Endothelial dysfunction in vascular complications of diabetes: a comprehensive review of mechanisms and implications.

Diabetic vascular complications are prevalent and severe among diabetic patients, profoundly affecting both their quality of life and long-term prospects. These complications can be classified into macrovascular and microvascular complications. Under the impact of risk factors such as elevated blood glucose, blood pressure, and cholesterol lipids, the vascular endothelium undergoes endothelial dysfunction, characterized by increased inflammation and oxidative stress, decreased NO biosynthesis, endothelial-mesenchymal transition, senescence, and even cell death. These processes will ultimately lead to macrovascular and microvascular diseases, with macrovascular diseases mainly characterized by atherosclerosis (AS) and microvascular diseases mainly characterized by thickening of the basement membrane. It further indicates a primary contributor to the elevated morbidity and mortality observed in individuals with diabetes. In this review, we will delve into the intricate mechanisms that drive endothelial dysfunction during diabetes progression and its associated vascular complications. Furthermore, we will outline various pharmacotherapies targeting diabetic endothelial dysfunction in the hope of accelerating effective therapeutic drug discovery for early control of diabetes and its vascular complications.

Metformin improves nonalcoholic fatty liver disease in db/db mice by inhibiting ferroptosis.

Nonalcoholic fatty liver disease (NAFLD) is the primary complication of type 2 diabetes (T2DM)-related liver disease, lacking effective treatment options. Metformin (Met), a widely prescribed anti-hyperglycemic medication, has been found to protect against NAFLD. Ferroptosis, a newly discovered form of cell death, is associated with the development of NAFLD. Despite this association, the extent of Met's protective effects on NAFLD through the modulation of ferroptosis has yet to be thoroughly investigated. In the present study, the administration of erastin or Ras-selective lethal 3 (RSL3), both known ferroptosis inducers, resulted in elevated cell mortality and reduced cell viability in AML12 hepatocytes. Notably, Met treatment demonstrated the capacity to mitigate these effects. Furthermore, we observed increased ferroptosis levels in both AML12 hepatocytes treated with palmitate and oleate (PA/OA) and in the liver tissue of db/db mice. Met treatment demonstrated significant reductions in iron accumulation and lipid-related reactive oxygen species production, simultaneously elevating the glutathione/glutathione disulfide ratio in both PA/OA-treated AML12 hepatocytes and the liver tissue of db/db mice. Interestingly, the anti-ferroptosis effects of Met were significantly reversed with the administration of RSL3, both in vitro and in vivo. Mechanistically, Met treatment regulated the glutathione peroxidase 4/solute carrier family 7 member 11/acyl-CoA synthetase long-chain family member 4 axis to alleviate ferroptosis in NAFLD hepatocytes. Overall, our findings highlight the crucial role of ferroptosis in the development of T2DM-related NAFLD and underscore the potential of Met in modulating key factors associated with ferroptosis in the context of NAFLD.

The Research Progress in Transforming Growth Factor-ß2.

Transforming growth factor-beta 2 (TGF-ß2), an important member of the TGF-ß family, is a secreted protein that is involved in many biological processes, such as cell growth, proliferation, migration, and differentiation. TGF-ß2 had been thought to be functionally identical to TGF-ß1; however, an increasing number of recent studies uncovered the distinctive features of TGF-ß2 in terms of its expression, activation, and biological functions. Mice deficient in TGF-ß2 showed remarkable developmental abnormalities in multiple organs, especially the cardiovascular system. Dysregulation of TGF-ß2 signalling was associated with tumorigenesis, eye diseases, cardiovascular diseases, immune disorders, as well as motor system diseases. Here, we provide a comprehensive review of the research progress in TGF-ß2 to support further research on TGF-ß2.

