Glutathione supplementation improves fat graft survival by inhibiting ferroptosis via the SLC7A11/GPX4 axis.

BACKGROUND: Autologous fat grafting is hampered by unpredictable graft survival, which is potentially regulated by ferroptosis. Glutathione (GSH), a powerful antioxidant used in tissue preservation, has ferroptosis-regulating activity; however, its effects on fat grafts are unclear. This study investigated the effects and mechanisms of GSH in fat graft survival. METHODS: Human lipoaspirates were transplanted subcutaneously into the backs of normal saline-treated (control) or GSH-treated nude mice. Graft survival was evaluated by magnetic resonance imaging and histology. RNA sequencing was performed to identify differentially expressed genes and enriched pathways. GSH activity was evaluated in vitro using an oxygen and glucose deprivation (OGD) model of adipose-derived stem cells. RESULTS: Compared with control group, GSH induced better outcomes, including superior graft retention, appearance, and histological structures. RNA sequencing suggested enhanced negative regulation of ferroptosis in the GSH-treated grafts, which showed reduced lipid peroxides, better mitochondrial ultrastructure, and SLC7A11/GPX4 axis activation. In vitro, OGD-induced ferroptosis was ameliorated by GSH, which restored cell proliferation, reduced oxidative stress, and upregulated ferroptosis defense factors. CONCLUSIONS: Our study confirms that ferroptosis participates in regulating fat graft survival and that GSH exerts a protective effect by inhibiting ferroptosis. GSH-assisted lipotransfer is a promising therapeutic strategy for future clinical application.

Single-cell RNA-seq and bulk-seq identify RAB17 as a potential regulator of angiogenesis by human dermal microvascular endothelial cells in diabetic foot ulcers.

Background: Angiogenesis is crucial in diabetic wound healing and is often impaired in diabetic foot ulcers (DFUs). Human dermal microvascular endothelial cells (HDMECs) are vital components in dermal angiogenesis; however, their functional and transcriptomic characteristics in DFU patients are not well understood. This study aimed to comprehensively analyse HDMECs from DFU patients and healthy controls and find the potential regulator of angiogenesis in DFUs. Methods: HDMECs were isolated from skin specimens of DFU patients and healthy controls via magnetic-activated cell sorting. The proliferation, migration and tube-formation abilities of the cells were then compared between the experimental groups. Both bulk RNA sequencing (bulk-seq) and single-cell RNA-seq (scRNA-seq) were used to identify RAB17 as a potential marker of angiogenesis, which was further confirmed via weighted gene co-expression network analysis (WGCNA) and least absolute shrink and selection operator (LASSO) regression. The role of RAB17 in angiogenesis was examined through in vitro and in vivo experiments. Results: The isolated HDMECs displayed typical markers of endothelial cells. HDMECs isolated from DFU patients showed considerably impaired tube formation, rather than proliferation or migration, compared to those from healthy controls. Gene set enrichment analysis (GSEA), fGSEA, and gene set variation analysis (GSVA) of bulk-seq and scRNA-seq indicated that angiogenesis was downregulated in DFU-HDMECs. LASSO regression identified two genes, RAB17 and CD200, as characteristic of DFU-HDMECs; additionally, the expression of RAB17 was found to be significantly reduced in DFU-HDMECs compared to that in the HDMECs of healthy controls. Overexpression of RAB17 was found to enhance angiogenesis, the expression of hypoxia inducible factor-1α and vascular endothelial growth factor A, and diabetic wound healing, partially through the mitogen-activated protein kinase/extracellular signal-regulated kinase signalling pathway. Conclusions: Our findings suggest that the impaired angiogenic capacity in DFUs may be related to the dysregulated expression of RAB17 in HDMECs. The identification of RAB17 as a potential molecular target provides a potential avenue for the treatment of impaired angiogenesis in DFUs.

Multiple system atrophy associated with Meige syndrome: A rare case report.

Multiple system atrophy (MSA) is a rare form of adult-onset α-synucleinopathy. Meige syndrome, identified as bilateral blepharospasm and oromandibular dystonia, is a type of focal dystonic movement disorder. This case report aims to highlight the clinical features of multiple system atrophy associated with Meige syndrome in a patient. Additionally, we aim to provide the treatment experience in a patient with Meige syndrome as this is an extremely rare clinical case.

Novel IKZF3 transcriptomic signature correlates with positive outcomes of skin cutaneous melanoma: A pan-cancer analysis.

