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BioRxiv : the Preprint Server For... Jun 2024Sjögren's disease (SjD) is a common exocrine disorder typified by chronic inflammation and dryness, but also profound fatigue, suggesting a pathological basis in...
OBJECTIVES
Sjögren's disease (SjD) is a common exocrine disorder typified by chronic inflammation and dryness, but also profound fatigue, suggesting a pathological basis in cellular bioenergetics. In healthy states, damaged or dysfunctional mitochondrial components are broken down and recycled by mitophagy, a specialized form of autophagy. In many autoimmune disorders, however, evidence suggests that dysfunctional mitophagy allows poorly functioning mitochondria to persist and contribute to a cellular milieu with elevated reactive oxygen species. We hypothesized that mitophagic processes are dysregulated in SjD and that dysfunctional mitochondria contribute to overall fatigue. We sought to link fatigue with mitochondrial dysfunction directly in SjD, heretofore unexamined, and further sought to assess the pathogenic extent and implications of dysregulated mitophagy in SjD.
METHODS
We isolated pan T cells via negative selection from the peripheral blood mononuclear cells of 17 SjD and 8 age-matched healthy subjects, all of whom completed fatigue questionnaires prior to phlebotomy. Isolated T cells were analyzed for mitochondrial oxygen consumption rate (OCR) and glycolysis using Seahorse, and linear correlations with fatigue measures were assessed. A mitophagy transcriptional signature in SjD was identified by reanalysis of whole-blood microarray data from 190 SjD and 32 healthy subjects. Differential expression analyses were performed by case/control and subgroup analyses comparing SjD patients by mitophagy transcriptional cluster against healthy subjects followed by bioinformatic interpretation using gene set enrichment analysis.
RESULTS
Basal OCR, ATP-linked respiration, maximal respiration, and reserve capacity were significantly lower in SjD compared to healthy subjects with no observed differences in non-mitochondrial respiration, basal glycolysis, or glycolytic stress. SjD lymphocytic mitochondria show structural alterations compared to healthy subjects. Fatigue scores related to pain/discomfort in SjD correlated with the altered OCR. Results from subgroup analyses by mitophagic SjD clusters revealed highly variable inter-cluster differentially expressed genes (DEGs) and expanded the number of SjD-associated gene targets by tenfold within the same dataset.
CONCLUSION
Mitochondrial dysfunction, associated with fatigue, is a significant problem in SjD and warrants further investigation.
PubMed: 38948768
DOI: 10.1101/2024.06.17.598269 -
Frontiers in Endocrinology 2024Cellular senescence is a common biological process with a well-established link to cancer. However, the impact of cellular senescence on tumor progression remains...
BACKGROUND
Cellular senescence is a common biological process with a well-established link to cancer. However, the impact of cellular senescence on tumor progression remains unclear. To investigate this relationship, we utilized transcriptomic data from a senescence gene set to explore the connection between senescence and cancer prognosis.
METHODS
We developed the senescence score by the Least Absolute Shrinkage and Selection Operator (LASSO) Cox model. We obtained transcriptomic information of the senescence gene set from The Cancer Genome Atlas (TCGA) program. Additionally, we created a nomogram that integrates these senescence scores with clinical characteristics, providing a more comprehensive tool for prognosis evaluation.
RESULTS
We calculated the senescence score based on the expression level of 42 senescence-related genes. We established the nomogram based on the senescence score and clinical characteristics. The senescence score showed a positive correlation with epithelial-to-mesenchymal transition, cell cycle, and glycolysis, and a negative correlation with autophagy. Furthermore, we carried out Gene Ontology (GO) analysis to explore the signaling pathways and biological process in different senescence score groups.
CONCLUSIONS
The senescence score, a novel tool constructed in this study, shows promise in predicting survival outcomes across various cancer types. These findings not only highlight the complex interplay between senescence and cancer but also indicate that cellular senescence might serve as a biomarker for tumor prognosis.
