X-Paste improves wound healing in diabetes via NF-E2-related factor/HO-1 signaling pathway.

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.

Overall Survival of Primary Single Intracranial Atypical Meningioma with Different Surgical and Postoperative Treatment Options: Evidence from the SEER Database.

Objective: The aim of this study is to evaluate the impact of different surgical and postoperative treatment options on the long-term overall survival (OS) in patients with primary single intracranial atypical meningioma. Methods: In this retrospective study, participants were drawn from the Surveillance, Epidemiology, and End Results (SEER) database. Inclusion criteria comprised patients who underwent either gross total resection (GTR) or subtotal resection (STR). The inverse probability weighting (IPW) method using generalized boosted models was used to achieve balance in variables across various treatment groups. Subsequent to IPW, multivariate Cox analysis and Kaplan-Meier analysis were conducted, with OS as the endpoint. Results: GTR was conducted on 1650 patients, while STR was conducted on 1109 patients. Among these, 432 patients who underwent GTR and 401 patients who underwent STR received postoperative radiotherapy (PORT). In the case of patients who were under 60 years old, PORT emerged as a significant protective factor for OS in those who underwent STR (HR 0.44; 95% CI 0.23-0.84; p = 0.013). Survival curves demonstrated that patients who underwent STR with PORT exhibited comparable OS to those who underwent GTR without PORT (p = 0.546). Conversely, for patients aged 60 years or older, PORT emerged as an independent risk factor for both GTR (HR 1.42; 95% CI 1.00-2.00; p = 0.048) and STR (HR 1.81; 95% CI 1.26-2.60; p = 0.001). Conclusion: PORT may contribute to improving OS in primary single atypical meningioma patients under 60 years old who receive STR. However, in older patients who underwent either GTR or STR, the administration of PORT may be associated with a potential risk of OS. Therefore, age should be taken into account in applying PORT therapy, and the optimal treatment strategy for PORT in patients with atypical meningiomas needs to be further explored and validated.

Rethinking the effects of adjuvant beam radiation therapy on overall survival in atypical meningioma patients: age considerations.

Background: This study aimed to investigate the effects of adjuvant beam radiation therapy (ABRT) on overall survival (OS) in patients with primary single intracranial atypical meningioma (AM), with a focus on age-related outcomes. Methods: We conducted a retrospective study using data from SEER database. Our cohort consisted of patients diagnosed with a primary single intracranial AM tumor and had undergone surgery. The primary endpoint was OS. For survival analysis, univariable and multivariable Cox regression analysis were performed. A multivariable additive Cox model was used to assess the functional relationship between age and OS in patients with or without ABRT. Results: Of the 2,759 patients included, 1,650 underwent gross total resection and 833 received ABRT. Multivariable Cox analysis indicated that ABRT did not significantly influence OS across the entire cohort. According to the multivariable generalized additive Cox model, the relative risk of all-cause mortality increased with advancing age in both ABRT-yes and ABRT-no group. ABRT-yes had a lower relative risk than ABRT-no when age ≤ 55 years old while a higher relative risk when age > 55 years old. Subsequent multivariable Cox analysis showed that ABRT was associated with a significant lower risk for all-cause mortality in patients with age ≤ 55 years old while a significant higher risk in patients with age > 55 years old. Conclusion: Our study found that ABRT enhanced OS in younger primary single intracranial AM patients. But we also revealed a negative correlation between OS and ABRT in older patients.

Comprehensive analysis of histone acetylation-related genes in glioblastoma and lower-grade gliomas: Insights into drug sensitivity, molecular subtypes, immune infiltration, and prognosis.

