SO2 derivatives induce dysfunction in human trophoblasts via inhibiting ROS/IL-6/STAT3 pathway.

BACKGROUND: Epidemiological studies have revealed that sulfur dioxides (SO2) can increase the risk of pregnancy complications such as missed abortion in the first trimester, stillbirth, preterm birth, small for gestational age, gestational diabetes mellitus and preeclampsia, but the mechanisms underlying these findings remains unknown. What is known, however, is that trophoblasts, a type of fetal cell exerting vital immunologic functions to maintain a successful pregnancy, are usually involved in the pathogenic mechanism of pregnancy complications. OBJECTIVE: To study the effect of SO2 derivatives (bisulfite and sulfite, 1:3 M/M) on the function of trophoblasts. METHODS: Swan.71 trophoblast cells were treated with various concentrations of SO2 derivatives to determine the effect of SO2 derivatives on cellular viability by CKK8. Flow cytometry was performed to analyze the effect of SO2 derivatives on apoptosis, cell cycle and intracellular ROS. Wound healing assay and transwell assay were conducted to examine the migration and invasion of Swan.71 cells. Inflammation-related cytokines in the supernatant (IL-1ß, IL-6, IL-8, IL-10 and TNF-α) were measured by IMMULITE®1000 Systems (SIEMENS). The expression level of NLRP3, Caspase1, MMP9, MMP2, STAT3, and p-STAT3 were evaluated by Western Blotting. RESULTS: Exposure to SO2 derivatives significantly decreased cellular viability, arrested cell cycle at S/G2/M phase and induced cell apoptosis of Swan.71 trophoblasts. In addition, the migration and invasion of Swan.71 cell were significantly inhibited. SO2 derivatives also significantly increased IL-1ß secretion while it is NLRP3/Caspase1 independent. IL-6 secretion was significant inhibited accompanied by decreased STAT3 phosphorylation and expression of MMP2 and MMP9. The intracellular ROS level was significantly suppressed by SO2 derivatives. CONCLUSION: SO2 derivatives exert toxic effects on trophoblasts which results in: suppressing cellular viability and intracellular ROS level, interfering with cell proliferation through arresting cell cycle, inducing cell apoptosis, disturbing inflammation-related cytokines secretion and inhibiting motility. Decreased ROS/IL-6/STAT3 levels play a role in inhibited cell viability, cell cycle arrest, apoptosis and defective motility.

LRRK2, but not pathogenic mutants, protects against H2O2 stress depending on mitochondrial function and endocytosis in a yeast model.

BACKGROUND: Mutations in LRRK2 are the most common genetic cause of Parkinson's disease (PD). Studies in the yeast Saccharomyces cerevisiae have provided valuable insights into the mechanisms of cellular dysfunction associated with the expression of faulty PD genes. METHODS: We developed a yeast model for full-length LRRK2 studies. We expressed wild-type (wt) LRRK2 and mutations and evaluated their role during oxidative stress conditions. The involvement of mitochondria was assessed by using rho-zero mutants and by evaluating reactive oxygen species (ROS) production and mitochondrial membrane potential by flow cytometry. The involvement of endocytosis was also studied by testing several endocytic mutants and by following the vacuolar delivery of the probe FM4-64. RESULTS: Expression of LRRK2 in yeast was associated to increased hydrogen peroxide resistance. This phenotype, which was dependent on mitochondrial function, was not observed for PD-mutants G2019S and R1441C or in the absence of the kinase activity and the WD40 repeat domain. Expression of the pathogenic mutants stimulated ROS production and increased mitochondrial membrane potential. For the PD-mutants, but not for wild-type LRRK2, endocytic defects were also observed. Additionally, several endocytic proteins were required for LRRK2-mediated protection against hydrogen peroxide. CONCLUSIONS: Our results indicate that LRRK2 confers cellular protection during oxidative stress depending on mitochondrial function and endocytosis. GENERAL SIGNIFICANCE: Both the loss of capacity of LRRK2 pathogenic mutants to protect against oxidative stress and their enhancement of dysfunction may be important for the development of PD during the aging process.

Posttraumatic stress disorder is characterized by functional dysregulation of dermal fibroblasts.