PubMed: 38948528
DOI: 10.3389/fendo.2024.1378356 -
Frontiers in Pharmacology 2024Diabetic nephropathy (DN) constitutes a major microvascular complication of diabetes and is a primary cause of mortality in diabetic individuals. With the global rise in... (Review)
Review
Diabetic nephropathy (DN) constitutes a major microvascular complication of diabetes and is a primary cause of mortality in diabetic individuals. With the global rise in diabetes, DN has become an urgent health issue. Currently, there is no definitive cure for DN. , a Chinese herbal medicine traditionally used, exhibits a wide range of pharmacological effects and is frequently used in the prevention and management of DN. This paper offers an extensive review of the biological mechanisms by which delivers therapeutic advantages in DN management. These mechanisms include activating podocyte autophagy, regulating non-coding RNA, modulating gut microbiota, alleviating lipotoxicity, counteracting oxidative stress, and diminishing inflammatory responses, underscoring the therapeutic potential of in DN treatment.
PubMed: 38948461
DOI: 10.3389/fphar.2024.1390672 -
Endoplasmic reticulum stress and quality control in relation to cisplatin resistance in tumor cells.Frontiers in Pharmacology 2024The endoplasmic reticulum (ER) is a crucial organelle that orchestrates key cellular functions like protein folding and lipid biosynthesis. However, it is highly... (Review)
Review
The endoplasmic reticulum (ER) is a crucial organelle that orchestrates key cellular functions like protein folding and lipid biosynthesis. However, it is highly sensitive to disturbances that lead to ER stress. In response, the unfolded protein response (UPR) activates to restore ER homeostasis, primarily through three sensors: IRE1, ATF6, and PERK. ERAD and autophagy are crucial in mitigating ER stress, yet their dysregulation can lead to the accumulation of misfolded proteins. Cisplatin, a commonly used chemotherapy drug, induces ER stress in tumor cells, activating complex signaling pathways. Resistance to cisplatin stems from reduced drug accumulation, activation of DNA repair, and anti-apoptotic mechanisms. Notably, cisplatin-induced ER stress can dualistically affect tumor cells, promoting either survival or apoptosis, depending on the context. ERAD is crucial for degrading misfolded proteins, whereas autophagy can protect cells from apoptosis or enhance ER stress-induced apoptosis. The complex interaction between ER stress, cisplatin resistance, ERAD, and autophagy opens new avenues for cancer treatment. Understanding these processes could lead to innovative strategies that overcome chemoresistance, potentially improving outcomes of cisplatin-based cancer treatments. This comprehensive review provides a multifaceted perspective on the complex mechanisms of ER stress, cisplatin resistance, and their implications in cancer therapy.
PubMed: 38948460
DOI: 10.3389/fphar.2024.1419468 -
World Journal of Experimental Medicine Jun 2024Mitochondrial dysfunction is a key driver of cardiovascular disease (CVD) in metabolic syndrome and diabetes. This dysfunction promotes the production of reactive oxygen... (Review)
Review
Mitochondrial dysfunction is a key driver of cardiovascular disease (CVD) in metabolic syndrome and diabetes. This dysfunction promotes the production of reactive oxygen species (ROS), which cause oxidative stress and inflammation. Angiotensin II, the main mediator of the renin-angiotensin-aldosterone system, also contributes to CVD by promoting ROS production. Reduced activity of sirtuins (SIRTs), a family of proteins that regulate cellular metabolism, also worsens oxidative stress. Reduction of energy production by mitochondria is a common feature of all metabolic disorders. High SIRT levels and 5' adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta, which promotes ketosis. Ketosis, in turn, increases autophagy and mitophagy, processes that clear cells of debris and protect against damage. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), a class of drugs used to treat type 2 diabetes, have a beneficial effect on these mechanisms. Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events. SGLT2i also increase mitochondrial efficiency, reduce oxidative stress and inflammation, and strengthen tissues. These findings suggest that SGLT2i hold great potential for the treatment of CVD. Furthermore, they are proposed as anti-aging drugs; however, rigorous research is needed to validate these preliminary findings.
