Insights into the skin microbiome of sickle cell disease leg ulcers.

Leg ulcers are estimated to occur in 1%-10% of North American patients with sickle cell disease (SCD). Their pathophysiology remains poorly defined, but as with other chronic wounds, it is hypothesised that the microbial milieu, or microbiome, contributes to their healing and clinical outcomes. This study utilises 16S ribosomal RNA (rRNA) gene sequencing to describe, for the first time, the microbiome of the SCD leg ulcer and its association with clinical factors. In a cross-sectional analysis of 42 ulcers, we recovered microbial profiles similar to other chronic wounds in the predominance of anaerobic bacteria and opportunistic pathogens including Staphylococcus, Corynebacterium, and Finegoldia. Ulcers separated into two clusters: one defined by predominance of Staphylococcus and smaller surface area, and the other displaying a greater diversity of taxa and larger surface area. We also find that the relative abundance of Porphyromonas is negatively associated with haemoglobin levels, a key clinical severity indicator for SCD, and that Finegoldia relative abundance is negatively associated with CD19+ B cell count. Finally, ratios of Corynebacterium:Lactobacillus and Staphylococcus:Lactobacillus are elevated in the intact skin of individuals with a history of SCD leg ulcers, while the ratio of Lactobacillus:Bacillus is elevated in that of individuals without a history of ulcers. Investigations of the skin microbiome in relation to SCD ulcer pathophysiology can inform clinical guidelines for this poorly understood chronic wound, as well as enhance broader understanding about the role of the skin microbiome in delayed wound healing.

Colocating Wound Care for Patients with Sickle Cell Ulcers in a Hematology Clinic.

OBJECTIVE: Leg ulcers affect 15% of people with sickle cell disease. However, wound centers typically treat few people with this condition, which makes it difficult to concentrate clinical expertise or support the scientific study of this orphan disease. This article describes an initiative to increase engagement in care through a partnership between wound healing and hematology leadership that led to colocating wound services within a sickle cell clinic. METHODS: Via a retrospective chart review, the authors collected records of all adult patients with sickle cell disease who received wound care in the last decade, including 7 years of wound center data and 3 years of data from the colocated services. Patient and visit characteristics were analyzed using descriptive analytics. RESULTS: The general wound center had previously treated 35 patients with sickle cell ulcers over 7 years. In contrast, colocated services engaged 56 patients within 3 years, including 20 who transferred care and 36 new patients. The majority of patients at the colocated site were women, unlike at the wound center (58% vs 47%, P = .07). Results indicated that 36% of patients healed initial wounds, and 45% had new wound occurrences. CONCLUSIONS: Colocation successfully increases the number of patients with sickle cell ulcers who will engage in wound care at a single site, laying the foundation for clinical studies to improve the evidence base for this difficult-to-treat condition.

Melatonin alleviates vascular calcification and ageing through exosomal miR-204/miR-211 cluster in a paracrine manner.

In the elderly with atherosclerosis, hypertension and diabetes, vascular calcification and ageing are ubiquitous. Melatonin (MT) has been demonstrated to impact the cardiovascular system. In this study, we have shown that MT alleviates vascular calcification and ageing, and the underlying mechanism involved. We found that both osteogenic differentiation and senescence of vascular smooth muscle cells (VSMCs) were attenuated by MT in a MT membrane receptor-dependent manner. Moreover, exosomes isolated from VSMCs or calcifying vascular smooth muscle cells (CVSMCs) treated with MT could be uptaken by VSMCs and attenuated the osteogenic differentiation and senescence of VSMCs or CVSMCs, respectively. Moreover, we used conditional medium from MT-treated VSMCs and Transwell assay to confirm exosomes secreted by MT-treated VSMCs attenuated the osteogenic differentiation and senescence of VSMCs through paracrine mechanism. We also found exosomal miR-204/miR-211 mediated the paracrine effect of exosomes secreted by VSMCs. A potential target of these two miRs was revealed to be BMP2. Furthermore, treatment of MT alleviated vascular calcification and ageing in 5/6-nephrectomy plus high-phosphate diet-treated (5/6 NTP) mice, while these effects were partially reversed by GW4869. Exosomes derived from MT-treated VSMCs were internalised into mouse artery detected by in vivo fluorescence image, and these exosomes reduced vascular calcification and ageing of 5/6 NTP mice, but both effects were largely abolished by inhibition of exosomal miR-204 or miR-211. In summary, our present study revealed that exosomes from MT-treated VSMCs could attenuate vascular calcification and ageing in a paracrine manner through an exosomal miR-204/miR-211.