Incidence of mental health disorders are rising in modernity, with psychological stress linked to a propensity for developing various chronic diseases due to a relative inability of the body to counter the allostatic load on cellular level. Despite these high rates of comorbidities associated with posttraumatic stress disorder (PTSD), there is still a lack of understanding in terms of the peripheral effects of PTSD on tissue level. Therefore, the purpose of this study was to profile basal dermal fibroblast functional status in PTSD using a wide range of markers involved in the cell-to-cell communication facilitated by fibroblasts. Primary dermal fibroblasts derived from patients diagnosed with PTSD (n = 11) and matched trauma exposed controls (i.e. who did not develop PTSD, n = 10) were cultured using standard techniques. The patients and controls were matched based on age, sex, body-mass index (BMI) and lifestyle. The growth rate, population doubling time, cell surface marker expression (CD31, FNDC5) (flow cytometry), secretome (TIMP-2, MMP-9) (ELISAs), intracellular signalling capacity (Fluo-4 Ca2+ flux) and gene expression (IL-6, IL-10, PTX-3, iNOS, Arg1) were compared between groups. The data illustrated significant PTSD-associated fibroblast conditioning resulting in a blunted signalling capacity. This observation highlights the importance of including tissue-specific investigations in future studies focused on elucidating the association between PTSD and subsequent risk for somatic disease.

Ghrelin Improves Glucolipotoxicity-Induced Pancreatic ß-Cellular Dysfunction and Apoptosis by Inhibiting Endoplasmic Reticulum Stress-Induced IRE1/JNK Pathway.

BACKGROUND: Glucose and fatty acid overload-induced glucolipid toxicity of pancreatic ß-cells is associated with the development of diabetes. Endoplasmic reticulum stress (ERS) plays an essential role in this process. Ghrelin, a peptide secreted by the pancreas, negatively correlates with oxidative stress. The study aimed to investigate ghrelin's role in glycolipid-induced ß-cell dysfunction and its possible mechanism. METHODS: Mouse insulinoma ß-cell, NIT-1 cells, were stimulated with high fat and high glucose to induce glucolipid toxicity. High fat and high glucose-induced NIT-1 cells were treated with acylated ghrelin (AG) or [d-Lys3]-growth hormone releasing peptide (GHRP)-6. Flow cytometry and Cell Counting Kit-8 (CCK-8) assay were performed to assess apoptosis and cell viability. The protein expression related to apoptosis, inositol-requiring kinase 1 (IRE1)/c-Jun N-terminal kinase (JNK) signaling, and ERS were investigated using western blot. Enzyme-linked immunosorbent assay (ELISA) was adopted to examine insulin's synthesis and secretion levels. RESULTS: Ghrelin treatment improved cell viability while inhibiting cell glucolipotoxicity-induced NIT-1 cell apoptosis. Ghrelin can promote the synthesis and secretion of insulin in NIT-1 cells. Mechanistically, ghrelin attenuates ERS and inhibits the IRE1/JNK signaling pathway in NIT-1 cells induced by glucolipotoxicity. CONCLUSION: Ghrelin improves ß-cellular dysfunction induced by glucolipotoxicity by inhibiting the IRE1/JNK pathway induced by ERS. It could be an effective treatment for ß-cellular dysfunction.

Enhancing endothelial colony-forming cells for treating diabetic vascular complications: challenges and clinical prospects.

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia, leading to various vascular complications. Accumulating evidence indicates that endothelial colony-forming cells (ECFCs) have attractive prospects for repairing and restoring blood vessels. Thus, ECFCs may be a novel therapeutic option for diabetic patients with vascular complications who require revascularization therapy. However, it has been reported that the function of ECFCs is impaired in DM, which poses challenges for the autologous transplantation of ECFCs. In this review, we summarize the molecular mechanisms that may be responsible for ECFC dysfunction and discuss potential strategies for improving the therapeutic efficacy of ECFCs derived from patients with DM. Finally, we discuss barriers to the use of ECFCs in human studies in light of the fact that there are no published reports using these cells in humans.

Contrasting mechanistic susceptibilities of hematopoietic and endothelial stem-progenitor cells in respective pathogeneses of HIV-1 and SARS-CoV-2 infections.

