantages, including lowered cost, simplified manufacturing procedure, and shortened administration time, this strategy is anticipated to provide a potentially cost-effective alternative to current autologous CAR-T cell manufacturing, thus facilitating the prevalence and improvement of CAR-T therapy.

多重耐药真菌的出现给抗真菌治疗提出严峻挑战,如耳念珠菌(Candida auris,C.auris).老药新用,又被称为药物再利用,是指将已获批上市或处于临床研究的药物用于新的适应症或者疾病的治疗.该文回顾了近几年来关于对C.auris有效的老药新用的文章,发现包括抗癌药、镇静止吐药、抗抑郁药、抗高血压药、抗寄生虫药、戒酒药物在内的药物对C.auris也有抑制作用.这些药物大多具有广谱的抗真菌效果,部分药物与传统的抗真菌药物联用时还显示出协同作用,表现出良好的临床抗C.auris感染的应用前景.

Invasive Aspergillus fumigatus infection poses a serious threat to global human health, especially to immunocompromised individuals. Currently, triazole drugs are the most commonly used antifungals for aspergillosis. However, owing to the emergence of drug-resistant strains, the effect of triazole drugs is greatly restricted, resulting in a mortality rate as high as 80%. Succinylation, a novel post-translational modification, is attracting increasing interest, although its biological function in triazole resistance remains unclear. In this study, we initiated the screening of lysine succinylation in A. fumigatus. We discovered that some of the succinylation sites differed significantly among strains with unequal itraconazole (ITR) resistance. Bioinformatics analysis showed that the succinylated proteins are involved in a broad range of cellular functions with diverse subcellular localizations, the most notable of which is cell metabolism. Further antifungal sensitivity tests confirmed the synergistic fungicidal effects of dessuccinylase inhibitor nicotinamide (NAM) on ITR-resistant A. fumigatus. In vivo experiments revealed that treatment with NAM alone or in combination with ITR significantly increased the survival of neutropenic mice infected with A. fumigatus. In vitro experiments showed that NAM enhanced the killing effect of THP-1 macrophages on A. fumigatus conidia. Our results suggest that lysine succinylation plays an indispensable role in ITR resistance of A. fumigatus. Dessuccinylase inhibitor NAM alone or in combination with ITR exerted good effects against A. fumigatus infection in terms of synergistic fungicidal effect and enhancing macrophage killing effect. These results provide mechanistic insights that will aid in the treatment of ITR-resistant fungal infections.

Neutropenia is a common complication in the treatment of hematological diseases and the most common predisposing factor for invasion by fungi, such as Candida krusei. Recent studies have shown that C. krusei, a life-threatening pathogen, has developed resistance to amphotericin B (AMB). However, the mechanisms that led to the rapid emergence of this AMB-resistant phenotype are unclear. In this study, we found the sensitivity for AMB could be promoted by inhibiting histone acyltransferase activity and western blot analysis revealed differences in the succinylation levels of C. krusei isolated from immunocompromised patients and of the corresponding AMB-resistant mutant. By comparative succinyl-proteome analysis, we identified a total of 383 differentially expressed succinylated sites in with 344 sites in 134 proteins being upregulated in the AMB-resistant mutant, compared to 39 sites in 23 proteins in the wild-type strain. These differentially succinylated proteins were concentrated in the ribosome and cell wall. The critical pathways associated with these proteins included those involved in glycolysis, gluconeogenesis, the ribosome, and fructose and mannose metabolism. In particular, AMB resistance was found to be associated with enhanced ergosterol synthesis and aberrant amino acid and glucose metabolism. Analysis of whole-cell proteomes, confirmed by parallel reaction monitoring, showed that the key enzyme facilitating lysine acylation was significantly upregulated in the AMB-resistant strain. Our results suggest that lysine succinylation may play an indispensable role in the development of AMB resistance in C. krusei. Our study provides mechanistic insights into the development of drug resistance in fungi and can aid in efforts to stifle the emergence of AMB-resistant pathogenic fungi.

Background The skin cutaneous melanoma (SKCM) is a devastating form of skin cancer triggered by genetic and environmental factors, and the incidence of SKCM has rapidly increased in recent years. Immune infiltration of the tumor microenvironment is positively associated with overall survival in many tumors. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily and a crucial signaling hub for multiple pathological pathways that mediate immunity. Although numerous evidences suggest a crucial role for TREM2 in tumorigenesis of some tumors, no systematic SKCM analysis of TREM2 is available. Mehods. The relationship between TREM2 expression and diagnostic and prognostic value of SKCM patients via using The Cancer Genome Atlas (TCGA) data. The expression level of TREM2 and clinical characteristic correlation in SKCM patients were assessed by the Wilcoxon rank sum test. The cox regression methods, Kaplan-Meier (KM), and log-rank test were used to assess the impact of TREM2 expression on the overall survival (OS). Furthermore, the Gene Set Enrichment Analysis (GSEA) and TIMER were performed to evaluate the enrichment pathways and potential functions and quantify the immune cell infiltration level for TREM2 expression. Results The TREM2 in SKCM sample expression levels was significantly higher than in normal tissues. Moreover, this expression level of TREM2 was also associated with the BMI of SKCM patients. KM overall survival analysis and OS curve displayed that a high-level TREM2 expression was significantly correlated with a better SKCM prognosis of patients as compared with a low level of TREM2 expression. The GSEA analysis also revealed that TREM2 was associated with immune functions, such as neutrophil activation. Conclusion TREM2 played a crucial role in SKCM, which might be a prognostic biomarker and correlated with immune infifiltrates in SKCM patients.

