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Anatolian Journal of Cardiology Jul 2024Myocardial ischemia-reperfusion injury (I/R) has been improved with drugs and effective reperfusion, but it still cannot be prevented.
BACKGROUND
Myocardial ischemia-reperfusion injury (I/R) has been improved with drugs and effective reperfusion, but it still cannot be prevented.
METHODS
To investigate whether renal denervation (RDN) reduces cardiomyocyte apoptosis by ameliorating endoplasmic reticulum stress, 60 male specific pathogen-free (SPF) Wistar rats were randomly divided into 6 groups (n = 6). We established the I/R rat model by ligating the left anterior descending artery. The I/R+ angiotensin receptor neprilysin inhibitors (ARNI) group received ARNIs for 2 weeks until euthanasia.
RESULTS
The I/R+RDN and I/R+ARNI groups have significantly ameliorated left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) and reversed expansion of the left ventricular end-systolic diameter (LVSD) and left ventricular end diastolic diameter (LVDD) compared to the I/R group. The levels of norepinephrine (NE), angiotensin II, and aldosterone (ALD) increased significantly in the I/R group, but decreased significantly after RDN and ARNI intervention. In the I/R+RDN and I/R+ARNI groups, the myocardial tissue edema was alleviated. The infarct size was smaller in the I/R+RDN and I/R+ARNI groups compared to the I/R group. Apoptosis of cardiomyocytes and fibroblasts in myocardial tissue increased significantly in the I/R group, which was greatly diminished by RDN and ARNI. The expression of Bax, caspase-3, CHOP, PERK, and ATF4 protein was significantly increased in the I/R group, which compared to other groups, and the level of CHOP, PERK, and ATF4 gene expression increased. After RDN intervention, these expression levels recovered to varying degrees.
CONCLUSION
The effect of RDN may be associated with regulating the endoplasmic reticulum stress PERK/ATF4 signaling pathway.
Topics: Animals; Male; Rats; Rats, Wistar; Apoptosis; Myocardial Reperfusion Injury; Myocytes, Cardiac; Kidney; Disease Models, Animal; Endoplasmic Reticulum; Mitochondria; Denervation; Random Allocation; Endoplasmic Reticulum Stress; Mitochondria Associated Membranes
PubMed: 38940410
DOI: 10.14744/AnatolJCardiol.2024.3579 -
Gut Microbes 2024Despite the observed decrease in liver fat associated with metabolic-associated fatty liver disease (MAFLD) in mice following fecal microbiota transplantation, the...
Washed microbiota transplantation promotes homing of group 3 innate lymphoid cells to the liver via the CXCL16/CXCR6 axis: a potential treatment for metabolic-associated fatty liver disease.
Despite the observed decrease in liver fat associated with metabolic-associated fatty liver disease (MAFLD) in mice following fecal microbiota transplantation, the clinical effects and underlying mechanisms of washed microbiota transplantation (WMT), a refined method of fecal microbiota transplantation, for the treatment of MAFLD remain unclear. In this study, both patients and mice with MAFLD exhibit an altered gut microbiota composition. WMT increases the levels of beneficial bacteria, decreases the abundance of pathogenic bacteria, and reduces hepatic steatosis in MAFLD-affected patients and mice. Downregulation of the liver-homing chemokine receptor CXCR6 on ILC3s results in an atypical distribution of ILC3s in patients and mice with MAFLD, characterized by a significant reduction in ILC3s in the liver and an increase in ILC3s outside the liver. Moreover, disease severity is negatively correlated with the proportion of hepatic ILC3s. These hepatic ILC3s demonstrate a mitigating effect on hepatic steatosis through the release of IL-22. Mechanistically, WMT upregulates CXCR6 expression on ILC3s, thereby facilitating their migration to the liver of MAFLD mice the CXCL16/CXCR6 axis, ultimately contributing to the amelioration of MAFLD. Overall, these findings highlight that WMT and targeting of liver-homing ILC3s could be promising strategies for the treatment of MAFLD.