The multitude of cellular types can be expected to behave differently when receiving invading pathogens such as mammalian viruses. The nature-dictated causes for such intrinsic cellular diversity become the criteria for the emergence of specific virus-receptor interactions on that particular host cellular surface, in order to accommodate contact with various other living entities whether desirable to the host or not. At present, we are presented with an example of two contrasting behaviours wherein the well-known HIV-1 and the more recently emergent SARS-CoV-2 cause adverse consequences to the differentiation and functions of progenitor stem cells. These include the two different downstream multipotent CD34+ hematopoietic (HSPC) and CD133+ endothelial (ESPC) stem-progenitor cells of their common pluripotent hemangioblast precursors. The two viruses target the respective endothelial and hematopoietic stem-progenitor cells to thrive upon the relevant host cellular surrounded stromal microenvironments by adopting reciprocally-driven mechanistic routes, which incidentally cause pathogenesis either directly of ESPC (SARS-CoV-2), or indirectly of HSPC (HIV-1). HIV-1 utilizes the CD4+ T-lymphocyte receptor thereby advancing pathogenesis indirectly to the CD34+ HSPC. SARS-CoV-2 directly targets the CD133+ ESPC via ACE2 receptor causing cytokine storms of the CD4+ T-lymphocytes. In this manner, these two viruses cause and extend their damage to the other cellular sub/types coexisting in the host cellular microenvironments. The infected individuals require clinical interventions that are efficacious to prevent cellular dysfunction and ultimate cell depletion or death. We infer from these viruses mediated pathogeneses mechanisms a potential common origin of microRNA molecular therapies to address cellular dysfunctions and prevent cell loss.

Biofunctionalization of cardiovascular stents to induce endothelialization: Implications for in- stent thrombosis in diabetes.

Stent thrombosis remains one of the main causes that lead to vascular stent failure in patients undergoing percutaneous coronary intervention (PCI). Type 2 diabetes mellitus is accompanied by endothelial dysfunction and platelet hyperactivity and is associated with suboptimal outcomes following PCI, and an increase in the incidence of late stent thrombosis. Evidence suggests that late stent thrombosis is caused by the delayed and impaired endothelialization of the lumen of the stent. The endothelium has a key role in modulating inflammation and thrombosis and maintaining homeostasis, thus restoring a functional endothelial cell layer is an important target for the prevention of stent thrombosis. Modifications using specific molecules to induce endothelial cell adhesion, proliferation and function can improve stents endothelialization and prevent thrombosis. Blood endothelial progenitor cells (EPCs) represent a potential cell source for the in situ-endothelialization of vascular conduits and stents. We aim in this review to summarize the main biofunctionalization strategies to induce the in-situ endothelialization of coronary artery stents using circulating endothelial stem cells.

PFKFB3 regulates lipopolysaccharide-induced excessive inflammation and cellular dysfunction in HTR-8/Svneo cells: Implications for the role of PFKFB3 in preeclampsia.

INTRODUCTION: Preeclampsia is characterized by overactive inflammation at the uteroplacental interface, leading to trophoblasts dysfunction. 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) is a crucial glycolytic regulator which has recently been found to participate in the pathological inflammatory states. This study aimed to investigate the role of PFKFB3 in the inflammation-induced damage in trophoblasts, and elucidate the underlying mechanisms. METHODS: Immunohistochemistry, qRT-PCR, and Western blot analysis (WB) were used to detect the expression of PFKFB3 in preeclamptic and normal placentas. Lipopolysaccharide (LPS)-induced HTR8/SVneo cells were established as the in vitro model to simulate the overactive inflammation at the uteroplacental interface of PE, which were subsequently transfected with PFKFB3 siRNA. The expression of PFKFB3, NF-κB-p-p65, phosphorylation states of NF-κB-p65, ICAM-1, Bcl-2, BAX, and MMP2 were detected by WB. qRT-PCR was used to detect the expression of TNF-α and IL-1ß. The ICAM-1 expression was also reflected by monocyte adhesion assay. Reactive Oxygen Species (ROS) levels were detected by DCFH-DA (2,7-Dichlorodi-hydrofluorescein diacetate). Apoptosis was detected using Annexin V-FITC staining. Migration and invasion were measured by wound-healing and transwell assays. RESULTS: PFKFB3 was up-regulated in the preeclamptic placenta. In LPS-treated HTR-8/Svneo cells, the inhibition of PFKFB3 blocked the NF-κB signal pathway, thereby downregulating the expression of proinflammatory cytokines and adhesion molecules, meanwhile, PFKFB3 knockdown significantly alleviated monocyte adhesion, oxidative stress, apoptosis, and reinstated migration and invasive capacity. DISCUSSION: PFKFB3 controls the LPS-induced inflammation via the NF-κB pathway and impacts trophoblasts function such as adhesion, oxidative stress, apoptosis, migration, and invasion, thereby potentially participating in the preeclamptic etiopathogenesis.

