When lipid homeostasis runs havoc: lipotoxicity links lysosomal dysfunction to autophagy.

payth.elady61 shared this article with you from Inoreader When lipid homeostasis runs havoc: lipotoxicity links lysosomal dysfunction to autophagy. Via pubmed: autophagy When lipid homeostasis runs havoc: lipotoxicity links lysosomal dysfunction to autophagy. Matrix Biol. 2020 Dec 05;: Authors: Tegeder I, Kögel D Abstract Autophagy is one of the major cellular degradation pathways, which prevents accumulation of cellular wastes including "hazardous" material such as oxidized proteins and lipids and allows removal of aggregates and dysfunctional organelles. Hence, autophagy is meant to preserve cell survival, and is mostly protective. However, autophagy may trigger a feedforward, exaggerated cycle in which cells continue to degrade proteins and organelles, finally leading to autophagy-dependent cell death (ADCD), a process that can be initiated with lysosomotropic detergents, which are protonated within the lysosome and cause a permeabilization of the membrane. Such drugs may be useful to combat cancer. In some paradigms of ADCD, there is evidence that the cellular fate is determined by the integrity of lysosomal membranes, transporters, enzymes and ion gradients. Detergent-like effects of lysosomotropic drugs can over-activate autophagy. A disruption of the lysosomal membrane barrier with leak age of lysosomal enzymes or lipids may trigger a vicious cycle via proteases and accumulation of lipids, which impair the functions of the plasma - and organelle membranes. This review summarizes the current evidence for a crosstalk between lysosomal dysfunction and autophagy and the lysosomal events, which progress toward ADCD with a focus on the role of sphingolipids and cholesterol as cargo and as regulators of ADCD. PMID: 33290835 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Age-related impairment of autophagy in cervical motor neurons.

payth.elady61 shared this article with you from Inoreader Age-related impairment of autophagy in cervical motor neurons. Via pubmed: autophagy Age-related impairment of autophagy in cervical motor neurons. Exp Gerontol. 2020 Dec 05;:111193 Authors: Pareja-Cajiao M, Gransee HM, Stowe JM, Rana S, Sieck GC, Mantilla CB Abstract Neuromuscular dysfunction is common in old age. Damaged cytoplasmic structures aggregate with aging, especially in post-mitotic cells like motor neurons. Autophagy is a ubiquitous cell process that aids in the clearance of damaged aggregates. Accordingly, we hypothesized that autophagy is impaired in old age, contributing to neuromuscular dysfunction via an effect in motor neurons. Autophagy flux may be impaired as a result of deficits in the initiation, elongation or degradation phases. Changes in the expression levels of core proteins necessary for each of the autophagy phases were evaluated by Western blotting in the cervical spinal cord (segments C2-C6 corresponding to the phrenic motor pool) of adult male and female mice at 6-, 18-, and 24-months of age (reflecting 100%, 90% and 75% survival, respectively). There was no evidence of an effect of age on the expression of the autophagy markers Beclin-1 (Becn-1; initiation), ATG7 and ATG5/12 complex (elongation) or LC3 (elon gation/degradation). Reduced p62 expression (a marker of degradation) was evident in the cervical spinal cord of adult mice at 18-months compared to 24-months. Accordingly, expression of LC3 and p62 in motor neurons was analyzed using immunofluorescence and confocal microscopy in separate animals. LC3 and p62 immunoreactivity was evident in the gray matter with minimal expression in the white matter across all age groups. A mixed linear model with animal as a random effect was used to compare relative LC3 and p62 expression in motor neurons to gray matter across age groups. Expression of both LC3 and p62 was higher in choline acetyl transferase (ChAT)-positive motor neurons (~2-3 fold vs. gray matter). Across age groups, there were differences in the relative expression of LC3 (F2,12 = 7.59, p < 0.01) and p62 (F2,12 = 8.00, p < 0.01) in cervical motor neurons. LC3 expression in motor neurons increased ~20% by 24-months of age in both male and female mice. p62 e xpression in motor neurons increased ~70% by 18-months compared to 6-months with no further changes by 24-months of age in male mice. p62 expression did not change across age groups in female mice, and was ~20% higher than in males. Our findings highlight important changes in autophagy pathways that likely contribute to the development of aging-related neuromuscular dysfunction in mice. At 18-months of age, increased autophagosome clearance (reduced p62 expression) appears to be a global effect not restricted to motor neurons. By 24-months of age, increased expression of LC3 and p62 indicates impaired autophagy with autophagosome accumulation in cervical motor neurons. PMID: 33290859 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