Comparing breast biomarker status between routine immunohistochemistry and FISH studies and Oncotype DX testing, a study of 610 cases.

INTRODUCTION: Oncotype DX (ODX) testing uses reverse transcription polymerase chain reaction (RT-PCR) to predict distant recurrence rate of estrogen receptor positive (ER+)/HER2-negative (HER2-)/lymph node-negative (LN-) breast cancers. ODX also reports the status of breast cancer biomarkers, ER, progesterone receptor (PR), and HER2. This study examined the discrepancy rate of breast cancer biomarker status as reported by ODX vs routinely used immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods. METHODS: A total of 610 breast cancer cases (609 ER+ and 1 ER-negative (ER-) by IHC) with ODX reports were reviewed. ER, PR, and HER2 status from ODX reports were compared with results from IHC and FISH studies. RESULTS: There was an overall high concordance rate between IHC and ODX for ER expression (603/610 concordant, 98.9%) and moderate concordance for PR expression (549/610 concordant, 90%). Of the seven ER-discrepant cases, six were positive by IHC but negative by ODX. Of the 61 PR-discrepant cases, 41 were positive by IHC but negative by ODX. Of the 610 cases, 568 had HER2 results reported by ODX. Five cases were HER2+ by IHC/FISH (0.88%). One of these five cases was reported as HER2+, two as HER2-, and two as HER2-equivocal by ODX. None of the cases that were HER2- or equivocal by IHC/FISH was reported as HER2+ by ODX. CONCLUSIONS: There is good concordance between IHC and ODX for ER and PR expression, but IHC is more sensitive. The significant discordance in HER2+ cases may discourage reporting HER2 status by ODX testing.

Neoalbaconol inhibits angiogenesis and tumor growth by suppressing EGFR-mediated VEGF production.

Neoalbaconol, derived from Albatrellus confluens, shows anti-cancer activities in the previously study, but its role in angiogenesis is unknown. Here, we determined whether neoalbaconol could attenuate angiogenesis and how does it occur. Data demonstrated that neoalbaconol could inhibit the proliferation of breast cancer cells and induce apoptosis. Also, neoalbaconol suppressed vascular endothelial growth factor (VEGF)-induced human umbilical vascular endothelial cells (HUVECs) proliferation, migration, invasion, and capillary-like tube formation in vitro and reduced tumor angiogenesis in vivo. VEGF receptor activation and the downstream signal transduction cascades activation were inhibited by neoalbaconol. Additionally, neoalbaconol blocked EGFR-mediated VEGF production. EGFR overexpression reversed the neoalbaconol-induced VEGF reduction, confirming the importance of the EGFR inhibition in anti-angiogenesis of neoalbaconol. Furthermore, neoalbaconol inhibited tumor growth and tumor angiogenesis in a breast cancer xenograft model in vivo. Taken together, these results indicate that neoalbaconol could inhibit tumor angiogenesis and growth through direct suppression effects on vascular endothelial cells and reduction of proangiogenic factors in cancer cells.