Reduced platelet 5-HT content is associated with rest tremor in Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is highly heterogeneous in manifestations and pathogenesis. Serotonergic neurotransmitter system dysfunction is frequently implicated in PD tremor. Serotonin (5-HT) content in platelets is highly correlated with that in cerebrospinal fluid. In this study, we aimed to understand whether and how platelet 5-HT content reflects tremor in PD. METHOD: A total of 139 Chinese PD patients met with inclusion criteria were recruited. Motor and non-motor scores, and disease severity were evaluated. Patients were classified into subtypes of tremor-dominant (TD) and non-tremor-dominant (NTD). Peripheral platelets were isolated, and platelet 5-HT levels were measured. RESULTS: Platelet 5-HT content was lower in PD patients of TD subtype than in NTD subtype. Multifactor risk analysis showed that this lower content was independently associated with the TD phenotype. Platelet 5-HT level was inversely correlated with total tremor score, rest tremor amplitude score, rest tremor constancy score, and index of rest tremor, but not with postural tremor score, and kinetic tremor score. CONCLUSION: The cross-sectional study demonstrates that reduced platelet 5-HT content is associated with PD rest tremor. Our results support the involvement of serotonergic disturbance in PD rest tremor and indicate that 5-HT reduction can be manifested in peripheral platelets.

Metabolites from the plant endophytic fungus Penicillium sp. CPCC 401423 and their cytotoxic activity against MIA PaCa-2 cells.

Twenty-two metabolites were isolated from Penicillium sp. CPCC 401423 cultured on rice. The structures of all compounds were elucidated mainly by MS and NMR analysis as well as the necessary CD experimental evidence, of which penicillidione A (1), penicillidione B (2), (E)-4-[(4-acetoxy-3-methyl-2-butenyl)oxy]phenylacetic acid (3), (S)-2-hydroxy-2-{4-[(3-methyl-2-butenyl)oxy]phenyl} (4), (S)-4-(2,3-dihydroxy-3-methyl-butoxy)phenylacetic acid (5), (E)-4-[(3-carboxy-2-butenyl)oxy]benzoic acid (6), (Z)-4-[(4-hydroxy-3-methyl-2-butenyl)oxy]benzoic acid (7), open-cycled N-demethylmelearoride A (12), and penostatin M (16) were identified as new compounds. The cytotoxic activity against human pancreatic carcinoma cell line MIA PaCa-2a was detected. Among them, compounds 13-15 and 22 displayed significant cytotoxicity against MIA-PaCa-2 cells with IC50 values of 8.9, 36.5, 31.8, and 22.3 µM, respectively (positive control gemcitabine IC50 65.0 µM).

A Novel Systemic Inflammation Prognostic Score to Stratify Survival in Elderly Patients With Cancer.

Background: Elderly patients with cancer face the challenge of systemic inflammation, which can lead to a poor prognosis. Existing inflammatory indices cannot fully reflect the immune-inflammatory status of patients. This study aimed to develop a new scoring system to predict the survival of elderly patients with cancer using inflammatory indices, namely, the systemic inflammation prognostic score (SIPS). Materials and Methods: This prospective multicenter study included a total of 1,767 patients with cancer, with a mean age of 70.97 ± 5.49 years, of whom 1,170 (66.2%) were men. We performed the least absolute shrinkage and selection operator (LASSO) regression to screen inflammatory indicators to include in constructing SIPS. Prognostic analysis of SIPS was performed using univariate and multivariate survival analyzes. The prognostic value of SIPS and its components were compared using the prognostic receiver operating characteristic curve and concordance index. The population was divided into the training cohort and the validation cohort in a 7:3 ratio and a SIPS prognostic analysis was performed. Results: The LASSO regression selected C-reactive protein (CRP) (≤ 9.81, "0"; > 9.81, "1"), geriatric nutritional risk index (GNRI) (≤ 93.85, "1"; 93.85, "0"), advanced lung cancer inflammation index (ALI) (≤ 23.49, "1"; > 23.49, "0"), and lymphocyte to C-reactive protein ratio (LCR) (≤ 2523.81, "1"; > 2523.81, "0") to develop SIPS. Patients were divided into the three groups based on the total SIPS: low-risk (0), moderate-risk (1-2), and high-risk (3-4). On the multivariate survival analysis, patients in the moderate-risk [P < 0.001, hazard ratio (HR) = 1.79, 95% CI: 1.47-2.17] and high-risk groups (P < 0.001, HR = 2.40, 95% CI: 1.98-2.92) showed a worse prognosis than those in the low-risk group. The total cohort, training cohort, and validation cohort all showed that SIPS had better survival prediction than CRP, GNRI, ALI, and LCR. The HRs were 2.81 times higher in patients in the high-risk group with malnutrition than in patients in the low-risk group without malnutrition. Conclusion: SIPS was an independent prognostic indicator in elderly patients with cancer. Malnutrition in the high-risk group increased the mortality risk.