MicroRNA-638 induces apoptosis and autophagy in human liver cancer cells by targeting enhancer of zeste homolog 2 (EZH2).

payth.elady61 shared this article with you from Inoreader MicroRNA-638 induces apoptosis and autophagy in human liver cancer cells by targeting enhancer of zeste homolog 2 (EZH2). Via pubmed: autophagy MicroRNA-638 induces apoptosis and autophagy in human liver cancer cells by targeting enhancer of zeste homolog 2 (EZH2). Environ Toxicol Pharmacol. 2020 Dec 05;:103559 Authors: Zhang H, Liang H, Wu S, Zhang Y, Yu Z Abstract Liver cancer is of the devastating human cancers and its incidence is increasing at an alarming rate. The clinical outcomes are far from descent due to lack of efficient therapeutic targets and chemotherapeutic agents. Studies have revealed the therapeutic implications of microRNAs in the management of different human cancers. This study was designed to explore the role and therapeutic potential of miR-638 in liver cancer via modulation of zeste homolog 2 (EZH2). The results revealed significant (P < 0.05) downregulation of miR-638 in human liver cancer tissues and cell lines. Overexpression of miR-638 led to a significant (P < 0.05) decline in liver cancer cell proliferation. Nonetheless, inhibition of miR-638 could promote the proliferation of the human liver cancer cells. The DAPI and annexin V/PI staining assays revealed that miR-638 induces apoptosis in human liver cancer cells which was accompanied by enhancement of Bax and depletion of Bcl-2 expression. F urthermore, miR-638 overexpression also leads to a significant (P < 0.05) increase of autophagosomes and autolysosomes in liver cancer cells suggestive of autophagy. The induction of autophagy was further confirmed by increase and decrease in expression of LC3B-II and Beclin-1 proteins, respectively. In contrary, inhibition of miR-638 prevented both apoptosis and autophagy of the liver cancer cells. In silico analysis and the dual luciferase assay revealed EZH2 as the molecular target of miR-638 at post-transcriptional level. The qRT-PCR showed that EZH2 to be significantly (P < 0.05) upregulated in the human liver cancer tissues and cell lines. However, the expression of EZH2 was considerably suppressed upon miR-638 overexpression in SNU-423 cells. Taken together, these findings suggest the tumor-suppressive role of miR-638/EZH2 axis liver cancer and point towards the potential of miR-638 as therapeutic target in the treatment of liver cancer. PMID: 33290872 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Nicotinamide adenine dinucleotide treatment alleviates the symptoms of experimental autoimmune encephalomyelitis by activating autophagy and inhibiting the NLRP3 inflammasome.