The Clinical Significance of miR-34a in Pancreatic Ductal Carcinoma and Associated Molecular and Cellular Mechanisms.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits poor prognosis and resistance to chemotherapy. This study was to identify the biomarkers associated with the progression, poor prognosis and chemoresistance of PDAC. METHODS: miR-34a and miR-150 levels in the plasma and tissues from PDAC patients were measured by real-time PCR. Xenograft PDAC tumor models were established in mice by inoculation of CD133+ stem cells isolated from PDAC tumors. Protein expression was measured by Western blot. RESULTS: The plasma miR-34a and miR-150 levels were significantly lower in PDAC patients than in patients with benign pancreatic lesions and in healthy subjects. The miR-34a and miR-150 levels in the tumor tissues were significantly lower than in pancreatic tissues with benign lesions. The protein levels of CD133, Notch1, Notch2 and Notch4 receptors in PDAC tumor tissues were significantly higher than in pancreatic tissues with benign lesions. miR-34a injection significantly inhibited the tumor growth of PDAC tumors and sensitized the anticancer effects of 5-fluorouracil (5-FU). miR-34a significantly inhibited Notch1, Notch2 and Notch4 expression in xenograft tumor tissues in vivo and BxPC-3 cells in vitro. miR-34a and miR-150 significantly induced apoptosis and inhibited proliferation, invasion and migration in BxPC-3 cells. miR-34a, but not miR-150, significantly sensitized the anticancer effect of 5-FU in BxPC-3 cells in vitro. CONCLUSION: A loss of expression of miR-34a, but not of miR-150, is associated with disease progression and poor prognosis in PDAC patients, and may be involved in the chemoresistance of PDAC cells.

Bcl2 inhibits recruitment of Mre11 complex to DNA double-strand breaks in response to high-linear energy transfer radiation.

High-linear energy transfer ionizing radiation, derived from high charge (Z) and energy (E) (HZE) particles, induces clustered/complex DNA double-strand breaks (DSBs) that include small DNA fragments, which are not repaired by the non-homologous end-joining (NHEJ) pathway. The homologous recombination (HR) DNA repair pathway plays a major role in repairing DSBs induced by HZE particles. The Mre11 complex (Mre11/Rad50/NBS1)-mediated resection of DSB ends is a required step in preparing for DSB repair via the HR DNA repair pathway. Here we found that expression of Bcl2 results in decreased HR activity and retards the repair of DSBs induced by HZE particles (i.e. (56)iron and (28)silicon) by inhibiting Mre11 complex activity. Exposure of cells to (56)iron or (28)silicon promotes Bcl2 to interact with Mre11 via the BH1 and BH4 domains. Purified Bcl2 protein directly suppresses Mre11 complex-mediated DNA resection in vitro. Expression of Bcl2 reduces the ability of Mre11 to bind DNA following exposure of cells to HZE particles. Our findings suggest that, after cellular exposure to HZE particles, Bcl2 may inhibit Mre11 complex-mediated DNA resection leading to suppression of the HR-mediated DSB repair in surviving cells, which may potentially contribute to tumor development.

The PI3K/Akt/mTOR pathway regulates the replicative senescence of human VSMCs.

Replicative senescence of vascular smooth muscle cells (VSMCs) contributes to aging as well as age-related cardiovascular diseases. Rapamycin can delay the onset of aging-related diseases via inhibition of the mammalian target of rapamycin (mTOR), but its role in vascular aging remains elusive. This study investigated the involvement of mTOR signaling in replicative senescence of VSMCs. Replicative senescence was induced by the extended passages of human VSMCs. Aging-related cell morphology was observed. The aging-related proteins and enzyme activity, and oxidative stress were measured. Significant increase in SA-ß-gal activity and protein expression, p53 and p16 protein expression, proliferation index (PI), malondialdehyde (MDA) concentration, superoxide dismutase (SOD) and glutathione peroxidase (GPX) activity, and significant decrease in telomerase activity was observed in aging VSMCs compared to young cells. Significant activation of PI3K/Akt/mTOR signaling was observed in aging cells but not young cells. Pretreatment of VSMCs with PI3K inhibitor blocked while PI3K activator increased the changes of the above replicative senescence-related parameters in VSMCs. Rapamycin and silencing of mTOR expression inhibited replicative senescence in VSMCs through decreasing the level of p-mTOR Ser2448, p-mTOR Thr2446, and S6K1 phosphorylation. This study for the first time demonstrated that the PI3K/Akt/mTOR/S6K1 signal pathway plays an important role in regulating replicative senescence of human VSMCs.