Topics: Animals; Receptors, CXCR6; Chemokine CXCL16; Mice; Fecal Microbiota Transplantation; Humans; Gastrointestinal Microbiome; Liver; Lymphocytes; Mice, Inbred C57BL; Male; Immunity, Innate; Fatty Liver; Interleukin-22; Non-alcoholic Fatty Liver Disease; Interleukins; Female
PubMed: 38940400
DOI: 10.1080/19490976.2024.2372881 -
International Journal of Molecular... Aug 2024The ubiquitin (Ub)‑proteasome system (UPS) plays a pivotal role in maintaining protein homeostasis and function to modulate various cellular processes including... (Review)
Review
The ubiquitin (Ub)‑proteasome system (UPS) plays a pivotal role in maintaining protein homeostasis and function to modulate various cellular processes including skeletal cell differentiation and bone homeostasis. The Ub ligase E3 promotes the transfer of Ub to the target protein, especially transcription factors, to regulate the proliferation, differentiation and survival of bone cells, as well as bone formation. In turn, the deubiquitinating enzyme removes Ub from modified substrate proteins to orchestrate bone remodeling. As a result of abnormal regulation of ubiquitination, bone cell differentiation exhibits disorder and then bone homeostasis is affected, consequently leading to osteoporosis. The present review discussed the role and mechanism of UPS in bone remodeling. However, the specific mechanism of UPS in the process of bone remodeling is still not fully understood and further research is required. The study of the mechanism of action of UPS can provide new ideas and methods for the prevention and treatment of osteoporosis. In addition, the most commonly used osteoporosis drugs that target ubiquitination processes in the clinic are discussed in the current review.
Topics: Humans; Osteoporosis; Ubiquitination; Animals; Ubiquitin; Proteasome Endopeptidase Complex; Bone Remodeling; Ubiquitin-Protein Ligases
PubMed: 38940355
DOI: 10.3892/ijmm.2024.5392 -
Oncology Reports Aug 2024The prognosis of patients with human papillomavirus (HPV)‑negative cervical cancer is significantly worse than that of patients with HPV‑positive cervical cancer....
The prognosis of patients with human papillomavirus (HPV)‑negative cervical cancer is significantly worse than that of patients with HPV‑positive cervical cancer. Understanding the mechanisms of this is crucial for preventing disease evolution. In the present study, the GV367‑snail family transcriptional repressor 2 (SNAI2) lentiviral vector was constructed and transduced into C‑33A cells. Subsequently, the proliferation of tumor cells was detected using the Cell Counting Kit (CCK)‑8 method. Flow cytometry was used to analyze the cell cycle progression of tumor cells. The glucose consumption of tumor cells was detected using an oxidase assay, and the senescence of tumor cells was detected using beta‑galactosidase staining. The gene expression and the activity of p38 and ERK1/2 were detected using reverse transcription‑quantitative PCR and western blotting, respectively. The C‑33A‑SNAI2 cell line was successfully established. Compared with HeLa and C‑33A‑Wild cells, the proliferation and percentage of G0/G1‑phase cells in the C‑33A‑SNAI2 group were decreased, as detected by the CCK‑8 assay (100±0 vs. 239.1±58.3 vs. 39.7±20.1, P<0.01) and flow cytometry (34.0±7.1% vs. 46.2±10.6% vs. 61.3±5.3%, P<0.05). Compared with the HeLa group, the glucose consumption of the C‑33A‑Wild and C‑33A‑SNAI2 groups was significantly decreased (P<0.01). The results of beta‑galactosidase staining showed that the proportion of beta‑galactosidase‑positive cells in the C‑33A‑SNAI2 group was significantly decreased compared with the C‑33A‑Wild group (P<0.01). Upregulation of SNAI2 enhanced the increase in p21 expression, and the decrease in CDK1, urokinase plasminogen activator receptor (u‑PAR) and cyclin D1 expression in C‑33A cells compared with C‑33A‑Wild cells (P<0.05). In addition, the activities of p38, ERK1/2 and the phosphorylated (p)‑ERK1/2/p‑p38 ratio were decreased in the C‑33A‑SNAI2 group compared with the C‑33A‑Wild and HeLa groups (P<0.05). In conclusion, SNAI2 enhanced HPV‑negative cervical cancer C‑33A cell dormancy, which was characterized by G0/G1 arrest, by the downregulation of u‑PAR expression, and a decrease in the activity of the p‑ERK1/2 and p‑p38MAPK signaling pathways . Cancer recurrence and metastases are responsible for most cancer‑related deaths. Given that SNAI2 is required for enhancing HPV‑negative cervical cancer cell dormancy, regulating this process may promote cervical tumor cells to enter a continuous dormant state, which could be a potential approach for tumor therapy.