OBJECTIVES: The purpose of this research was to study the impact of histone acetylation on glioblastoma multiforme (GBM) and lower-grade gliomas (LGG) and its potential implications for patient prognosis. We aimed to assess the histone acetylation score (HAs) and its relationship with key genes involved in histone acetylation regulation. METHOD: The TCGA-GBMLGG dataset, which provides comprehensive genomic and clinical information, was utilized for this study. We calculated the HAs by analyzing the expression levels of histone acetylation-related genes, including histone acetyltransferases and histone deacetylases, in GBM and LGG patients. Kaplan-Meier survival analysis was performed to evaluate the prognostic value of the HAs. Furthermore, correlation analysis and differential expression analysis were conducted to assess the relationship between the HAs and key genes involved in histone acetylation regulation, as well as the expression differences of immune checkpoint genes. RESULTS: Our analysis revealed a significant association between the HAs and patient prognosis, with higher HAs correlating to poorer outcomes in GBM and LGG patients. We observed a positive correlation between the HAs and key genes involved in histone acetylation regulation, indicating their potential role in modulating histone acetylation levels. Moreover, we found significant expression differences for immune checkpoint genes between high and low HAs groups, suggesting a potential impact of histone acetylation on the immune response in GBM and LGG. CONCLUSION: This study highlights the significance of histone acetylation in GBM and LGG. The HAs demonstrated prognostic value, indicating its potential as a clinically relevant biomarker. The correlation between the HAs and key genes involved in histone acetylation regulation provides insights into the underlying mechanisms driving histone acetylation dysregulation in GBM and LGG. Furthermore, the observed expression differences of immune checkpoint genes suggest a potential link between histone acetylation and the immune response. These findings contribute to our understanding of the molecular basis of GBM and LGG and have implications for personalized treatment approaches targeting histone acetylation and the immune microenvironment. Further validation and functional studies are needed to confirm these findings and explore potential therapeutic strategies.

A study on molecular mechanism of Xihuang pill in the treatment of glioblastoma based on network pharmacology and validation in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Xihuang pill has been utilized to treat cancer for more than three hundred years in China. The molecular mechanisms of Xihuang pill in treating glioblastoma remains unclear. AIM OF THE STUDY: This study aimed to explore the core molecular mechanisms of Xihuang pill in treating glioblastoma by an integrative pharmacology-based investigation. MATERIALS AND METHODS: The main active compounds of Xihuang pill were identified from TCMSP, BATMAN-TCM, TCMID and CNKI. Glioblastoma-related therapeutic targets were retrieved from GeneCards and UniProt. Subsequently, a protein-protein interaction (PPI) network analysis was constructed using STRING. GO and KEGG enrichment were performed to analyze the intersection targets between the active compounds of Xihuang pill and glioblastoma. Based on the above analysis, we built a CTP network. The in vitro and in vivo experiments were further performed to validate the crucial molecular targets of Xihuang pill for the treatment of glioblastoma. RESULTS: A total of sixty active compounds of Xihuang pill and ten potential targets related to glioblastoma were found. Based on topological analysis, fourteen ingredients were selected as the main active compounds, and MY11 might be the most important metabolite in Xihuang pill. PI3K/Akt signaling pathway and receptor tyrosine kinases were considered as crucial targets for Xihuang pill against glioblastoma through KEGG enrichment and CTP analysis. The present experiments indicated that Xihuang pill suppressed the activation of PI3K/Akt/mTOR signaling pathway in glioblastoma cells and mouse xenografts via modulating the expression of PTEN and Rheb proteins, the interaction between TSC2 and Rheb, and the production of PIP3. Meanwhile, after glioblastoma cells treatment with Xihuang pil, the release of IL-1ß, INF-γ was increased and the production of IL-10, TGF-ß1 was decreased in glioblastoma cells after incubated with Xihuang pill. In addition, the activation of the upstream positive modulators of PI3K/Akt/mTOR pathway including PDGF/PDGFR and FGF/FGFR signaling were down-regulated in glioblastoma cells and mouse xenografts after treatment with Xihuang pill. CONCLUSION: Taken together, Xihuang pill inhibiting glioblastoma cell growth might be partly through down-regulating the activation of PDGF/PDGFR or FGF/FGFR-PI3K/Akt/mTOR signaling axis and improving immuno-suppressive micro-environment of glioblastoma.

Downregulation of Preso protects against ischemic/reperfusion-mediated neuronal injury through regulating PSD95-nNOS/YAP pathways.