Adiponectin attenuates the osteoblastic differentiation of vascular smooth muscle cells through the AMPK/mTOR pathway.

Vascular calcification is common in patients with peripheral artery diseases and coronary artery diseases. The osteoblastic differentiation of vascular smooth muscle cells (VSMCs) contributes significantly to vascular calcification. Adiponectin has been demonstrated to exert a protective effect in osteoblastic differentiation of VSMCs through regulating mTOR activity. However, the upstream and downstream signaling molecules of adiponectin-regulated mTOR signaling have not been identified in VSMCs with osteoblastic differentiation. In this study, the VSMC differentiation model was established by beta-glycerophosphate (ß-GP) induction. The mineralization was identified by Alizarin Red S staining. Protein expression and phosphorylation were detected by Western blot or immunofluorescence. Adiponectin attenuated osteoblastic differentiation and mineralization of ß-GP-treated VSMCs. Adiponectin inhibited osteoblastic differentiation of VSMCs through increasing the level of p-AMPKα. Pretreatment of VSMCs with AMPK inhibitor blocked while AMPK activator enhanced the effect of adiponectin on osteoblastic differentiation of VSMCs. Adiponectin upregulated TSC2 expression and downregulated mTOR and S6K1 phosphorylation in ß-GP-treated VSMCs. Adiponectin treatment significantly attenuates the osteoblastic differentiation and calcification of VSMCs through modulation of AMPK-TSC2-mTOR-S6K1 signal pathway.

Exenatide can inhibit calcification of human VSMCs through the NF-kappaB/RANKL signaling pathway.

BACKGROUND: Arterial calcification is an important pathological change of diabetic vascular complication. Osteoblastic differentiation of vascular smooth muscle cells (VSMCs) plays an important cytopathologic role in arterial calcification. The glucagon-like peptide-1 receptor agonists (GLP-1RA), a novel type of antidiabetic drugs, exert cardioprotective effects through the GLP-1 receptor (GLP-1R). However, the question of whether or not GLP-1RA regulates osteoblastic differentiation and calcification of VSMCs has not been answered, and the associated molecular mechanisms have not been examined. METHODS: Calcifying VSMCs (CVSMCs) were isolated from cultured human arterial smooth muscle cells through limiting dilution and cloning. The extent of matrix mineralization was measured by Alizarin Red S staining. Protein expression and phosphorylation were detected by Western blot. Gene expression of receptor activator of nuclear factor-κB ligand (RANKL) was silenced by small interference RNA (siRNA). RESULTS: Exenatide, an agonist of GLP-1 receptor, attenuated ß-glycerol phosphate (ß-GP) induced osteoblastic differentiation and calcification of human CVSMCs in a dose- and time-dependent manner. RANKL siRNA also inhibited osteoblastic differentiation and calcification. Exenatide decreased the expression of RANKL in a dose-dependent manner. 1,25 vitD3 (an activator of RANKL) upregulated, whereas BAY11-7082 (an inhibitor of NF-κB) downregulated RANKL, alkaline phosphatase (ALP), osteocalcin (OC), and core binding factor α1 (Runx2) protein levels and reduced mineralization in human CVSMCs. Exenatide decreased p-NF-κB and increased p-AMPKα levels in human CVSMCs 48 h after treatment. Significant decrease in p-NF-κB (p-Ser(276), p-Ser(536)) level was observed in cells treated with exenatide or exenatide + BAY11-7082. CONCLUSION: GLP-1RA exenatide can inhibit human VSMCs calcification through NF-κB/RANKL signaling.

Association between macro- and microvascular damage and sarcopenia index in individuals with type 2 diabetes mellitus.