BackgroundThe global burden of invasive fungal infections (IFIs) has shown an upsurge in recent years due to the higher load of immunocompromised patients suffering from various diseases. The role of early and accurate diagnosis in the aggressive containment of the fungal infection at the initial stages becomes crucial thus, preventing the development of a life-threatening situation. With the changing demands of clinical mycology, the field of fungal diagnostics has evolved and come a long way from traditional methods of microscopy and culturing to more advanced non-culture-based tools. With the advent of more powerful approaches such as novel PCR assays, T2 Candida, microfluidic chip technology, next generation sequencing, new generation biosensors, nanotechnology-based tools, artificial intelligence-based models, the face of fungal diagnostics is constantly changing for the better. All these advances have been reviewed here giving the latest update to our readers in the most orderly flow.Main textA detailed literature survey was conducted by the team followed by data collection, pertinent data extraction, in-depth analysis, and composing the various sub-sections and the final review. The review is unique in its kind as it discusses the advances in molecular methods; advances in serology-based methods; advances in biosensor technology; and advances in machine learning-based models, all under one roof. To the best of our knowledge, there has been no review covering all of these fields (especially biosensor technology and machine learning using artificial intelligence) with relevance to invasive fungal infections.ConclusionThe review will undoubtedly assist in updating the scientific community's understanding of the most recent advancements that are on the horizon and that may be implemented as adjuncts to the traditional diagnostic algorithms.

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections with Candida of the skin, nails, and mucous membranes (e.g., mouth, esophagus, and vagina). Compared with that of other infectious diseases, the immune pathogenic mechanism of CMC is still poorly understood. We identified a signal transducer and activator of transcription 1 gain-of-function (c.Y289C) mutation in a CMC patient. Single-cell transcriptional profiling on peripheral blood mononuclear cells from this patient revealed decreases in immature B cells and monocytes. Further analysis revealed several differentially expressed genes related to immune regulation, including RGS1, TNFAIP3, S100A8/A9, and CTSS. In our review of the literature on signal transducer and activator of transcription 1 gain-of-function (c.Y289C) mutations, we identified seven cases in total. The median age of onset for CMC (n=4, data lacking for three cases) was 10.5 years (range: birth to 11 years), with an average onset age of 8 years. There were no reports linking tumors to the c.Y289C mutation, and the incidence of pre-existing clinical disease in patients with the c.Y289C mutation was similar to previous data.

Objective To understand the clinical characteristics,susceptible factors,distribution of fungal pathogens of dermatophytosis in Shanghai.Methods All 1031cases of dermatophytosis presented with typical clinical features and positive culture results were collected during January 2013to December 2017in our outpatient department for analysis.SPSS 23. 0was used in statistic analysis.Results Of 1031cases of dermatophytosis,535were males and 496were females,1033 strains of dermatophytosis were isolated.The peak incidence of dermatophytosis was 21-30years old and 31-40years old. 71cases(6.89％)had one or more other fungi isolated from patients with dermatophytosis,and 2cases(0.19％)had two kinds of dermatophytes,in which the most isolated other fungi were Rhodotorula.The most common dermatophytosis was onychomycosis(n=344,33.37％),followed by tinea cruris(n=200,19.40％),tinea corporis(n=162,15.71％),tinea pedis(n=138,13.39％),tinea manus(n=108,10.48％),tinea facialis(n=45,4.36％)and tinea capitis(n=34,3.30％), in which there were significant gender differences in tinea cruris and onychomycosis.In the distribution of strains,the top three were Trichophyton mentagrophytes (n =542,52.47％),Trichophyton rubrum (n =397,38.43％)and Microsporum canis (n =66,6.39％),in which there were significant gender differences between Trichophyton rubrumand Microsporum canis.Conclusion The main type of dermatophytosis in our hospital was onychomycosis,and the main pathogen was Trichophyton mentagrophytes.The distribution and epidemic trend of dermatophytosis and dermatophytosis are similar to those in most areas of China in recent years,but it has its own characteristics.