Cerebral ischemic/reperfusion (I/R) injury has become a great challenge harming patients' life. This study aims to explore the regulatory role of Preso during cerebral I/R injury and to elucidate the potential mechanism. Here, we established a middle cerebral artery occlusion/reperfusion (MCAO/IR) rat model and an oxygen-glucose deprivation/reoxygenation (OGD/R)-mediated PC12 cell model to evaluate the expression and role of Preso following cerebral I/R injury. Histopathological injury and infarct size were assessed by hematoxylin and eosin (HE) and 2,3,5-Triphenyltertrazolium chloride (TTC) staining. Double immunofluorescence staining was performed to assess neuronal apoptosis in brain tissues. Cell counting kit-8 (CCK-8) and flow cytometry were performed to evaluate cell viability and apoptosis, respectively. The reactive oxygen species (ROS) and nitric oxide (NO) levels were detected using their respective detection kits, and the expression of corresponding proteins was examined adopting Western blot. The results showed that Preso was upregulated in OGD/R-induced PC12 cells and MCAO rats. Preso knockdown significantly reduced OGD/R-caused viability loss, apoptosis and oxidative stress in PC12 cells, and reduced infarct size, attenuated histological injury, and inhibited apoptosis and oxidative stress in the brain tissues from MCAO rats, as well as inhibiting the expression of postsynaptic density protein-95 (PSD95) and nitric oxide synthase (nNOS) and repressing YAP phosphorylation in vitro. In addition, the protective role of Preso knockdown against cerebral I/R injury was partly strengthened by IC87201, the nNOS/PSD95 interaction inhibitor, or weakened by Verteporfin (Vert), an inhibitor of YAP. In conclusion, Perso knockdown might exert a protective role against cerebral I/R injury via regulating PSD95-nNOS and YAP pathways, providing a potential therapeutic target for the treatment of ischemic stroke.

Human umbilical cord mesenchymal stem cell treatment alleviates symptoms in an atopic dermatitis-like mouse model.

BACKGROUND: Atopic dermatitis (AD) is one of the most common immune and inflammatory skin disorders, leading to insufferable itching and skin abnormalities that seriously affect life quality of patients. There are still huge unmet needs for long-term and effective disease control, despite currently available therapies. Evidenced by some preclinical and clinical studies of AD treatment with stem cells, stem cell treatment could significantly and effectively ameliorate AD symptoms. OBJECTIVES: To elucidate underlying mechanisms of how stem cells therapy alleviates AD-like symptoms. METHODS: An AD-like mouse model was constructed and treated with mesenchymal stem cells (MSCs) subcutaneously or subcutaneously combined with intravenously. The differentially expressed genes were sorted out from RNA sequencing results of dorsal skin and blood. RESULTS: Two injection routes of MSCs could alleviate AD-like symptoms and pathologic changes of the skin and immune organs. RNA sequencing of dorsal skin sections and blood provided gene expression signatures for amelioration of skin defects, inflammatory and immune modulation by MSCs, as well as common AD molecular markers for the skin and blood, which may benefit for clinical diagnosis. IL-1ß and its signaling pathway were specifically found to be associated with the development of AD-like dermatitis lesions. MSC treatment effectively inhibited the JAK-STAT pathway and receptors of IL-4, IL-13, IL-17, and IgE. CONCLUSIONS: MSC therapy could regulate abnormal immune and inflammatory status in AD. Mechanistic exploration will contribute to the development of personalized AD treatment based on MSCs.

Xihuang pill in the treatment of cancer: TCM theories, pharmacological activities, chemical compounds and clinical applications.