Topics: Humans; Uterine Cervical Neoplasms; Female; Snail Family Transcription Factors; Cell Proliferation; Gene Expression Regulation, Neoplastic; MAP Kinase Signaling System; HeLa Cells; Receptors, Urokinase Plasminogen Activator; Cell Line, Tumor; Papillomaviridae; Cellular Senescence; p38 Mitogen-Activated Protein Kinases; Cell Cycle
PubMed: 38940353
DOI: 10.3892/or.2024.8763 -
International Journal of Oncology Aug 2024Obesity is a chronic disease caused by the accumulation of excessive adipose tissue. This disorder is characterized by chronic low‑grade inflammation, which promotes... (Review)
Review
Obesity is a chronic disease caused by the accumulation of excessive adipose tissue. This disorder is characterized by chronic low‑grade inflammation, which promotes the release of proinflammatory mediators, including cytokines, chemokines and leptin. Simultaneously, chronic inflammation can predispose to cancer development, progression and metastasis. Proinflammatory molecules are involved in the recruitment of specific cell populations in the tumor microenvironment. These cell populations include myeloid‑derived suppressor cells (MDSCs), a heterogeneous, immature myeloid population with immunosuppressive abilities. Obesity‑associated MDSCs have been linked with tumor dissemination, progression and poor clinical outcomes. A comprehensive literature review was conducted to assess the impact of obesity‑associated MDSCs on cancer in both preclinical models and oncological patients with obesity. A secondary objective was to examine the key role that leptin, the most important proinflammatory mediator released by adipocytes, plays in MDSC‑driven immunosuppression Finally, an overview is provided of the different therapeutic approaches available to target MDSCs in the context of obesity‑related cancer.
Topics: Humans; Myeloid-Derived Suppressor Cells; Obesity; Neoplasms; Tumor Microenvironment; Disease Progression; Animals; Leptin; Inflammation
PubMed: 38940351
DOI: 10.3892/ijo.2024.5667 -
Journal of Cell Science Jun 2024Some chemotherapy drugs modulate the formation of stress granules (SGs), which are RNA-containing cytoplasmic foci contributing to stress response pathways. How SGs...
Some chemotherapy drugs modulate the formation of stress granules (SGs), which are RNA-containing cytoplasmic foci contributing to stress response pathways. How SGs mechanistically contribute to pro-survival or pro-apoptotic functions must be better defined. The chemotherapy drug lomustine promotes SG formation by activating the stress-sensing eIF2α kinase HRI (encoded by the EIF2AK1 gene). Here, we applied a DNA microarray-based transcriptome analysis to determine the genes modulated by lomustine-induced stress and suggest roles for SGs in this process. We found that the expression of the pro-apoptotic EGR1 gene was specifically regulated in cells upon lomustine treatment. The appearance of EGR1-encoding mRNA in SGs correlated with a decrease in EGR1 mRNA translation. Specifically, EGR1 mRNA was sequestered to SGs upon lomustine treatment, probably preventing its ribosome translation and consequently limiting the degree of apoptosis. Our data support the model where SGs can selectively sequester specific mRNAs in a stress-specific manner, modulate their availability for translation, and thus determine the fate of a stressed cell.
Topics: Humans; RNA, Messenger; Early Growth Response Protein 1; Lomustine; Stress Granules; Apoptosis; Antineoplastic Agents, Alkylating
PubMed: 38940347
DOI: 10.1242/jcs.261825 -
Oncology Reports Aug 2024Intrahepatic cholangiocarcinoma (ICC) is a type of liver cancer associated with poor prognosis and increased mortality; the limited treatment strategy highlights the...