The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging.

According to the WHO, 38 million individuals were living with human immunodeficiency virus (HIV), 25.4 million of which were using antiretroviral therapy (ART) at the end of 2019. Despite ART-mediated suppression of viral replication, ART is not a cure and is associated with viral persistence, residual inflammation, and metabolic disturbances. Indeed, due to the presence of viral reservoirs, lifelong ART therapy is required to control viremia and prevent disease progression into acquired immune deficiency syndrome (AIDS). Successful ART treatment allows people living with HIV (PLHIV) to achieve a similar life expectancy to uninfected individuals. However, recent studies have illustrated the presence of increased comorbidities, such as accelerated, premature immune aging, in ART-controlled PLHIV compared to uninfected individuals. Studies suggest that both HIV-infection and ART-treatment lead to mitochondrial dysfunction, ultimately resulting in cellular exhaustion, senescence, and apoptosis. Since mitochondria are essential cellular organelles for energy homeostasis and cellular metabolism, their compromise leads to decreased oxidative phosphorylation (OXPHOS), ATP synthesis, gluconeogenesis, and beta-oxidation, abnormal cell homeostasis, increased oxidative stress, depolarization of the mitochondrial membrane potential, and upregulation of mitochondrial DNA mutations and cellular apoptosis. The progressive mitochondrial damage induced by HIV-infection and ART-treatment likely contributes to accelerated aging, senescence, and cellular dysfunction in PLHIV. This review discusses the connections between mitochondrial compromise and cellular dysfunction associated with HIV- and ART-induced toxicities, providing new insights into how HIV and current ART directly impact mitochondrial functions and contribute to cellular senescence and aging in PLHIV. Identifying this nexus and potential mechanisms may be beneficial in developing improved therapeutics for treating PLHIV.

Notch Signalling: A Potential Therapeutic Pathway in Oral Squamous Cell Carcinoma.

Cancer, a set of diseases characterized by abnormal cell growth resulting from alteration in the expression pattern of diverse genes, is one of the prominent causes of mortality and morbidity worldwide. This modification of various genes leads to altered signalling cascades and changes in the molecular network. These changes eventually give rise to cellular dysfunction and then to systemic failure causing death. Of the several pathways that are aberrantly activated in cancer, Notch signalling pathway is a prominent one. Notch signalling pathway is a juxtracrine signalling pathway which activates the genes associated with cell proliferation, survival and angiogenesis. Notch signalling pathway components are seen to be upregulated in several types of cancer. Oral squamous cell carcinoma (OSCC) is a predominant category of oral cancer where aberrant activation of Notch signalling causes tumour progression and metastasis. In this review, we discuss the Notch signalling pathway, its components, forms and its role in the progression and metastasis of oral squamous cell carcinoma.

The antiaging property of aqueous extract of Millingtonia hortensis flowers in aging neuron.

Cellular senescence is the key mediator of cellular dysfunction before undergoing degenerative disease such as Alzheimer's disease. The aging process was mainly by the overactivation of senescence associated ß-galactosidase (SA-ß-gal) enzyme before mediated several negative responses, including intracellular reactive oxygen species (ROS) production, cellular senescence regulation, and death prior encourage synaptic loss. Thus, in the recent work, we evaluated the in vitro effects of aqueous extract of Millingtonia hortensis L. (MH) from flower in hydrogen peroxide (H2O2)-induced senescence in SK-N-SH cells. Herein, we demonstrated that MH significantly increased cell viability and decreased both of apoptotic cells and ROS production in a dose-dependent manner comparing to aging group (P < 0.01) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, and ROS assay. Furthermore, the number of SA-ß-gal-positive cells was also reduced in MH treatment (P < 0.01) together with the promotion of Sirt-1 protein. Importantly, MH also promoted the synaptic plasticity by decreased acetylcholinesterase activity and increased synaptophysin expression in aging neurons comparing to aging group (P < 0.01). Hispidulin (the active ingredient in MH) was also revealed the similarly effects to MH. Therefore, we suggested that MH might be beneficially for neurodegenerative disease that caused by aging.

Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells.

BACKGROUND: Chronic inflammatory conditions like obesity may adversely impact the biological functions underlying the regenerative potential of mesenchymal stromal/stem cells (MSC). Obesity can impair MSC function by inducing cellular senescence, a growth-arrest program that transitions cells to a pro-inflammatory state. However, the effect of obesity on adipose tissue-derived MSC in human subjects remains unclear. We tested the hypothesis that obesity induces senescence and dysfunction in human MSC. METHODS: MSC were harvested from abdominal subcutaneous fat collected from obese and age-matched non-obese subjects (n = 40) during bariatric or kidney donation surgeries, respectively. MSC were characterized, their migration and proliferation assessed, and cellular senescence evaluated by gene expression of cell-cycle arrest and senescence-associated secretory phenotype markers. In vitro studies tested MSC effect on injured human umbilical vein endothelial cells (HUVEC) function. RESULTS: Mean age was 59 ± 8 years, 66% were females. Obese subjects had higher body-mass index (BMI) than non-obese. MSC from obese subjects exhibited lower proliferative capacities than non-obese-MSC, suggesting decreased function, whereas their migration remained unchanged. Senescent cell burden and phenotype, manifested as p16, p53, IL-6, and MCP-1 gene expression, were significantly upregulated in obese subjects' MSC. BMI correlated directly with expression of p16, p21, and IL-6. Furthermore, co-incubation with non-obese, but not with obese-MSC, restored VEGF expression and tube formation that were blunted in injured HUVEC. CONCLUSION: Human obesity triggers an early senescence program in adipose tissue-derived MSC. Thus, obesity-induced cellular injury may alter efficacy of this endogenous repair system and hamper the feasibility of autologous transplantation in obese individuals.

AIF knockdown induce apoptosis and mitochondrial dysfunction in cochlear spiral ganglion neurons in vitro.

The underlying mechanism involved in auditory neuropathy spectrum disorder (ANSD) remains largely unclear. It has been previously reported that mutations in the apoptosis­inducing factor (AIF) gene are associated with auditory neuropathy and delayed peripheral neuropathy, which can eventually cause ANSD. In the present study, the regulatory effects of AIF knockdown on the cellular functions of spiral ganglion neurons (SNGs) and the molecular mechanism(s) of AIF knockdown in inducing cell apoptosis in SGNs were further investigated. The results showed that the AIF knockdown via siRNA transfection resulted in high levels of oxidative stress, and impaired mitochondrial respiration activity and membrane potential in SGNs. Western blotting further proved that the knockdown of AIF can decrease the content of anti­apoptotic and anti­oxidative proteins, as well as mitochondrial respiratory chain Complex I proteins. The present experimental data suggested that the abnormal expression of AIF may affect SGNs cellular function, and may contribute to the progress of ANSD.

Cellular parabiosis and the latency of age-related diseases.

Cellular parabiosis is tissue-based phenotypic suppression of cellular dysfunction by intercellular molecular traffic keeping initiated age-related diseases and conditions in long latency. Interruption of cellular parabiosis (e.g. by chronic inflammation) promotes the onset of initiated pathologies. The stability of initiated latent cancers and other age-related diseases (ARD) hints to phenotypically silent genome alterations. I propose that latency in the onset of ageing and ARD is largely due to phenotypic suppression of cellular dysfunctions via molecular traffic among neighbouring cells. Intercellular trafficking ranges from the transfer of ions and metabolites (via gap junctions) to entire organelles (via tunnelling nanotubes). Any mechanism of cell-to-cell communication resulting in functional cross-complementation among the cells is called cellular parabiosis. Such 'cellular solidarity' creates tissue homeostasis by buffering defects and averaging cellular functions within the tissues. Chronic inflammation is known to (i) interrupt cellular parabiosis by the activity of extracellular proteases, (ii) activate dormant pathologies and (iii) shorten disease latency, as in tumour promotion and inflammaging. Variation in cellular parabiosis and protein oxidation can account for interspecies correlations between body mass, ARD latency and longevity. Now, prevention of ARD onset by phenotypic suppression, and healing by phenotypic reversion, become conceivable.