ETHNOPHARMACOLOGICAL RELEVANCE: Xihuang pill as a famous traditional Chinese formula has long been used as an adjuvant therapy for cancer. AIM OF THE STUDY: This study is aimed at summarizing recent advances in research of Xihuang pill's anti-cancer efficacies from the theoretical basis of traditional Chinese medicine, pharmacological activities, chemical components and its clinical application. MATERIALS AND METHODS: The literature information was obtained from several authoritative databases including PubMed, Embase, Cochrane Library, CNKI and Wan Fang before April 30, 2023. We also analyzed the representatively chemical compounds of Xihuang pill in vivo experiments using HPLC-Q/TOF-MS. RESULTS: The present study indicated that Xihuang pill, a classic anti-tumor prescription, had efficacies of strengthening body resistance, clearing heat and detoxification, and promoting blood circulation for removing blood stasis. Modern basic researches showed that Xihuang pill played anti-cancer roles through inducing cancer cell apoptosis, inhibiting cell proliferation, migration, invasion and angiogenesis, improving immune function and tumor microenvironment, and regulating related signaling pathways. Its chemical components are primarily consisted of amino acids, terpenoids, fatty acids, fatty acid esters, phenolics, bile acids, bile pigments and volatile oil. Clinically, Xihuang pill, as an adjuvant drug for cancer treatment, was mostly combined with chemotherapy, which could prolong survival, enhance response rate, improve patients' life quality, regulate immune function and alleviate chemotherapy-induced toxicities. CONCLUSIONS: This present study suggests that Xihuang pill may be a promising adjuvant therapy for cancer, and proposes the possibility of future research directions for Xihuang pill based on the current research status.

RNA sequencing and metabolic analysis of imiquimod-induced psoriasis-like mice with chronic restrain stress.

AIM: Psoriasis is one of the most common dermatological disorders, characterized by increased epidermal hyperplasia and immune cell infiltration. Psychological stress has been reported to contribute to the severity, aggravation, and relapse of psoriasis. However, the exact mechanism involved in psychological stress's impact on psoriasis is still unclear. We aim to investigate the role of psychological stress in psoriasis from a transcriptomic and metabolomic perspective. MAIN METHOD: We developed a chronic restrain stress (CRS)-imiquimod (IMQ)-induced psoriasis-like mouse model and performed a comprehensive comparative transcriptomic and metabolic analysis with control mice, CRS-treated mice, and IMQ-treated mice to investigate how psychological stress affects psoriasis. KEY FINDING: We found that CRS-IMQ-induced psoriasis-like mice showed significant exacerbation of psoriasis-like skin inflammation compared with mice treated with IMQ only. Mice of the CRS + IMQ group showed increased expression of keratinocyte proliferation and differentiation genes, differential regulation of cytokines, and promotion of linoleic acid metabolism. Correlation analysis of differentially expressed genes in the CRS-IMQ-induced psoriasis-like mice and human psoriasis datasets compared with respective controls revealed 96 overlapping genes of which 30 genes showed consistent induced or repressed expression in all human and mouse datasets. SIGNIFICANCE: Our study provides new insights into the effects of psychological stress on psoriasis pathogenesis and the mechanisms involved, which provides clues for development of therapeutics or biomarkers.

Succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant Aspergillus fumigatus infection.

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.

Low-coverage and cost-effective whole-genome sequencing assay for glioma risk stratification.

PURPOSE: To investigate chromosomal instability (CIN) as a biomarker for glioma risk stratifications, with cost-effective, low-coverage whole-genome sequencing assay (WGS). METHODS: Thirty-five formalin-fixed paraffin-embedded glioma samples were collected from Huashan Hospital. DNA was sent for WGS by Illumina X10 at low (median) genome coverage of 1.86x (range: 1.03-3.17×), followed by copy number analyses, using a customized bioinformatics workflow-Ultrasensitive Copy number Aberration Detector. RESULTS: Among the 35 glioma patients, 12 were grade IV, 10 grade III, 11 grade II, and 2 Grade I cases, with high chromosomal instability (CIN +) in 24 (68.6%) of the glioma patients. The other 11 (31.4%) had lower chromosomal instability (CIN-). CIN significantly correlates with overall survival (P = 0.00029). Patients with CIN + /7p11.2 + (12 grade IV and 3 grade III) had the worst survival ratio (hazard ratio:16.2, 95% CI:6.3-41.6) with a median overall survival of 24 months. Ten (66.7%) patients died during the first two follow-up years. In the CIN + patients without 7p11.2 + (6 grade III, 3 grade II), 3 (33.3%) patients died during follow-up, and the estimated overall survival was around 65 months. No deaths were reported in the 11 CIN- patients (2 grade I, 8 grade II, 1 grade III) during the 80-month follow-up period. In this study, chromosomal instability served as a prognosis factor for gliomas independent of tumor grades. CONCLUSION: It is feasible to use cost-effective, low-coverage WGS for risk stratification of glioma. Elevated chromosomal instability is associated with poor prognosis.