Sarcopenia was recently reported to be relevant to an increased macro-and microvascular disease risk. Sarcopenia index (SI) has been identified as a surrogate marker for sarcopenia. The aim of the present study was to investigate the association between macro- and microvascular disease and SI in patients with type 2 diabetes mellitus (T2DM). A total of 783 patients with T2DM were enrolled in this cross-sectional study. The SI was calculated by (serum creatinine [mg/dL]/cystatin C [mg/L]) × 100. The subjects were divided into three groups according to SI tertiles: T1 (41.27-81.37), T2 (81.38- 99.55), and T3 (99.56-192.31). Parameters of macro- and microvascular complications, including diabetic retinopathy (DR), micro- and macroalbuminuria (MAU), diabetic peripheral neuropathy (DPN), and lower extremity peripheral artery disease (LEAD) were evaluated. Multivariate logistic regression analysis revealed that when taking the top tertile of SI as a reference, an increasing trend of the prevalence of DR, MAU, DPN, and LEAD were presented (all P for trend  < 0.05), where the OR (95% CI) for DR prevalence was 1.967 (1.252-3.090) in T2, 2.195 (1.278-3.769) in T1, for MAU was 1.805 (1.149-2.837) in T2, 2.537 (1.490-4.320) in T1, for DPN was 2.244 (1.485-3.391) in T2, 3.172 (1.884-5.341) in T1, and for LEAD was 2.017 (1.002-4.057) in T2, 2.405 (1.107-5.225) in T1 (all P < 0.05). Patients with lower SI were more inclined to have an increased risk of macro- and microvascular damage in T2DM population, which may be related to sarcopenia.

Vaspin attenuates the apoptosis of human osteoblasts through ERK signaling pathway.

It has been hypothesized that adipocytokines originating from adipose tissue may have an important role in bone metabolism. Vaspin is a novel adipocytokine isolated from visceral white adipose tissue, which has been reported to have anti-apoptotic effects in vascular endothelial cells. However, to the best of our knowledge there is no information regarding the effects of vaspin on osteoblast apoptosis. This study therefore examined the possible effects of vaspin on apoptosis in human osteoblasts (hOBs). Our study established that vaspin inhibits hOBs apoptosis induced by serum deprivation, as determined by ELISA and TUNEL assays. Western blot analysis revealed that vaspin upregulates the expression of Bcl-2 and downregulates that of Bax in a dose-dependent manner. Vaspin stimulated the phosphorylation of ERK, and pretreatment of hOBs with the ERK inhibitor PD98059 blocked the vaspin-induced activation of ERK, however, vaspin did not stimulate the phosphorylation of p38, JNK or Akt. Vaspin protects hOBs from serum deprivation-induced apoptosis, which may be mediated by activating the MAPK/ERK signaling pathway.

miRNA-195-5p/PSAT1 feedback loop in human triple-negative breast cancer cells.

BACKGROUND: Substantial evidence suggests that non-coding RNAs, such as microRNAs (miRNAs), play a vital role in human cancer. Phosphoserine aminotransferase 1 (PSAT1) is a serine biosynthesis-related member of the aminotransferase family and is closely associated with worse prognosis in triple-negative breast cancer (TNBC). OBJECTIVE: The present study elucidated the molecular mechanisms underlying PSAT1 regulation by miRNAs in TNBC. METHODS: After collecting breast cancer and para-cancerous tissues, expression and functional testing of microRNA-195-5p (miR-195-5p) and PSAT1 were implemented both in vivo and in vitro. RESULTS: Abnormally low miR-195-5p expression was confirmed in TNBC tissues and cells. The specific targeting effect of miR-195-5p on PSAT1 was screened. Our observations revealed that biological tumor behavior was inhibited after miR-195-5p upregulation and this inhibition could be reversed by PSAT1 overexpression both in vivo and in vitro. CONCLUSION: Our study revealed the regulatory axis of miR-195-5p/PSAT1 in TNBC, suggesting a promising targeted therapy for clinical application.

N6-Methyladenosine in Vascular Aging and Related Diseases: Clinical Perspectives.