payth.elady61 shared this article with you from Inoreader Nicotinamide adenine dinucleotide treatment alleviates the symptoms of experimental autoimmune encephalomyelitis by activating autophagy and inhibiting the NLRP3 inflammasome. Via pubmed: autophagy Nicotinamide adenine dinucleotide treatment alleviates the symptoms of experimental autoimmune encephalomyelitis by activating autophagy and inhibiting the NLRP3 inflammasome. Int Immunopharmacol. 2020 Dec 04;90:107092 Authors: Wang X, Li B, Liu L, Zhang L, Ma T, Guo L Abstract Nicotinamide adenine dinucleotide (NAD + ) is an essential cofactor in numerous metabolic pathways, and so may support protective and reparative processes against central nervous system diseases such as multiple sclerosis (MS). Here, we investigated the therapeutic potential of NAD + administration in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS and the contributions of autophagic regulation and NLRP3 inflammasome activity. EAE was induced in female C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG) p35-55 and disease severity analyzed by neurological function score and histological scores of spinal cord sections stained with hematoxylin-eosin or luxol fast blue. Outcomes were compared among control mice and EAE groups receiving daily post-immunization vehicle injections, NAD + injections, injection of the autophagy inhibitor 3-methyladenine (3-MA), or co-injection of NAD + and 3-MA. Exp ression levels of autophagy-related proteins (Beclin1, LC3-II/I, and p62/SQSTM1) were assessed by Western blotting, the activated microglial cells were evaluated by immunohistochemistry, while mRNA expression levels of NOD-like receptor family pyrin domain containing 3 (NLRP3), interleukin (IL)-1β, IL-2, IL-17, IL-18, interferon-γ (IFN-γ) and IL-10 were detected by real-time PCR. The proportions of Th1 and Th17 cells in spleen were evaluated using flow cytometry. Treatment with NAD + alleviated demyelination, nerve injury, microglial activation and motor function abnormalities of EAE mice. In addition, NAD + increased the expressions of the autophagy-related proteins LC3-II/I and Beclin 1, and reduced the expression of p62. Treatment with NAD + also inhibited the expressions of NLRP3 and modulated the differentiation of Th1 and Th17 cells, reduced the expressions of the pro-inflammatory factors IL-1β, IL-2, IL-18, IFN-γ and IL-17, and increased the expression of anti-inflammatory IL-10. Conversely, 3-MA aggravated spinal cord inflammation and demyelination, and delayed spontaneous remission from EAE. Furthermore, the beneficial effects of NAD + were abolished by 3-MA cotreatment. Our results indicate that NAD + suppresses the NLRP3 inflammasome at least in part through the activation of autophagy to relieve the symptoms of EAE. Therefore, regulation of autophagy by NAD + treatment may be an effective therapeutic strategy for MS. PMID: 33290962 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The apple dihydrochalcone phloretin suppresses growth and improves chemosensitivity of breast cancer cells via inhibition of cytoprotective autophagy.

payth.elady61 shared this article with you from Inoreader The apple dihydrochalcone phloretin suppresses growth and improves chemosensitivity of breast cancer cells via inhibition of cytoprotective autophagy. Via pubmed: autophagy The apple dihydrochalcone phloretin suppresses growth and improves chemosensitivity of breast cancer cells via inhibition of cytoprotective autophagy. Food Funct. 2020 Dec 08;: Authors: Chen M, Gowd V, Wang M, Chen F, Cheng KW Abstract The inhibitory effect and mechanism of the apple dihydrochalcone, phloretin, on breast cancer cell growth were evaluated in in vitro conditions simulating complete nutrition and glucose-restriction, respectively. In two breast cancer cell lines with different histological backgrounds, phloretin consistently exhibited much stronger activity against cell growth in glucose-limiting than in full media. RNA-seq analysis showed that key autophagy-related genes were downregulated upon phloretin treatment in both estrogen-receptor-positive MCF7 and triple-negative MDA-MB-231 cells. Immunoblotting verified significantly decreased expression of LC3B-II by phloretin in low-glucose and glucose-free media, but not in full medium. Together with the use of two pharmacological autophagy inhibitors, chloroquine and 3-methyladenine, and confocal microscopy of breast cancer cell lines transfected with GFP-LC3B, phloretin demonstrated a strong capability to suppress autophagic flux, which was li kely mediated through downregulation of mTOR/ULK1 signaling, whereas the expression of canonical autophagy regulators ATG5 and ATG7 was not significantly affected. Phloretin also reversed tamoxifen- and doxorubicin-induced cytoprotective autophagy in the breast cancer cell lines, and this was manifested in its synergistic growth inhibitory effect with these chemotherapeutic agents. Furthermore, it was able to restore or enhance the chemosensitivity of a tamoxifen-resistant cell line. Taken together, our study has, for the first time, revealed that phloretin could effectively suppress glucose-starvation- and chemotherapeutic-induced cytoprotective autophagy in breast cancer cell lines likely through downregulation of mTOR/ULK1 signaling. PMID: 33291138 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Retinal and Callosal Activity-Dependent Chandelier Cell Elimination Shapes Binocularity in Primary Visual Cortex.