Mitochondria autophagy: a potential target for cancer therapy.

Mitophagy is a selective form of macroautophagy in which dysfunctional and damaged mitochondria can be efficiently degraded, removed and recycled through autophagy. Selective removal of damaged or fragmented mitochondria is critical to the functional integrity of the entire mitochondrial network and cells. In past decades, numerous studies have shown that mitophagy is involved in various diseases; however, since the dual role of mitophagy in tumour development, mitophagy role in tumour is controversial, and further elucidation is needed. That is, although mitophagy has been demonstrated to contribute to carcinogenesis, cell migration, ferroptosis inhibition, cancer stemness maintenance, tumour immune escape, drug resistance, etc. during cancer progression, many research also shows that to promote cancer cell death, mitophagy can be induced physiologically or pharmacologically to maintain normal cellular metabolism and prevent cell stress responses and genome damage by diminishing mitochondrial damage, thus suppressing tumour development accompanying these changes. Signalling pathway-specific molecular mechanisms are currently of great biological significance in the identification of potential therapeutic targets. Here, we review recent progress of molecular pathways mediating mitophagy including both canonical pathways (Parkin/PINK1- and FUNDC1-mediated mitophagy) and noncanonical pathways (FKBP8-, Nrf2-, and DRP1-mediated mitophagy); and the regulation of these pathways, and abovementioned pro-cancer and pro-death roles of mitophagy. Finally, we summarise the role of mitophagy in cancer therapy. Mitophagy can potentially be acted as the target for cancer therapy by promotion or inhibition.

Association Analyses of Autonomic Dysfunction and Sympathetic Skin Response in Motor Subtypes of Parkinson's Disease.

Introduction: Autonomic dysfunction is a common and disabling non-motor symptom of Parkinson's disease (PD). We aimed to understand autonomic dysfunction in PD motor subtypes, the pattern of sympathetic skin response (SSR) to motor asymmetry, and the association of SSR with autonomic and motor dysfunctions. Methods: A total of 101 PD patients of Han Chinese were included. Unified PD rating scale (UPDRS), scales for outcomes in PD-autonomic symptoms (SCOPA-AUT), orthostatic hypotension, and SSR were evaluated. Results: SCOPA-AUT and incidences of orthostatic hypotension and absent SSR were worse in the subtype of postural instability gait disorder (PIGD) than the subtypes of tremor dominant and intermediate. SSR latency and amplitude were asymmetrical corresponding to the accentuation of motor severity. Patients with absent SSR had worse UPDRS and SCOPA-AUT scores. SSR parameters of the severe side in patients with SSR showed no independent association with the scores. Conclusion: Our results support that autonomic dysfunction is more severe in the PIGD than other subtypes and demonstrate an asymmetry of SSR in PD patients. Absent SSR may indicate worse autonomic and motor symptoms, but SSR parameters are not sufficient to evaluate the severity of the dysfunctions.

The novel quinolizidine derivate IMB-HDC inhibits STAT5a phosphorylation at 694 and 780 and promotes DNA breakage and cell apoptosis via blocking STAT5a nuclear translocation.

Sophoridine is a quinolizidine natural product and the exploration of its derivatives has been carried out, and the potent anticancer compound IMB-HDC was acquired. Although previous studies have revealed that some sophoridine derivatives could induce DNA breakage, the underlying mechanisms of inhibition of DNA damage repair (ATR inactivation) and the apoptosis independent of p53, have not been elucidated. Our research reveals a novel DNA response mechanism different from general DNA-damaging agents, and that sophoridine derivate inhibits the phosphorylation of Tyr694 and Ser780 of STAT5a to induce the lessened shuttle from the cytoplasm to the nucleus, and leads to the decreased nuclear STAT5a and subsequently inhibits the expression of STAT5a target gene RAD51 that contributes to the checkpoint activation, thus inhibiting ATR activation. Meanwhile, IMB-HDC that induced the diminished expression of STAT5a target gene contributes to proliferation and leads to apoptosis. More importantly, we give the first evidence that promoting the effect of Tyr694 phosphorylation on nuclear location and subsequent STAT5a target gene transcription depends on Ser780 increased or unchanged phosphorylation and was not correlated with Ser726 phosphorylation.