Aging leads to progressive deterioration of the structure and function of arteries, which eventually contributes to the development of vascular aging-related diseases. N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic RNAs. This reversible m6A RNA modification is dynamically regulated by writers, erasers, and readers, playing a critical role in various physiological and pathological conditions by affecting almost all stages of the RNA life cycle. Recent studies have highlighted the involvement of m6A in vascular aging and related diseases, shedding light on its potential clinical significance. In this paper, we comprehensively discuss the current understanding of m6A in vascular aging and its clinical implications. We discuss the molecular insights into m6A and its association with clinical realities, emphasizing its significance in unraveling the mechanisms underlying vascular aging. Furthermore, we explore the possibility of m6A and its regulators as clinical indicators for early diagnosis and prognosis prediction and investigate the therapeutic potential of m6A-associated anti-aging approaches. We also examine the challenges and future directions in this field and highlight the necessity of integrating m6A knowledge into patient-centered care. Finally, we emphasize the need for multidisciplinary collaboration to advance the field of m6A research and its clinical application.

Modification and application of "zero-line" incision design in total endoscopic gasless unilateral axillary approach thyroidectomy: A preliminary report.

Introduction: Gasless unilateral trans-axillary approach (GUA) thyroidectomy has witnessed rapid development in technologies and applications. However, the existence of surgical retractors and limited space would increase the difficulty of guaranteeing the visual field and disturb safe surgical manipulation. We aimed to develop a novel zero-line method for incision design to access optimal surgical manipulation and outcomes. Methods: A total of 217 patients with thyroid cancer who underwent GUA were enrolled in the study. Patients were randomly classified into two groups (classical incision and zero-line incision), and their operative data were collected and reviewed. Results: 216 enrolled patients underwent and completed GUA; among them, 111 patients were classified into the classical group, and 105 patients were classified into the zero-line group, respectively. Demographic data, including age, gender, and the primary tumor side, were similar between the two groups. The duration of surgery in the classical group was longer (2.66 ± 0.68 h) than in the zero-line group (1.40 ± 0.47 h) (p < 0.001). The counts of central compartment lymph node dissection were higher in the zero-line group (5.03 ± 3.02 nodes) than that in the classical group (3.05 ± 2.68 nodes) (p < 0.001). The score of postoperative neck pain was lower in the zero-line group (1.0 ± 0.36) than that in the classical group (3.3 ± 0.54) (p < 0.05). The difference in cosmetic achievement was not statistically significant (p > 0.05). Conclusion: The "zero-line" method for GUA surgery incision design was simple but effective for GUA surgery manipulation and worth promoting.

Sirtuins at the Crossroads between Mitochondrial Quality Control and Neurodegenerative Diseases: Structure, Regulation, Modifications, and Modulators.

Sirtuins (SIRT1-SIRT7), a family of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes, are key regulators of life span and metabolism. In addition to acting as deacetylates, some sirtuins have the properties of deacylase, decrotonylase, adenosine diphosphate (ADP)-ribosyltransferase, lipoamidase, desuccinylase, demalonylase, deglutarylase, and demyristolyase. Mitochondrial dysfunction occurs early on and acts causally in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Sirtuins are implicated in the regulation of mitochondrial quality control, which is highly associated with the pathogenesis of neurodegenerative diseases. There is growing evidence indicating that sirtuins are promising and well-documented molecular targets for the treatment of mitochondrial dysfunction and neurodegenerative disorders by regulating mitochondrial quality control, including mitochondrial biogenesis, mitophagy, mitochondrial fission/fusion dynamics, and mitochondrial unfolded protein responses (mtUPR). Therefore, elucidation of the molecular etiology of sirtuin-mediated mitochondrial quality control points to new prospects for the treatment of neurodegenerative diseases. However, the mechanisms underlying sirtuin-mediated mitochondrial quality control remain obscure. In this review, we update and summarize the current understanding of the structure, function, and regulation of sirtuins with an emphasis on the cumulative and putative effects of sirtuins on mitochondrial biology and neurodegenerative diseases, particularly their roles in mitochondrial quality control. In addition, we outline the potential therapeutic applications for neurodegenerative diseases of targeting sirtuin-mediated mitochondrial quality control through exercise training, calorie restriction, and sirtuin modulators in neurodegenerative diseases.