payth.elady61 shared this article with you from Inoreader Retinal and Callosal Activity-Dependent Chandelier Cell Elimination Shapes Binocularity in Primary Visual Cortex. Via pubmed: frontiers neuroscien... Retinal and Callosal Activity-Dependent Chandelier Cell Elimination Shapes Binocularity in Primary Visual Cortex. Neuron. 2020 Nov 25;: Authors: Wang BS, Bernardez Sarria MS, An X, He M, Alam NM, Prusky GT, Crair MC, Huang ZJ Abstract In mammals with binocular vision, integration of the left and right visual scene relies on information in the center visual field, which are relayed from each retina in parallel and merge in the primary visual cortex (V1) through the convergence of ipsi- and contralateral geniculocortical inputs as well as transcallosal projections between two visual cortices. The developmental assembly of this binocular circuit, especially the transcallosal pathway, remains incompletely understood. Using genetic methods in mice, we found that several days before eye-opening, retinal and callosal activities drive massive apoptosis of GABAergic chandelier cells (ChCs) in the binocular region of V1. Blockade of ChC elimination resulted in a contralateral eye-dominated V1 and deficient binocular vision. As pre-vision retinal activities convey the left-right organization of the visual field, their regulation of ChC density through the transcallosal pathway may prime a nascent binocular territory for subsequent experience-driven tuning during the post-vision critical period. PMID: 33290732 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Colonoscopic evaluation of diarrhea/colitis occurring as an immune-related adverse event.

payth.elady61 shared this article with you from Inoreader Colonoscopic evaluation of diarrhea/colitis occurring as an immune-related adverse event. Via pubmed: "jpn j clin oncol"[j... Colonoscopic evaluation of diarrhea/colitis occurring as an immune-related adverse event. Jpn J Clin Oncol. 2020 Dec 09;: Authors: Yamauchi Y, Arai M, Akizue N, Ohta Y, Okimoto K, Matsumura T, Fan MM, Imai C, Tawada A, Kato J, Kato N, Takiguchi Y Abstract OBJECTIVE: Diarrhea is often observed as an immune-related adverse event. In this study, we conducted a retrospective review of the severity of diarrhea, its treatment and the endoscopic findings in patients developing diarrhea as an immune-related adverse event. METHODS: From August 2015 to June 2019, a total of 369 patients received treatment with immune checkpoint inhibitors at our hospital. For this study, development of grade 2 or more diarrhea in these patients was defined as an immune-related adverse event. We analyzed the histopathological severity of the bowel lesions according to the Nancy histological index for ulcerative colitis. RESULTS: Of the 369 patients, 27 (7.3%) developed diarrhea as an immune-related adverse event. Of these 27 patients, 18 received steroid treatment. Colonoscopy was performed in 17 patients and culture of the feces in 18. The tests revealed evidence of bacterial colitis (Aeromonas hydrophila) in two patients. The Nancy histological index was 4, 3, 2, 1 and 0 in two, three, two, two and seven patients, respectively. No findings on colonoscopy were observed in 7 of the 17 patients (41%) who underwent colonoscopy, and most of these patients recovered without steroid treatment. Patients with lower values of the Nancy histological index tended to show better responses to steroid treatment. CONCLUSIONS: To avoid unnecessary steroid administration, colonoscopic evaluation is essential in patients receiving treatment with immune checkpoint inhibitors who present with diarrhea as an immune-related adverse event. In addition, the endoscopic findings could be useful to predict the response to steroid treatment. PMID: 33290513 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck.