Intrahepatic cholangiocarcinoma (ICC) is a type of liver cancer associated with poor prognosis and increased mortality; the limited treatment strategy highlights the urgent need for investigation. Traditional Chinese Medicine (TCM), used alone or in combination with other treatments, can enhance therapeutic efficacy, improve life quality of patients and extend overall survival. In total, two rounds of screening of a TCM library of 2,538 active compounds were conducted using a Cell Counting Kit‑8 assay and ICC cell lines. Cell proliferation and migration abilities were assessed through colony formation, 5‑ethynyl‑2'‑deoxyuridine, would healing and Transwell assays. The impact of digitoxin (DT) on signaling pathways was initially investigated using RNA sequencing and further validated using reverse transcription‑quantitative PCR, western blotting, lectin blotting and flow cytometry. ICC cells stably overexpressing ST6 β‑galactoside α‑2,6‑sialyltransferase 1 (ST6GAL1) were generated through lentiviral transfection. It was shown that DT emerged as a highly effective anti‑ICC candidate from two rounds high‑throughput library screening. DT could inhibit the proliferation and migration of ICC cells by suppressing NF‑κB activation and reducing nuclear phosphorylated‑NF‑κB levels, along with diminishing ST6GAL1 mRNA and protein expression. The aforementioned biological effects and signal pathways of DT could be counteracted by overexpressing ST6GAL1 in ICC cells. In conclusion, DT suppressed ICC cell proliferation and migration by targeting the NF‑κB/ST6GAL1 signaling axis. The findings of the present study indicated the promising therapeutic effects of DT in managing ICC, offering new avenues for treatment strategies.
Topics: Humans; Signal Transduction; NF-kappa B; Cell Proliferation; Sialyltransferases; Digitoxin; Cholangiocarcinoma; Cell Movement; Cell Line, Tumor; Bile Duct Neoplasms; Antigens, CD; Gene Expression Regulation, Neoplastic; beta-D-Galactoside alpha 2-6-Sialyltransferase
PubMed: 38940341
DOI: 10.3892/or.2024.8762 -
Oncology Reports Aug 2024The incidence of tumors in the human digestive system is relatively high, including esophageal cancer, liver cancer, pancreatic cancer, gastric cancer and colorectal... (Review)
Review
The incidence of tumors in the human digestive system is relatively high, including esophageal cancer, liver cancer, pancreatic cancer, gastric cancer and colorectal cancer. These malignancies arise from a complex interplay of environmental and genetic factors. Among them, long non‑coding RNAs (lncRNAs), which cannot be translated into proteins, serve an important role in the development, progression, migration and prognosis of tumors. Small nucleolar RNA host gene 16 (SNHG16) is a typical lncRNA, and its relationship with digestive system tumors has been widely explored. The prevailing hypothesis suggests that the principal molecular mechanism of SNHG16 in digestive system tumors involves it functioning as a competitive endogenous RNA that interacts with other proteins, regulates various genes and influences a downstream target molecule. The present review summarizes recent research on the relationship between SNHG16 and numerous types of digestive system cancer, encompassing its biological functions, underlying mechanisms and potential clinical implications. Furthermore, it outlines the association between SNHG16 expression and pertinent risk factors, such as smoking, infection and diet. The present review indicated the promise of SNHG16 as a potential biomarker and therapeutic target in human digestive system cancer.
Topics: Humans; RNA, Long Noncoding; Digestive System Neoplasms; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor; Prognosis
PubMed: 38940337
DOI: 10.3892/or.2024.8765 -
International Journal of Molecular... Aug 2024Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer‑associated death in young people. GNE‑477 belongs to the second...
Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer‑associated death in young people. GNE‑477 belongs to the second generation of mTOR inhibitors and possesses promising potential in the treatment of OS but dose tolerance and drug toxicity limit its development and utilization. The present study aimed to prepare a novel HO stimulus‑responsive dodecanoic acid (DA)‑phenylborate ester‑dextran (DA‑B‑DEX) polymeric micelle delivery system for GNE‑477 and evaluate its efficacy. The polymer micelles were characterized by morphology, size and critical micelle concentration. The GNE‑477 loaded DA‑B‑DEX (GNE‑477@DBD) tumor‑targeting drug delivery system was established and the release of GNE‑477 was measured. The cellular uptake of GNE‑477@DBD by three OS cell lines (MG‑63, U2OS and 143B cells) was analyzed utilizing a fluorescent tracer technique. The hydroxylated DA‑B was successfully grafted onto dextran at a grafting rate of 3%, suitable for forming amphiphilic micelles. Following exposure to HO, the DA‑B‑DEX micelles ruptured and released the drug rapidly, leading to increased uptake of GNE‑477@DBD by cells with sustained release of GNE‑477. The experiments, including MTT assay, flow cytometry, western blotting and RT‑qPCR, demonstrated that GNE‑477@DBD inhibited tumor cell viability, arrested cell cycle in G1 phase, induced apoptosis and blocked the PI3K/Akt/mTOR cascade response. , through the observation of mice tumor growth and the results of H&E staining, the GNE‑477@DBD group exhibited more positive therapeutic outcomes than the free drug group with almost no adverse effects on other organs. In conclusion, HO‑responsive DA‑B‑DEX presents a promising delivery system for hydrophobic anti‑tumor drugs for OS therapy.
Topics: Animals; Humans; Micelles; Osteosarcoma; Hydrogen Peroxide; Cell Line, Tumor; Dextrans; Mice; Lauric Acids; Apoptosis; Polymers; Xenograft Model Antitumor Assays; Bone Neoplasms; Mice, Nude; Antineoplastic Agents; Mice, Inbred BALB C; Male; TOR Serine-Threonine Kinases
PubMed: 38940336
DOI: 10.3892/ijmm.2024.5393 -
Molecular Medicine Reports Aug 2024Elevated levels of blood glucose in patients with ischemic stroke are associated with a worse prognosis. The present study aimed to explore whether hyperglycemia...
Elevated levels of blood glucose in patients with ischemic stroke are associated with a worse prognosis. The present study aimed to explore whether hyperglycemia promotes microglial pyroptosis by increasing the oxygen extraction rate in an acute ischemic stroke model. C57BL/6 mice that underwent middle cerebral artery occlusion were used for assessment of blood glucose level and neurological function. The cerebral oxygen extraction ratio (CERO), oxygen consumption rate (OCR) and partial pressure of brain tissue oxygen (PbtO) were measured. To investigate the significance of the NOD‑like receptor protein 3 (NLRP3) inflammasome, NLRP3 mice were used, and the expression levels of NLRP3, caspase‑1, full‑length gasdermin D (GSDMD‑FL), GSDMD‑N domain (GSDMD‑N), IL‑1β and IL‑18 were evaluated. In addition, Z‑YVAD‑FMK, a caspase‑1 inhibitor, was used to treat microglia to determine whether activation of the NLRP3 inflammasome was required for the enhancing effect of hyperglycemia on pyroptosis. It was revealed that hyperglycemia accelerated cerebral injury in the acute ischemic stroke model, as evidenced by decreased latency to fall and the percentage of foot fault. Hyperglycemia aggravated hypoxia by increasing the oxygen extraction rate, as evidenced by increased CERO and OCR, and decreased PbtO in response to high glucose treatment. Furthermore, hyperglycemia‑induced microglial pyroptosis was confirmed by detection of increased levels of caspase‑1, GSDMD‑N, IL‑1β and IL‑18 and a decreased level of GSDMD‑FL. However, the knockout of NLRP3 attenuated these effects. Pharmacological inhibition of caspase‑1 also reduced the expression levels of GSDMD‑N, IL‑1β and IL‑18 in microglial cells. These results suggested that hyperglycemia stimulated NLRP3 inflammasome activation by increasing the oxygen extraction rate, thus leading to the aggravation of pyroptosis following ischemic stroke.
Topics: Animals; Pyroptosis; Microglia; Ischemic Stroke; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Oxygen; Male; Hyperglycemia; Inflammasomes; Mice, Inbred C57BL; Caspase 1; Disease Models, Animal; Mice, Knockout; Interleukin-1beta; Phosphate-Binding Proteins; Oxygen Consumption; Gasdermins
PubMed: 38940333
DOI: 10.3892/mmr.2024.13270