TREM2 as a Potential Immune-Related Biomarker of Prognosis in Patients with Skin Cutaneous Melanoma Microenvironment.

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.

Integrated transcriptomic and metabolomic analyses of DNCB-induced atopic dermatitis in mice.

AIMS: Atopic dermatitis (AD) is a common chronic inflammatory skin disorder that affects up to 20 % of children and 10 % of adults worldwide; however, the exact molecular mechanisms remain largely unknown. MATERIALS AND METHODS: In this study, we used integrated transcriptomic and metabolomic analyses to study the potential mechanisms of 1-chloro-2,4-dinitrobenzene (DNCB)-induced AD-like skin lesions. KEY FINDINGS: We found that DNCB induced AD-like skin lesions, including phenotypical and histomorphological alterations and transcriptional and metabolic alterations in mice. A total of 3413 differentially expressed metabolites were detected between DNCB-induced AD-like mice and healthy controls, which includes metabolites in taurine and hypotaurine metabolism, phenylalanine metabolism, biosynthesis of unsaturated fatty acids, tryptophan metabolism, arachidonic acid metabolism, pantothenate and CoA biosynthesis, pyrimidine metabolism, and glycerophospholipid metabolism pathways. Furthermore, the differentially expressed genes associated (DEGs) with these metabolic pathways were analyzed using RNA sequencing (RNA-seq), and we found that the expression of pyrimidine metabolism-associated genes was significantly increased. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the glycolysis/gluconeogenesis, glucagon signaling pathway and pentose phosphate pathway-associated metabolic genes were dramatically altered. SIGNIFICANCE: Our results explain the possible mechanism of AD at the gene and metabolite levels and provide potential targets for the development of clinical drugs for AD.

Guggulsterone from Commiphora mukul potentiates anti-glioblastoma efficacy of temozolomide in vitro and in vivo via down-regulating EGFR/PI3K/Akt signaling and NF-κB activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Myrrh is an aromatic oleo-gum resin extracted from the stem of Commiphora myrrha (Nees) Engl., and has the efficacies to promote blood circulation and remove blood stasis. Myrrh is mainly used for the treatment of chronic diseases including cancer. Guggulsterone, a major active steroid extracted from myrrh, has been found to inhibit cancer cell growth. Glioblastoma is the most common malignancy of central nervous system, and its prognosis remains very poor mainly due to chemotherapeutic resistance. The active status of EGFR/PI3K/Akt and NF-κB signaling in glioblastoma contributed to poor response for chemotherapy, and blocking this signaling with antagonists sensitized glioblastoma cells to chemotherapy. AIM OF THE STUDY: The present study will investigate whether guggulsterone potentiates the anti-glioblastoma efficacy of temozolomide by down-regulating EGFR/PI3K/Akt signaling and NF-κB activation. MATERIALS AND METHODS: Cell viability and proliferation was determined by cell counting Kit-8 and colony formation assays. Cell apoptosis was evaluated by Annexin V/PI and hoechst 33342 staining assays. Molecular techniques such as western blotting and real-time quantitative PCR were used to demonstrate guggulsterone in vitro effect on EGFR/PI3K/Akt signaling and NF-κB activation. Finally, in vivo studies were performed in orthotopic mouse models of glioblastoma. RESULTS: The results demonstrated that guggulsterone enhanced temozolomide-induced growth inhibition and apoptosis in human glioblastoma U251 and U87 cells. Furthermore, the synergistic anti-glioblastoma efficacy between guggulsterone and temozolomide was intimately associated with the inhibition of EGFR/PI3K/Akt signaling and NF-κB activation in U251 and U87 cells. Our in vivo results on orthotopic xenograft models similarly indicated that guggulsterone potentiated temozolomide-induced tumor growth inhibition through suppressing EGFR/PI3K/Akt signaling pathway and NF-кB activity. CONCLUSIONS: The present study suggested that guggulsterone potentiated anti-glioblastoma efficacy of temozolomide through down-regulating EGFR/PI3K/Akt signaling pathway and NF-кB activation.