payth.elady61 shared this article with you from Inoreader Induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck. Via pubmed: "jpn j clin oncol"[j... Induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck. Jpn J Clin Oncol. 2020 Dec 09;: Authors: Okano S, Homma A, Kiyota N, Tahara M, Hanai N, Asakage T, Matsuura K, Ogawa T, Saito Y, Sano D, Kodaira T, Motegi A, Yasuda K, Takahashi S, Tanaka K, Onoe T, Yokota T, Imamura Y, Ariizumi Y, Akimoto T, Hayashi R Abstract In order to maximize the benefit of induction chemotherapy, practice based on a comprehensive interpretation of a large number of clinical trials, as in this review, is essential. The standard treatment for locally advanced squamous cell carcinoma of the head and neck is surgery or chemoradiation. However, induction chemotherapy followed by (chemo) radiotherapy may be used in some circumstances. Although many clinical trials of induction chemotherapy have been conducted, a rationale other than to preserve the larynx is still controversial. Selection of this modality should therefore be made with care. The current standard regimen for induction chemotherapy is docetaxel, cisplatin and 5-FU, but concerns remain about toxicity, cost and the duration of treatment. Regarding treatment after induction chemotherapy, it is also unclear whether radiation alone or chemoradiation is the better option. Furthermore, there is no answer as to what drugs should be used in combination with ra diation therapy after induction chemotherapy. Several new induction chemotherapy treatment developments are currently underway, and future developments are expected. This review article summarizes the current position of induction chemotherapy for head and neck squamous cell carcinoma, based on the evidence produced to date, and discusses the future prospects for this treatment. PMID: 33290543 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Date seeds alleviate behavioural and neuronal complications of metabolic syndrome in rats.

payth.elady61 shared this article with you from Inoreader Date seeds alleviate behavioural and neuronal complications of metabolic syndrome in rats. Via pubmed: "arch physiol bioche... Date seeds alleviate behavioural and neuronal complications of metabolic syndrome in rats. Arch Physiol Biochem. 2020 Dec 08;:1-15 Authors: Dallagi Y, Rahali D, Perrotte M, Dkhili H, Korsan A, El May MV, El Fazaa S, Ramassamy C, El Golli N Abstract Unhealthy dietary habits can play a crucial role in metabolic damages, promoting alteration of neural functions through the lifespan. Recently, dietary change has been perceived as the first line intervention in prevention and/or treatment of metabolic damages and related diseases. In this context, our study was designed to assess the eventual therapeutic effect of date seeds administration on memory and learning and on neuronal markers in a rat Metabolic Syndrome model. For this purpose, 32 adult male Wistar rats were fed with standard diet or high-fat high-sugar diet during ten weeks. After this, 16 rats were sacrified and the remaining rats received an oral administration of 300 mg of date seeds/kg of body weight during four supplementary weeks. Before sacrifice, we evaluate cognitive performances by the Barnes maze test. Afterwards, neuronal, astrocytic, microtubular and oxidative markers were investigated by immunoblotting methods. In Metabolic syndrome rats, results s howed impairment of spatial memory and histological alterations. We identified neuronal damages in hippocampus, marked by a decrease of NeuN and an increase of GFAP and pTau396. Finally, we recorded an increase in protein oxidation and lipid peroxidation, respectively identified by an up-regulation of protein carbonyls and 4-HNe. Interestingly, date seeds administration improved these behavioural, histological, neuronal and oxidative damages highlighting the neuroprotective effect of this natural compound. Liquid Chromatography-Mass Spectrometry (LC-MS) identified, in date seeds, protocatechuic acid, caffeoylshikimic acid and vanillic acid, that could potentially prevent the progression of neurodegenerative diseases, acting through their antioxidant properties. PMID: 33290103 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The potential association between metabolic syndrome and risk of post-surgical adhesion.