Atorvastatin reverses the dysfunction of human umbilical vein endothelial cells induced by angiotensin II.

Statins exert pleiotropic effects on endothelial cells, in addition to lowering cholesterol. This study evaluated angiotensin II (Ang II)-induced dysfunction in human umbilical vein endothelial cells (HUVECs), and the effects of atorvastatin (Ator) on induced HUVECs in vitro. The cytotoxicity of Ang II and Ator was determined by the MTT assay. A series of cellular responses were screened, including oxidative stress, cellular apoptosis, inflammatory response, autophagy, expression of endothelial nitric oxide synthase and the angiogenic function of HUVECs. Ator returned these cellular responses to a normal level. The present study also examined cellular organelle dysfunction. In HUVECs, Ang II triggered mitochondrial damage, as demonstrated by a decreased mitochondrial membrane potential, while Ator attenuated this Ang II-induced damage. The observed cellular dysfunction may cause endothelial senescence due to excessive cell injury. The current study examined several aging markers, which revealed that these disorders of cellular functions triggered endothelial senescence, which was delayed by Ator. Ator also suppressed Ang II-induced angiogenesis damage. The data presented in this study strongly suggested that Ang II induced a series of processes that lead to cellular dysfunction in HUVECs, including oxidative stress, inflammation, and mitochondrial damage, leading to apoptosis and endothelial senescence. However, Ator significantly reversed these effects and modulated intracellular stability. The present study indicated that Ator serves an antagonistic role against HUVEC dysfunction and may potentially prevent several diseases, including coronary disease and atherosclerosis, by maintaining cellular homeostasis.

IgY Reduces AFB1-Induced Cytotoxicity, Cellular Dysfunction, and Genotoxicity in Human L-02 Hepatocytes and Swan 71 Trophoblasts.

Aflatoxin B1 (AFB1) causes hepatotoxic, genotoxic, and immunotoxic effects in a variety of species. Although various neutralizing agents of AFB1 toxicity have been studied, the egg yolk immunoglobulin (IgY) detoxification of small molecular toxins and the mechanisms underlying such effects have not yet been reported. In this investigation, anti-AFB1 IgY against AFB1 was successfully raised, and a competitive indirect enzyme-linked immunosorbent assay was established with a sensitive half-maximal inhibitory concentration (IC50, 2.4 ng/mL) and dynamic working range (0.13-43.0 ng/mL). The anti-AFB1 IgY obtained reduced AFB1-induced cytotoxicity, cellular dysfunction, and genotoxicity by protecting cells against apoptotic body formation and DNA strand breaks, preventing G2/M phase cell cycle arrest, reducing AFB1-DNA adduct and reactive oxygen species production and maintaining cell migration and invasion and the mitochondrial membrane potential. Anti-AFB1 IgY significantly inhibited the AFB1-induced expression of proteins related to antioxidative, pro-apoptotic, and antiapoptotic processes in a strong dose-dependent manner. These experiments demonstrated that the anti-AFB1 IgY-bound AFB1 could not enter cells. This is the first time that IgY has been found to reduce the effects of small molecular toxins, which will be beneficial for the development of antibodies as detoxication agents.

Long non-coding RNAs in coronary atherosclerosis.

Coronary atherosclerosis (CAS), a leading cause of cardiovascular disease, is a major cause of death worldwide. CAS is a chronic disease in the aorta that can be caused by dyslipidemia, abnormal glucose metabolism, endothelial cell dysfunction, vascular smooth muscle cell (VSMC) or fibrous connective tissue hyperplasia, immune inflammatory reactions, and many other factors. The pathogenesis of CAS is not fully understood, as it is a complex lesion complicated by multiple factors. Damage-response theories have put forward endothelial cell (EC) injury as the initiating factor for CAS; the addition of lipid metabolism disorders may enhance monocyte adhesion, increase the proliferation and migration of fibroblasts and VSMCs, and accelerate the development of CAS. Furthermore, inflammatory and immune responses can create a vicious cycle of endothelial injury, which also plays key roles in the formation of CAS. Therefore, in order to elucidate the mechanisms controlling CAS, it is important to study the etiology of vascular cell dysfunction, abnormal energy and metabolism disorders, and immune and inflammatory reactions. Non-coding RNAs play regulatory roles in the pathogenesis of CAS, especially long non-coding RNAs (lncRNAs); lncRNAs have recently become a major focus for cardiovascular disease mechanisms, as they play numerous roles in the progression of CAS. Therefore, in this review, we discuss the role of lncRNAs in the pathogenesis of coronary CAS, and their role in the prevention and treatment of coronary CAS.

