Sema4C Is Required for Vascular and Primary Motor Neuronal Patterning in Zebrafish.

Endothelial cells (ECs) and neurons share a number of common signaling pathways and molecular mediators to orchestrate directional migration and guide the pattern of the vascular network and nervous system. So far, research concerning the functional coupling between vascular and neuronal pathfinding remains insufficient. Semaphorin4C (sema4C), a member of class 4 semaphorins, is initially described in the nervous system, whose role has been demonstrated in diverse biological developments. The present study focused on the role of sema4C in the vascular and neural development process in zebrafish embryos. It confirmed that sema4C is expressed in both the nervous system and intersegmental vessels (ISVs) in zebrafish embryos by diverse expression analysis. It also showed that the knockdown of sema4C caused a serious pathfinding anomaly both in the ISVs and primary motor neurons (PMNs) of zebrafish embryos. In addition, overexpressing exogenous sema4C mRNA in sema4C morphants remarkably neutralized the defective pattern of the vascular and neural system. Collectively, this report suggests that sema4C acts as a dual guiding factor regulating vascular and neuronal development. These findings elucidate a new molecular mechanism underlying blood vessel and nerve development and might serve as groundwork for future research on functional coupling between both systems.

Single-cell immune ecosystem and metabolism reprogramming imprinted by psoriasis niche.

Background: A major challenge of psoriasis is its dysfunctional immune niche. Remarkable gaps remain in understanding how immune cell state transitions are linked to clinical outcomes in psoriasis. Thus, there is a pressing need to discover immunomodulatory programs governing psoriasis progression. Methods: Here, by using the state-of-the-art single-cell RNA-sequencing (RNA-seq) data, we observed the unique immune cell profile inside the psoriasis niche compared with the normal skins. Results: In detail, the immunosuppressive T cells such as regulatory T (Treg) cells and CTLA4+ CD8 T cells showed higher infiltration in the psoriasis niche, indicating the immunosuppressive state was imprinted by such disease. Interestingly, unbiased trajectory and pathway enrichment analysis showed that those suppressive T cells potentially showed developmental and metabolic abnormalities. Intercellular crosstalk modeling shows that exhausted CTLA4+ CD8 T cells can send out cytokine signaling via utilizing CXCL13-CXCR3 ligand-receptor pair. We finally quantified the metabolism profile of T cells and strikingly observed their enhanced metabolic activity. Conclusions: Taken together, these data highlight cell-type specific reprogramming within the psoriasis microenvironment and provide evidence for immune-related biomarkers of psoriasis clinical outcome. Our work not only revealed the unique immune ecosystem of psoriasis, but also opened new opportunities for targeting immunometabolism in treating such skin diseases.

NDUFS4 promotes tumor progression and predicts prognosis in gastric cancer.

Gastric cancer ranked third worldwide in terms of mortality. The immediate priority is to search for new prognosticative or therapeutic targets. This research aims to examine the function of the NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4) in the malignant phenotype of gastric carcinoma. We analyzed the correlation between NDUFS4 expression and gastric cancer via bioinformatics analysis and cancer tissue microarray via immunohistochemistry. Also, we detected the phenotype change in gastric cancer cells after NDUFS4 was downregulated. NDUFS4's high expression in gastric cancer tissues showed an association with terminal TNM stage and unfavorable survival. Furthermore, downregulation of NDUFS4 decreased gastric cancer cell proliferation, migration and invasion. Nude mouse models revealed that NDUFS4 promotes tumor growth. This investigation highlights the prognostic role of NDUFS4 in gastric cancer. Our results also creatively ascertained NDUFS4 as a candidate for gastric cancer therapeutic targets.

Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Attenuate Myocardial Infarction Injury via miR-24-3p-Promoted M2 Macrophage Polarization.

Exosomes derived from human umbilical cord mesenchymal stem cells (UMSC-Exos) have shown encouraging effects in regulating inflammation and attenuating myocardial injury. Macrophages are regulated dynamically in response to environmental cues. However, the underlying mechanisms by which UMSC-Exos regulate macrophage polarization are still not well understood. Herein, it is aimed to explore the effects of UMSC-Exos on macrophage polarization and their roles in cardiac repair after myocardial infarction (MI). These results show that UMSC-Exos improve cardiac function by increasing M2 macrophage polarization and reducing excessive inflammation. RNA-sequencing results identify Plcb3 as a key gene involved in UMSC-Exo-facilitated M2 macrophage polarization. Further bioinformatic analysis identifies exosomal miR-24-3p as a potential effector mediating Plcb3 downregulation in macrophages. Increasing miR-24-3p expression in macrophages effectively enhances M2 macrophage polarization by suppressing Plcb3 expression and NF-κB pathway activation in the inflammatory environment. Furthermore, reducing miR-24-3p expression in UMSC-Exos attenuates the effects of UMSC-Exos on M2 macrophage polarization. This study demonstrates that the cardiac therapeutic effects of UMSC-Exos are at least partially through promoting M2 macrophage polarization in an inflammatory microenvironment. Mechanistically, exosomal miR-24-3p is found to inhibit Plcb3 expression and NF-κB pathway activation to promote M2 macrophage polarization.

Combination therapy for an elderly patient with chromoblastomycosis caused by Fonsecaea monophora: a case report.

We report the first case of combined treatment using oral drugs, thermotherapy, and carbon dioxide fractional laser for an elderly patient with skin chromoblastomycosis caused by Fonsecaea monophora. Chromoblastomycosis is a chronic and refractory granulomatous disease of the skin and subcutaneous tissues caused by a group of dematiaceous fungi, which can cause teratogenesis, disability, and even cancer. One of the subtypes, F. monophora, is not only limited to the skin and subcutaneous tissues but also affects the central nervous system. Therefore, a timely and clear diagnosis, as well as active and effective treatment, are particularly important. This case report presents a 75-year-old male patient whose left forearm had a plaque with mild pruritus for more than three years. The patient's skin lesions were histopathologically examined, and the fungus on the surface of the scabbed skin was examined by fluorescence microscopy and cultured. The strains obtained by the culture were identified by morphological and molecular biology, and a drug susceptibility test was conducted in vitro. Histopathology revealed hyperkeratosis of the epidermis with pseudoepitheliomatous hyperplasia, chronic granulomatous changes in the dermis, and brown thick-walled sclerotic corpuscles both inside and outside giant cells. Septate hyphae and sclerotic corpuscles could be observed in the fungus on the surface of the scabbed skin by fluorescence staining, and black villous colonies could be observed in vitro. Under the scanning electron microscope, rhinocladiella was the primary sporulation type, and the conidia were oval. Molecular identification results showed that the similarity between its internal transcribed spacer (ITS) sequence and that of F. monophora, a Chinese strain (IFM41705), was the highest, reaching 100%. The results of the drug susceptibility test showed that the minimum inhibitory concentrations of itraconazole and voriconazole were 0.125 mg/L and 0.06 mg/L, respectively. The patient was given oral itraconazole 0.2 qd, combined with local thermotherapy and carbon dioxide fractional laser treatment. After 16 weeks, the microscopic examination of the fungus was negative, showing good efficacy.