Analysis of influencing factors for multidrug-resistant pulmonary tuberculosis in Hainan Province from 2014 to 2020 / 中国热带医学

@#Abstract: Objective To investigate the occurrence of multidrug-resistance among tuberculosis patients in Hainan Province from 2014 to 2020 and to analyze the influencing factors, aiming to provide reference for formulating drug-resistant tuberculosis control strategies in this region. Methods This study collected sputum samples from the patients with pulmonary tuberculosis admitted to the Second Affiliated Hospital of Hainan Medical University from 2014 to 2020, and performed isolation and identification of Mycobacterium tuberculosis and drug susceptibility testing. After the strains were identified as positive, drug sensitivity tests were conducted, and multi-drug resistant patients were found. Clinical data was retrospectively collected, and chi-square test and unconditioned logistic regression were used to analyze the influencing factors of multidrug resistance. Results A total of 2 672 patients underwent sputum culture, strain identification, and drug susceptibility testing in TB designated hospitals in Hainan Province from January 1, 2014 to December 31, 2020. Among them, 1 942 patients with available drug susceptibility test results and complete clinical data were enrolled, among which 398 cases with drug-resistant TB were included in the case group, and 1 544 cases without drug resistance were included in the control group. Multivariate logistic regression analysis showed that farmers, rural residence, treatment history of retreatment, irregular medication history, number of pulmonary cavities ≥3, and BMI<18.5 were independent risk factors for MDR-TB. The risk of MDR-TB in farmers was higher than that in non-farmers (OR=1.542, 95%CI: 1.150-2.020); patients living in rural areas had a higher risk of multidrug resistance than those living in urban areas (OR=1.445, 95%CI: 1.095-1.907); the risk of MDR in the retreatment patients was higher than that in the initial treatment patients (OR=5.616, 95%CI: 4.250-7.421); the risk of multi-drug resistance in patients with irregular medication was higher than that in patients with regular medication (OR=2.665, 95%CI: 2.012-3.531); the risk of multidrug resistance in patients with pulmonary cavity number ≥3 was higher than that in patients with pulmonary cavity number <3 (OR=5.040, 95%CI: 3.768-6.740); compared with patients with BMI<18.5, patients with BMI=18.5-24.0 and BMI≥24.0 had a lower risk of multidrug resistance (OR=0.735, 95%CI: 0.555-0.975 and OR=0.447，95%CI:0.225-0.888, respectively). Conclusions Retreatment, farmer occupation, rural residence, irregular medication and low BMI may be the risk factors for multidrug resistance in Hainan Province.

TRAF3IP3 promotes glioma progression through the ERK signaling pathway.

TRAF3IP3 was reportedly associated with poor prognosis in patients with melanoma; however, its role in glioma is unknown. We aimed to demonstrate the relationship between TRAF3IP3 and glioma and to investigate the potential role of TRAF3IP3 in glioma. Datasets were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We used the Wilcoxon rank-sum test to compared TRAF3IP3 expression in normal and glioma tissues. Kaplan-Meier analysis was performed to evaluate the correlation between TRAF3IP3 and patient survival rate. Gene set enrichment analysis (GSEA) was used to annotate the biological function of TRAF3IP3 in glioma. We also examined the effects of TRAF3IP3 on glioma progression, including characteristics such as cell proliferation, migration, and invasion, using cell proliferation, wound healing, and Transwell assays, respectively, paired with in vitro glioma cell lines and in vivo mouse xenograft models to determine the molecular mechanisms underlying these effects. High TRAF3IP3 expression in glioma tissues was associated with patients with neoplasm cancer tissue source site, and poorer overall survival (OS) (p = 0.03), which was validated using TCGA. GSEA revealed the enrichment of neuroactive ligand-receptor interactions, the olfactory pathway, proteasome pathway, cytokine-cytokine receptor interactions, and calcium signaling pathway in the TRAF3IP3 high-expression phenotype. TRAF3IP3 knockdown markedly suppressed the proliferation, migration, and invasion abilities of U251 glioma cells, whereas TRAF3IP3 overexpression notably promoted the progression of U118 cell tumors. Mechanistic studies revealed that TRAF3IP3 upregulated p-ERK expression in glioma cells. Notably, the ERK signaling pathway inhibitor U0126 drastically attenuated the effects of TRAF3IP3 on p-ERK and markedly blocked its tumor-promoting activity. TRAF3IP3 overexpression also promoted in vivo tumor growth in a nude mouse xenograft model. Collectively, TRAF3IP3 stimulates glioma cell proliferation, migration, and invasion, at least partly by activating the ERK signaling pathway. We hypothesize that TRAF3IP3 may participate in glioma development via the ERK signaling pathway and that elevated TRAF3IP3 expression may serve as a potential biomarker for glioma prognosis.