To investigate the potential relationship between Ikaros family genes and skin cutaneous melanoma (SKCM), we undertook a pan-cancer analysis of the transcriptional signature and clinical data of melanoma through multiple databases. First, 10,327 transcriptomic samples from different cancers were included to determine the overall characteristics and clinical prognoses associated with Ikaros gene expression across cancer types. Second, differentially expressed genes analysis, prognostic evaluation, and gene set enrichment analysis were employed to investigate the role of Ikaros (IKZF) genes in SKCM. Third, we evaluated the relationship between Ikaros family genes and SKCM immune infiltrates and verified the findings using the GEO single-cell sequencing dataset. The results show that Ikaros genes were widely expressed among different cancer types with independently similar patterns as follows: 1. IKZF1 and IKZF3, and 2. IKZF2 and IKZF4-5. IKZF2 and IKZF5 were downregulated in the primary tumor, and IKZF1-3 expression decreased significantly as the T-stage or metastasis increased in SKCM. Moreover, high IKZF1-3 expression was associated with better overall survival, disease-specific survival, and progression-free interval. IKZF3 is an independent prognostic factor of SKCM. Among Ikaros genes, the expression of IKZF1 and IKZF3 positively correlated with the infiltration level of CD4+ T cells and CD8+ T cells, B cells, and Tregs in SKCM and negatively correlated with the infiltration level of M0 and M1 macrophages. Moreover, single-cell sequencing data analysis revealed that IKZF1 and IKZF3 were mainly expressed by immune cells. Correlation analysis shows the immune factors and drug responses associated with IKZF3 expression. In conclusion, the present study is the first, to our knowledge, to identify a pan-cancer genomic signature of the Ikaros gene family among different cancers. Expression of these family members, particularly high levels of IKZF3, indicate positive immunological status and beneficial clinical outcomes of SKCM. IKZF3 may therefore serve as potential targets for immunotherapy of melanoma.

Identification of Metastasis-Associated Genes in Cutaneous Squamous Cell Carcinoma Based on Bioinformatics Analysis and Experimental Validation.

INTRODUCTION: Cutaneous squamous cell carcinoma (cSCC) is a global malignant tumor with a high degree of malignancy. Once metastasis occurs, it will lead to poor prognosis and even death. This study attempts to find out the central genes closely related to cSCC metastasis, so as to clarify the molecular regulatory mechanism of cSCC metastasis and open up new ideas for clinical treatment. METHODS: Firstly, cSCC data set GSE98767 was used to establish a tumor metastasis model via clustering analysis. The key module and hub genes associated with cSCC metastasis were analyzed by weighted gene co-expression analysis (WGCNA). Next, the prognostic functions of hub genes were identified by functional and pathway enrichment analysis, pan-cancer analysis, and receiver operating characteristic-area under the curve (ROC-AUC) validation. Finally, the key genes were verified by clinical sample detection and biological in vitro test. RESULTS: A total of 19 hub genes related to cSCC metastasis were identified. They were highly expressed in cSCC metastatic tissues and were mainly enriched in cellular material and energy metabolism pathways. Overall survival (OS) and disease-free survival (DFS) results from pan-cancer analysis showed that eight and six highly expressed genes, respectively, with PAPSS2 and SCG5 had highly reliable ROC-AUC validation values and were poor prognostic factors. Clinical and biological tests also confirmed the upregulation of PAPSS2 and SCG5 in cSCC. Deletion of PAPSS2 and SCG5 resulted in decreased viability, migration, and invasion of A-431 cells. CONCLUSION: PAPSS2 and SCG5 may be important factors for cSCC metastasis, and they are involved in the regulation of cSCC cell viability, migration, and invasion.

Efficacy of topical and systemic transplantation of mesenchymal stem cells in a rat model of diabetic ischemic wounds.

BACKGROUND: Mesenchymal stem cells (MSCs) exert positive effects in chronic wounds. However, critical parameters, such as the most effective administration routes, remain unclear. Accordingly, the purpose of this study was to compare the effects of topical and systemic transplantation MSCs on diabetic ischemic wound healing and explored the underlying mechanisms. METHOD: A diabetic ischemic wound model was created on the dorsal foot of type 2 diabetes mellitus (T2DM) rat. Bone marrow-derived mesenchymal stem cells (BM-MSCs) were administered via two routes: topical injection and intravenous (IV) infusion. Wound healing outcomes and blood glucose level were assessed dynamically. Meanwhile, blood flow recovery was evaluated in ischemic gastrocnemius muscles. The homing and transdifferentiation of mKate2-labeled BM-MSCs were assessed by fluorescence imaging and immunohistochemistry (IHC) analysis. RESULT: Both topical and systemic treatments had a positive effect on the diabetic ischemic wound showing a significant reduction in wound area at day 14. Histological results showed an increase in the length of epithelial edges, collagen content, microvessel density in the wound bed, and a higher expression of vascular endothelial growth factor (VEGF). Meanwhile, systemic administration can ameliorate hyperglycemia and improve the blood perfusion of the ischemic hindlimb. BM-MSCs administered systemically were found distributed in wounded tissue and transdifferentiated into endothelial cells. Furthermore, BM-MSCs stimulated angiogenesis at wound sites by downregulating phosphatase and tensin homolog (PTEN) and activation of AKT signaling pathway. CONCLUSIONS: The results demonstrated that both transplantation delivery method (topical and systemic) of BM-MSCs accelerated wound healing remarkably under pathological conditions. Nevertheless, systemic administration has the potential to ameliorate hyperglycemia and repair the damaged tissue.