Angiopoietin-1 attenuates angiotensin II-induced ER stress in glomerular endothelial cells via a Tie2 receptor/ERK1/2-p38 MAPK-dependent mechanism.

Research has indicated that endoplasmic reticulum (ER) stress in endothelial cells affects vascular pathologies and induces cellular dysfunction and apoptosis. Angiopoietin1 (Angpt1) has been shown to have therapeutic potential in some vascular diseases, including chronic kidney disease. This study showed that Angpt1 is a powerful factor that attenuated ER stress-induced cellular dysfunction and apoptosis in glomerular endothelial cells (GEnCs). Furthermore, Angpt1 significantly decreased the angiotensin II (Ang II)-induced expression of the ER stress response proteins GRP78, GRP94, p-PERK and CHOP. These results suggest that the Angpt1-mediated cellular protection may occur downstream of the ER stress response. In addition, both specific inhibitors and siRNAs for Tie2 reversed these changes, implying the importance of Tie2 receptor activation in the signalling pathways that prevent ER stress. The protective effects of Angpt1 are related to the activation of two downstream signalling pathways, ERK1/2 and p38 MAPK. The inhibition of these pathways with specific inhibitors, PD98059 and SB203580, respectively, partially increased the expression of chaperones that assist in folding proteins in the ER and reduce the protective effects of Angpt1. In conclusion, Angpt1 attenuated ER stress-induced cellular dysfunction and apoptosis via the Tie2 receptor/ERK1/2-p38 MAPK pathways in GEnCs. This study may provide insights into a novel underlying mechanism and a strategy for alleviating ER stress-induced injury.

Patient-Specific Age: The Other Side of the Coin in Advanced Mesenchymal Stem Cell Therapy.

Multipotential mesenchymal stromal cells (MSC) are present as a rare subpopulation within any type of stroma in the body of higher animals. Prominently, MSC have been recognized to reside in perivascular locations, supposedly maintaining blood vessel integrity. During tissue damage and injury, MSC/pericytes become activated, evade from their perivascular niche and are thus assumed to support wound healing and tissue regeneration. In vitro MSC exhibit demonstrated capabilities to differentiate into a wide variety of tissue cell types. Hence, many MSC-based therapeutic approaches have been performed to address bone, cartilage, or heart regeneration. Furthermore, prominent studies showed efficacy of ex vivo expanded MSC to countervail graft-vs.-host-disease. Therefore, additional fields of application are presently conceived, in which MSC-based therapies potentially unfold beneficial effects, such as amelioration of non-healing conditions after tendon or spinal cord injury, as well as neuropathies. Working along these lines, MSC-based scientific research has been forged ahead to prominently occupy the clinical stage. Aging is to a great deal stochastic by nature bringing forth changes in an individual fashion. Yet, is aging of stem cells or/and their corresponding niche considered a determining factor for outcome and success of clinical therapies?

Anorectal physiology and pathophysiology in the elderly.

Anorectal medical disorders facing the elderly include fecal incontinence, fecal impaction with overflow fecal incontinence, chronic constipation, dyssynergic defecation, hemorrhoids, anal fissure, and pelvic floor disorders. This article discusses the latest advances in age-related changes in morphology and function of anal sphincter, changes in cellular and molecular biology, alterations in neurotransmitters and reflexes, and their impact on functional changes of the anorectum in the elderly. These biophysiologic changes have implications for the pathophysiology of anorectal disorders. A clear understanding and working knowledge of the functional anatomy and pathophysiology will enable appropriate diagnosis and treatment of these disorders.