High serum Bhlhe40 levels are associated with subclinical atherosclerosis in patients with type 2 diabetes mellitus: A cross-sectional study.

BACKGROUND: Our previous studies have shown that the basic helix-loop-helix family member e40 (Bhlhe40) plays a critical role in regulating calcification and senescence of vascular smooth muscle cells induced by high glucose. In this study, we determined the association between serum Bhlhe40 levels and subclinical atherosclerosis in patients with type 2 diabetes mellitus (T2DM). METHODS: 247 patients with T2DM were included in this cross-sectional study between June 2021 and July 2022. The presence of subclinical atherosclerosis was evaluated by carotid ultrasonography. Serum Bhlhe40 concentrations were measured with an ELISA kit. RESULTS: Serum Bhlhe40 levels were remarkably higher in the subclinical atherosclerosis group than in the subjects without subclinical atherosclerosis (p < 0.001). Correlation analysis showed a positive correlation between serum Bhlhe40 and carotid intima-media thickness (C-IMT) (r = 0.155, p = 0.015). The optimal threshold of serum Bhlhe40 > 5.67 ng/mL had an area under the ROC curve (AUC) was 0.709 (p < 0.001). In addition, serum Bhlhe40 levels were associated with the prevalence of subclinical atherosclerosis (OR: 1.790, 95% CI: 1.414-2.266, p < 0.001). CONCLUSION: Serum Bhlhe40 levels were significantly higher in T2DM subjects with subclinical atherosclerosis and positively associated with C-IMT.

BMF-AS1/BMF Promotes Diabetic Vascular Calcification and Aging both In Vitro and In Vivo.

Vascular calcification and aging often increase morbidity and mortality in patients with diabetes mellitus (DM); however, the underlying mechanisms are still unknown. In the present study, we found that Bcl-2 modifying factor (BMF) and BMF antisense RNA 1 (BMF-AS1) were significantly increased in high glucose-induced calcified and senescent vascular smooth muscle cells (VSMCs) as well as artery tissues from diabetic mice. Inhibition of BMF-AS1 and BMF reduced the calcification and senescence of VSMCs, whereas overexpression of BMF-AS1 and BMF generates the opposite results. Mechanistic analysis showed that BMF-AS1 interacted with BMF directly and up-regulated BMF at both mRNA and protein levels, but BMF did not affect the expression of BMF-AS1. Moreover, knocking down BMF-AS1 and BMF suppressed the calcification and senescence of VSMCs, and BMF knockout (BMF-/-) diabetic mice presented less vascular calcification and aging compared with wild type diabetic mice. In addition, higher coronary artery calcification scores (CACs) and increased plasma BMF concentration were found in patients with DM, and there was a positive correlation between CACs and plasma BMF concentration. Thus, BMF-AS1/BMF plays a key role in promoting high glucose-induced vascular calcification and aging both in vitro and in vivo. BMF-AS1 and BMF represent potential therapeutic targets in diabetic vascular calcification and aging.

Roles of Long Non-coding RNAs in the Development of Aging-Related Neurodegenerative Diseases.

Aging-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), are gradually becoming the primary burden of society and cause significant health-care concerns. Aging is a critical independent risk factor for neurodegenerative diseases. The pathological alterations of neurodegenerative diseases are tightly associated with mitochondrial dysfunction, inflammation, and oxidative stress, which in turn stimulates the further progression of neurodegenerative diseases. Given the potential research value, lncRNAs have attracted considerable attention. LncRNAs play complex and dynamic roles in multiple signal transduction axis of neurodegeneration. Emerging evidence indicates that lncRNAs exert crucial regulatory effects in the initiation and development of aging-related neurodegenerative diseases. This review compiles the underlying pathological mechanisms of aging and related neurodegenerative diseases. Besides, we discuss the roles of lncRNAs in aging. In addition, the crosstalk and network of lncRNAs in neurodegenerative diseases are also explored.