payth.elady61 shared this article with you from Inoreader The potential association between metabolic syndrome and risk of post-surgical adhesion. Via pubmed: "arch physiol bioche... The potential association between metabolic syndrome and risk of post-surgical adhesion. Arch Physiol Biochem. 2020 Dec 08;:1-6 Authors: Ferns GA, Shahini Shams Abadi M, Arjmand MH Abstract Metabolic syndrome (MetS) is defined by the clustering of several associated with a group of disorders that include: obesity, dyslipidemia, hypertension, and insulin resistance. The incidence of MetS is increasing globally around the world. Indeed the rates of different types of surgery in older or younger patients with Mets are increasing and they are exposed to a wide range of operations including abdominal, pelvic, urologic, or any invasive procedures. Post-surgical adhesion is a common problem and is a challenge for the surgeon. Despite many studies on its pathogenesis, there remain many un-answered questions about it, for example why certain tissues and patients are more at higher risk of post-surgical adhesions. Many studies have suggested that MetS is associated with up-regulating molecular mechanisms leading to chronic inflammation and hypercoagulability. In this review, we discuss some of the molecular mechanisms by MetS may enhance post-surgical adhesion, and partic ularly regarding those involved in coagulation and inflammation. PMID: 33290664 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Emergency Orthopaedic surgery in the pandemic era: A case series at a national tertiary hospital in Jakarta, Indonesia.

payth.elady61 shared this article with you from Inoreader Emergency Orthopaedic surgery in the pandemic era: A case series at a national tertiary hospital in Jakarta, Indonesia. Via pubmed: "int j surg case rep... Emergency Orthopaedic surgery in the pandemic era: A case series at a national tertiary hospital in Jakarta, Indonesia. Int J Surg Case Rep. 2020 Dec 02;: Authors: Kamal AF, Widodo W, Kuncor MW, Karda IWAM, Prabowo Y, Habib H, Liastuti LD, Trimartani, Hutagalung EU, Saleh I, Tobing SDAL, Gunawan B, Dilogo IH, Lubis AM, Kurniawan A, Rahyussalim AJ, Oesman I, Ifran NN, Latief W, Wijaya MT, Ivansyah MD, Primaputra MRA, Reksoprodjo AY, Hendriarto A, Novriandi KMA, Alaztha Z, Canintika AF, Sitanggang AHR Abstract Introduction: Every emergency surgery performed is aimed at saving lives; however, during COVID-19 pandemic, surgeries are often postponed. Many existing recommendations take into account postponing surgery during a pandemic. How these surgeries can lead to increasing infection rates has not been widely published. This study aims to investigate the relationship of emergency orthopaedic surgery and the incidence rate of COVID-19. Presentation of case: : This was a case series of 14 patients. The study was performed at the emergency department unit at a national tertiary hospital in Jakarta, Indonesia. A total of 14 patients underwent orthopaedic surgery in the emergency room of our institution. The mean age of the subjects was 40.07 ± 20.5 years. Twelve (85.7%) were male patients and 2 (14.3%) were female patients. The average duration of surgery was 125 minutes. The most used type of anaesthesia was general anaesthesia for 6 operations (50%). Patients were hospitalized for an average length of 4 days. Three patients had infiltrates found on plain x-ray examination, which required further examination to determine whether the cause was COVID-19 infection or not. There was no ground glass appearance (GGO) in the three patients in further follow-up examination. Conclusions: We found that emergency orthopaedic surgery was not associated with increasing number of COVID-19 cases. Factors including duration of surgery, length of stay, types of anaesthesia and comorbidities were also not associated with COVID-19 cases in this study. PMID: 33288992 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.