Corrigendum: The risk of heart disease-related death among anaplastic astrocytoma patients after chemotherapy: A SEER population-based analysis.

[This corrects the article DOI: 10.3389/fonc.2022.870843.].

Establishment of an induced pluripotent stem cell line (ZJULLi004-A) from a hypertrophic cardiomyopathy patient carrying MYBPC3/c.3764C>A mutation.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disease characterized by left ventricular hypertrophy and a high risk of sudden death. In this study, a skin biopsy was obtained from a HCM patient harboring a heterozygous missense mutation (c.3764C>A; p.A1225D) in the myosin binding protein C3 (MYBPC3) gene. The isolated fibroblasts were reprogrammed using non-integrated Sendai viral method to establish the patient-specific induced pluripotent stem cell (iPSC) line. The established iPSC line displayed normal morphology and karyotype, expressed pluripotency markers, and can differentiate into three germ layers in vivo.

Is intervertebral disc degeneration associated with reduction in serum ferritin?

OBJECTIVE: Ferritin autophagy is characterized by intracellular ferroptosis and selective ferritin degradation. However, the role of ferritin in the development of intervertebral disc degeneration (IDD) has not been elucidated. The study aimed to investigate the role of serum iron metabolism markers, especially serum ferritin (SF), in IDD. METHODS: 217 patients who came to the spine surgery department of our hospital for low back pain were recruited, and blood samples were collected for routine examination after admission. The cumulative grade was also calculated by summing up the Pfirrmann grade of all lumbar discs. RESULTS: Correlation analysis showed that cumulative grade was correlated with SF (r = - 0.185, p = 0.006), not with serum iron (SI), transferrin saturation (TS), unsaturated iron-binding capacity (UIBC) and total iron-binding capacity (TIBC) (all p > 0.05). In addition, SF levels in the low severity IDD were significantly higher than high severity IDD in cumulative grade (p = 0.003) and single disc grade. No statistically significant difference was found in the other four indicators. A statistically significant difference was observed between the high (cumulative grade > 17) and low score (cumulative grade ≤ 17) groups in terms of age. According to the ROC curve, the cut-off value of SF levels was 170.5. Patients with SF < 170.5 ng/mL had severe disc degeneration. The sensitivity and specificity were 0.635 and 0.602, respectively. CONCLUSION: This study preliminarily showed that SF was negatively correlated with the degree of IDD and can be used to predict IDD severity.

Generation of an induced pluripotent stem cell line (ZJULLi003-A) from a hypertrophic cardiomyopathy patient carrying MYH7/c.4384G > A mutation.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited cardiovascular disease characterized by left ventricular hypertrophy and cardiomyocyte disarray. In this study, a skin biopsy was obtained from a HCM patient, who carried a missense mutation (c.4384G > A; p.E1462K) in the myosin heavy chain 7 (MYH7) gene. The skin fibroblasts were subsequently reprogrammed with a non-integrated Sendai viral method to generate a patient-specific induced pluripotent stem cell (iPSC) line. The generated iPSC line showed typical morphology and normal karyotype, expressed pluripotency markers, and was capable to differentiate into three germ layers.