PubMed: 38948421
DOI: 10.5493/wjem.v14.i2.91519 -
Asian Journal of Pharmaceutical Sciences Jun 2024Autophagy and mitophagy pose unresolved challenges in understanding the pathology of diabetic heart condition (DHC), which encompasses a complex range of cardiovascular... (Review)
Review
Autophagy and mitophagy pose unresolved challenges in understanding the pathology of diabetic heart condition (DHC), which encompasses a complex range of cardiovascular issues linked to diabetes and associated cardiomyopathies. Despite significant progress in reducing mortality rates from cardiovascular diseases (CVDs), heart failure remains a major cause of increased morbidity among diabetic patients. These cellular processes are essential for maintaining cellular balance and removing damaged or dysfunctional components, and their involvement in the development of diabetic heart disease makes them attractive targets for diagnosis and treatment. While a variety of conventional diagnostic and therapeutic strategies are available, DHC continues to present a significant challenge. Point-of-care diagnostics, supported by nanobiosensing techniques, offer a promising alternative for these complex scenarios. Although conventional medications have been widely used in DHC patients, they raise several concerns regarding various physiological aspects. Modern medicine places great emphasis on the application of nanotechnology to target autophagy and mitophagy in DHC, offering a promising approach to deliver drugs beyond the limitations of traditional therapies. This article aims to explore the potential connections between autophagy, mitophagy and DHC, while also discussing the promise of nanotechnology-based theranostic interventions that specifically target these molecular pathways.
PubMed: 38948399
DOI: 10.1016/j.ajps.2024.100927 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024Endometriosis (EMT), a common benign gynecological disease, is a leading cause of infertility in women. EMT affects female fertility in various aspects. However, the...
Endometriosis (EMT), a common benign gynecological disease, is a leading cause of infertility in women. EMT affects female fertility in various aspects. However, the underlying mechanisms have not been fully elucidated. Mitochondria are known as the "powerhouse" of a cell. They play pivotal roles in the physiological processes of cellular energy metabolism, calcium homeostasis, oxidative stress, autophagy, the regulation of cell cycle, and cell death, and are involved in the pathophysiology of many diseases. Cellular mitochondria are highly dynamic, continuously undergoing cyclic fission and fusion to meet the demands of cellular activities. Balanced mitochondrial dynamics are critical for maintaining normal reproductive function in women. In addition, mitochondria are the major source of reactive oxygen species (ROS). Cell damage, cell death, and fibrosis mediated by the imbalance in the oxidative-antioxidant system in EMT patients lead to decreased oocyte quality and ovarian reserve. Currently, the treatment of EMT-associated infertility remains a challenging and controversial topic. We herein reviewed the latest findings on the role of mitochondrial dysfunction in EMT-associated infertility and the potential therapeutic targets.
PubMed: 38948278
DOI: 10.12182/20240560404 -
Avicenna Journal of Phytomedicine 2024Baicalin and baicalein are natural flavonoids reported for the first time from Georgi. Recently, attention has been paid to these valuable flavonoids due to their... (Review)
Review
OBJECTIVE
Baicalin and baicalein are natural flavonoids reported for the first time from Georgi. Recently, attention has been paid to these valuable flavonoids due to their promising effects. This paper aims to have a comprehensive review of their pharmacological effects.
MATERIALS AND METHODS
An extensive search through scientific databases including Scopus, PubMed, and ISI Web of Science was established.
RESULTS
According to literature, these compounds have been mainly effective in the treatment of neurological and neurodegenerative diseases, hepatic and cardiovascular disorders, metabolic syndrome, and cancers through anti-inflammatory and antioxidant pathways. Induction of apoptosis and autophagy, and inhibition of migration and metastasis are the main mechanisms for their cytotoxic and antitumor activities. Decreasing inflammation, reducing oxidative stress, regulating the metabolism of lipids, and decreasing fibrosis, apoptosis, and steatosis are their main hepatoprotective mechanisms. Inhibiting the development of cardiac fibrosis and reducing inflammation, oxidative stress, and apoptosis are also the mechanisms suggested for cardioprotective activities. Decreasing the accumulation of inflammatory mediators and improving cognitive function and depressive-like behaviours are the main mechanisms for neurological and neurodegenerative activities.