Surgical treatment of foreign body embolus in the Middle cerebral artery secondary to neck injury.

Background: We report a case of a foreign body embolus to the middle cerebral artery and reviewed similar cases previously reported. Methods: A 30-year-old man was seen 72 days after a penetrating neck injury with a 1-month history of numbness in the left limb and impairment of the fine movement in the left hand. Radiological examination revealed a foreign body in the M2 portion of the right middle cerebral artery (MCA). The patient received arteriotomy and in situ suturing. Results: During the operation, we found a metallic foreign body at the bifurcation of the M2 upper trunk of the right MCA, narrowed distal blood vessels and thinned vessel walls. The foreign body was surrounded by granulation tissue. Both foreign body and granulation tissue were removed slowly followed by in situ suturing. Indocyanine green angiography confirmed arterial patency. Three days after the surgery, the patient developed numbness and weakness in the left arm, with a muscle strength of grade 4. Computed tomography showed partial infarction in the right temporal lobe. Then, antispasmodic drugs were used. Muscle strength recovered by 14 days after the operation. Conclusions: In the subacute stage, surgery can be conducted to remove intra-arterial foreign bodies along with their surrounding granulation tissue if computed tomography perfusion suggests a decreased blood flow reserve capacity.

Effects of superficial temporal artery-middle cerebral artery bypass on hemodynamics and clinical outcomes in the patients with atherosclerotic stenosis in the intracranial segment of internal carotid artery and middle cerebral artery.

OBJECTIVE: To observe the effects of superficial temporal artery-middle cerebral artery bypass (STA-MCA bypass) on hemodynamics and clinical outcomes in the patients with atherosclerotic stenosis in the intracranial segment of internal carotid artery and (or) middle cerebral artery. PATIENTS AND METHODS: The data of 63 patients who had the symptoms of cerebral ischemia in recent 3 months, intracranial segment of internal carotid artery (ISICA) and (or) middle cerebral artery (MCA) stenoses or occlusion showed by digital subtraction angiography (DSA), and reduced cerebral perfusion displayed by CT perfusion (CTP) imaging were retrospectively collected in this study. According to the patient's choice of different treatment methods (STA-MCA bypass and drugs), these patients were allocated into two groups: Bypass group (30 cases) and Drug group (33 cases). Postoperative symptoms, anastomotic patency and hemodynamics were observed in the Bypass group. Post-treatment ischemic events and clinical outcomes were recorded in the two groups and were compared between the two groups. RESULTS: In the Bypass group, DSA all showed anastomotic patency in 28 patients (93.3%, 28/30), and the improvement rate of CTP was all significantly higher in the patients with stage-III CTP than in the patients with stage-II CTP at post-operative 3 days and 6 months (95% vs 60%). Post-treatment ischemic event incidence (13.3% vs 48.5%) and annual stroke rate (6.7% vs 25.6%) were significantly lower in the Bypass group than in the Drug group (All P < 0.05). Pre-treatment National Institutes of Health Stroke Scale (NIHSS) score and Modified Rankin Scale (MRS) score were not significantly different between the two groups, but the NIHSS (2.87±0.19 and 2.4±0.19 vs 4.03±0.47 and 3.97±0.49) and MRS (1.13±0.09 and 1.0±0.07 vs 1.55±0.14 and 1.52±0.15) all were significantly lower in the Bypass group than in the Drug group at post-treatment 6 and 24 months (all P < 0.05). CONCLUSION: STA-MCA bypass can improve cerebral blood perfusion and reduce the incidence of stroke in the patients who have ISICA and (or) MCA-related symptoms, 70%-100% of stenosis, and above stage-ⅠCTP. However, this conclusion remains to be further confirmed.

[Comparison of efficacy and safety between two kinds of injection therapy in the treatment of I-II degree rectal prolapse].

OBJECTIVE: To explore the safety and efficacy of Shaobei injection in the management of I(-II( degree rectal prolapse. METHODS: A total of 80 patients eligible for the inclusion criteria were divided into 2 groups: 40 patients in the treatment group (treated with Shaobei injection) and 40 cases in the control group (treated with Xiaozhiling) respectively. The short-term efficacy was identified by the length of rectal prolapse and the depth of rectocele demonstrated by the defecography while the long-term efficacy was evaluated by the length of rectal prolapse. In addition, the safety was assessed by the occurrence of postoperative complications. RESULTS: The variation of the lengths of rectal prolapse and the depth of rectocele demonstrated by the defecography at the sixth month follow up in the two groups did not reach significant difference (P>0.05). After 2 year follow up, 37 patients (92.5%) in the treatment group and 35 cases(87.5%) in the control group was cured. Therefore, there was no significant difference in the long term efficacy between the two groups (P>0.05). The adverse events in the therapy group(10%) was less than that in the control group (45%)(P<0.01). CONCLUSIONS: Shaobei injection in the management of I(-II( degree rectal prolapse has a similar efficacy of short-term and long-term higher safety compared to Xiaozhiling injection.