Role of co- and post-translational modifications of SFKs in their kinase activation.

Src family kinases (SFKs) are non-receptor tyrosine kinases and are involved in various cellular functions (proliferation, differentiation, migration, survival and invasion) by regulating downstream pathways. Considerable evidence suggests that co- and post-translational modifications are highly related to the activation of SFKs and their downstream signals. How SFKs are activated and how their subsequent cascades were regulated has been reviewed in previous reports. However, the contribution of co- and post-translational modification to SFKs activation has not been fully elucidated. This review focuses on the effect of these modifications on SFKs activity according to structural and biochemical studies and uncovers the significance of co-and post-translational modifications in the regulation of SFKs activity.

Role and molecular mechanism of stem cells in colorectal cancer initiation.

In recent years, the rate of colorectal cancer has sharply increased, especially in China, where it ranks second for the number of cancer fatalities. Currently, the treatment of colorectal cancer patients involves the combination of resection surgery and treatment with postoperative anticancer drugs such as 5-FU and oxaliplatin. However, recurrence and metastasis after treatment are still the dominant reasons for the low survival rate. Colorectal cancer stem cells (CSCs) are regarded as the key contributors to tumour recurrence and metastasis due to their resistance to chemotherapy drugs and their extremely high tumourigenicity. Once CSCs overcome chemotherapy treatment, they continue to survive and reinitiate proliferation to form tumours, leading to recurrence. The dominant reason for CSC resistance is that most anticancer drugs are aimed at inhibiting proliferative pathways in cancer cells that differ from those in CSCs. Therefore, studies on the characteristics of CSCs and their intracellular molecular pathways are essential for the exploration of CSC-targeted drugs. In this report, we review recent advances in the research of CSCs and, in particular, review the important intracellular molecular pathways, such as HOXA5-catenin, STRAP-NOTCH and YAP/TAZ, related to the maintenance and differentiation of stem cells to generate a theoretical basis for the exploration of CSC-targeted drugs.

Pathogenesis, disease course, and prognosis of adult-onset Still's disease: an update and review.

OBJECTIVE: Adult-onset Still's disease (AOSD) is a rare but clinically well-known polygenic systemic autoinflammatory disease. In this review, we aim to present frontiers in the pathogenesis, clinical features, diagnosis, biomarkers, disease course, prognosis, and treatment in AOSD. DATA SOURCES: We retrieved information from the PubMed database up to July 2019, using various search terms and relevant words, including AOSD and Still's disease. STUDY SELECTION: We included data from peer-reviewed journals. Both basic and clinical studies were selected. RESULTS: Pathogenesis of AOSD involves genetic background, infectious triggers, and immunopathogenesis, mainly the activation of macrophages and neutrophils followed by a cytokine storm. Diagnosis and prognosis evaluation of AOSD is still challenging; therefore, there is an urgent need to identify better biomarkers. Biologic agents, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α antagonists in the treatment of AOSD, have good prospect. CONCLUSION: This review highlights the advances in pathogenesis, potential biomarkers, disease course, and treatment in AOSD.

A homozygous mutation of alanyl-transfer RNA synthetase 2 in a patient of adult-onset leukodystrophy: A case report and literature review.

INTRODUCTION: Leukodystrophy is a group of hereditary leukoencephalopathies predominantly affecting the white matter. Multiple genes and mutations have been reported to be associated with this disorder. Identification of pathogenic genes can facilitate diagnosis of leukodystrophy and development of therapeutic strategies. METHODS: A case was presented with clinical examinations. Exome sequencing was applied to identify potential mutations. Sanger sequencing of blood DNA was applied to confirm the mutation and to examine additional members. RESULTS: We reported a Chinese male patient of adult-onset leukodystrophy. Genetic examinations identified a homozygous mutation, c. 452T>C (p. M151T), in alanyl-tRNA synthetase 2 (AARS2) in the patient. The disease was autosomal recessive as suggested by the genotypic analyses of his family members. We also reviewed phenotypic spectra of AARS2 mutation-associated leukodystrophies from a total of 16 reported cases. CONCLUSIONS: Our data provide further evidence that mutations of AARS2 are implicated in adult-onset leukodystrophy.

[Autologous transplantation of bone marrow stem cells versus peripheral blood stem cells for treatment of decompensate liver cirrhosis: a comparative study of 30 cases].

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