CONCLUSION
The findings suggest the therapeutic potential of baicalin and baicalein. However, complementary research in different and models to investigate their mechanisms of action as well as clinical trials to evaluate their efficacy and safety are suggested.
PubMed: 38948180
DOI: 10.22038/AJP.2023.22307 -
Britannin suppresses MCF-7 breast cancer cell growth by inducing apoptosis and inhibiting autophagy.Avicenna Journal of Phytomedicine 2024Breast cancer is the main reason for cancer-related death in women. Britannin is a sesquiterpene lactone compound derived from with anti-tumor properties. We aimed to...
OBJECTIVE
Breast cancer is the main reason for cancer-related death in women. Britannin is a sesquiterpene lactone compound derived from with anti-tumor properties. We aimed to explore the impacts of britannin on apoptosis and autophagy in MCF-7 breast cancer cell line.
MATERIALS AND METHODS
The cytotoxic influences of britannin on MCF-7 cells were estimated by the MTT method. The expression levels of apoptosis-associated genes such as , , , , and and transcripts of autophagy markers including , , , , , , and were quantified using quantitative real time-PCR (qRT-PCR). Western blotting method was used to evaluate the amount of caspase 3, phosphorylated JAK2, phosphorylated STAT3, ATG1, ATG4, ATG5, Beclin1, and LC-III.
RESULTS
Treatment of MCF-7 cells with various concentrations of britannin remarkably hindered the viability of these cells compared to the controls. This compound significantly elevated the expression of pro-apoptotic caspase-3 but did not influence the levels of anti-apoptotic and . Britannin decreased the levels of phosphorylated forms of JAK2 and STAT3 proteins causing the blockage of the JAK/STAT pathway. Four autophagy factors expressions, including ATG4, ATG5, Beclin1, and LCIII, were reduced due to the effect of britannin on MCF-7 cells.
CONCLUSION
Britannin triggered apoptosis in MCF-7 cells by a mechanism that led to the blockade of the JAK/STAT pathway. Moreover, britannin prohibited autophagy in these cancer cells. This may suggest britannin as an agent for the suppression of breast tumors or as an adjutant for the enhancement of anti-breast cancer drugs effect.
PubMed: 38948174
DOI: 10.22038/AJP.2023.22995 -
World Journal of Stem Cells Jun 2024Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease that affects premature infants. Although mounting evidence supports the therapeutic effect of...
BACKGROUND
Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease that affects premature infants. Although mounting evidence supports the therapeutic effect of exosomes on NEC, the underlying mechanisms remain unclear.
AIM
To investigate the mechanisms underlying the regulation of inflammatory response and intestinal barrier function by umbilical cord mesenchymal stem cell (UCMSCs) exosomes, as well as their potential in alleviating NEC in neonatal mice.
METHODS
NEC was induced in 5-d-old C57BL/6 pups through hypoxia and gavage feeding of formula containing lipopolysaccharide (LPS), after which the mice received human UCMSC exosomes (hUCMSC-exos). The control mice were allowed to breastfeed with their dams. Ileal tissues were collected from the mice and analyzed by histopathology and immunoblotting. Colon tissues were collected from NEC neonates and analyzed by immunofluorescence. Molecular biology and cell culture approaches were employed to study the related mechanisms in intestinal epithelial cells.
RESULTS
We found that autophagy is overactivated in intestinal epithelial cells during NEC, resulting in reduced expression of tight junction proteins and an increased inflammatory response. The ability of hUCMSC-exos to ameliorate NEC in a mouse model was dependent on decreased intestinal autophagy. We also showed that hUCMSC-exos alleviate the inflammatory response and increase migration ability in intestinal epithelial cells induced by LPS.
CONCLUSION
These results contribute to a better understanding of the protective mechanisms of hUCMSC-exos against NEC and provide a new theoretical and experimental foundation for NEC treatment. These findings also enhance our understanding of the role of the autophagy mechanism in NEC, offering potential avenues for identifying new therapeutic targets.
PubMed: 38948093
DOI: 10.4252/wjsc.v16.i6.728