Search

An increasing body of evidence has revealed that the aberrant expression of microRNAs (miRNAs/miRs) is involved in the development and progression of ovarian cancer (OC). miR‑183 has been demonstrated to act as a tumor suppressor and oncogene in various types of human cancers. However, the biological role of miR‑183 in OC still remains unclear. The aim of the present study was to investigate the role of miR‑183 and evaluate its underlying mechanism in OC. In the present study, miR‑183 was observed to be upregulated in OC tissues and cell lines as determined by reverse transcription‑quantitative polymerase chain reaction. The effects of miR‑183 on OC were further investigated via western blotting, MTT, wound healing, Transwell and immunofluorescence analyses. Downregulation of miR‑183 markedly inhibited cell proliferation, migration and invasion, and promoted apoptosis in OC cells. Furthermore, it was initially confirmed that mothers against decapentaplegic homolog 4 (Smad4) was identified as an efficient target of miR‑183 by luciferase activity assay. Finally, the results revealed that miR‑183 directly regulated biological function via the transforming growth factor (TGF)‑β/Smad4 signaling pathway in OC cells. In conclusion, the results of the present study suggested that miR‑183 exerted tumor‑promoting roles in OC, at least partially by regulating Smad4 via the TGF‑β/Smad4 signaling pathway. Therefore, miR‑183 may serve as a potential target for the diagnosis and prognosis of OC.

It is well recognized that mandibular growth, which is caused by a variety of functional appliances, is considered to be the result of both neuromuscular and skeletal adaptations. Accumulating evidence has demonstrated that apoptosis plays an important role in the adaptation of skeletal muscle function. However, the underlying mechanism of apoptosis that is induced by stretch continues to be incompletely understood. Endoplasmic reticulum stress (ERS), a newly defined signaling pathway, initiates apoptosis. This study seeks to determine if caspase-12 is involved in stretch-induced apoptosis mediated endoplasmic reticulum stress in myoblast and its underlying mechanism. Apoptosis was assessed by Hochest staining, DAPI staining and annexin V binding and PI staining. ER chaperones, such as GRP78, CHOP and caspase-12, were determined by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Furthermore, caspase-12 inhibitor was used to value the mechanism of the caspase-12 pathway. Apoptosis of myoblast, which is subjected to cyclic stretch, was observed in a time-dependent manner. We found that GRP78 mRNA and protein were significantly increased and CHOP and caspase-12 were activated in myoblast that was exposed to cyclic stretch. Caspase-12 inhibition reduced stretch-induced apoptosis, and caspase-12 activated caspase-3 to induce apoptosis. We concluded that caspase-12 played an important role in stretch-induced apoptosis that is associated by endoplasmic reticulum stress by activating caspase-3.

Ischaemia/reperfusion (I/R) injury is a common clinical condition that results in apoptosis and oxidative stress injury. Thyroid hormone was previously reported to elicit cardiac myocyte hypertrophy and promote cardiac function after cardiac injury. We used an in vivo mouse model of I/R injury and in vitro primary cardiomyocyte culture assays to investigate the effects of thyroid hormone on cardiomyocytes during hypoxia/reoxygenation (H/R) injury. The results showed that T3 pretreatment in vivo significantly improved left ventricular function after I/R injury. In vitro, T3 pretreatment decreased cell apoptosis rate, inhibited caspase‐3 activity and decreased the Bax/Bcl‐2 ration induced by H/R injury. T3 pretreatment significantly attenuated the loss of mitochondrial membrane potential. Furthermore, it was observed that T3 diminished the expression of NCX1 protein and decreased SERCA2a protein expression in H/R‐induced cardiomyocytes, and T3 prevented intracellular Ca2+ increase during H/R injury. Also, T3 increased the expression of IGF‐1, and PI3K/Akt signalling in cardiomyocytes under H/R‐induced injury, and that the protective effect of T3 against H/R‐induced injury was blocked by the PI3K inhibitor LY294002. IGF‐1 receptor (IGF‐1R) inhibitor GSK1904529A significantly inhibited the expression of IGF‐1R and PI3K/Akt signalling. In summary, T3 pretreatment protects cardiomyocytes against H/R‐induced injury by activating the IGF‐1‐mediated PI3K/Akt signalling pathway. [ABSTRACT FROM AUTHOR]

Excessive manganese (Mn) exposure has been linked to neurotoxicity, cognitive impairments. Neurotrophic Receptor Kinase 1 (NTRK1) encodes Tropomyosin kinase A (TrkA), a neurotrophic receptor, as a mediator of neuron differentiation and survival. Insulin-like growth factor 2 (IGF2), a pivotal member of the insulin gene family, plays a crucial role in brain development and neuroprotection. Despite this knowledge, the precise mechanisms through which NTRK1 and IGF2 influence cell responses to Mn-induced neuronal damage remain elusive. Cell apoptosis was assessed using CCK8, TUNEL staining, and Western blot analysis of cleaved Caspase-3. Lentiviral vectors facilitated NTRK1 overexpression, while small interfering RNAs (siRNAs) facilitated IGF2 knockdown. Real-time Quantitative PCR (qPCR) determined gene expression levels, while Western blotting measured protein expression. The study reveals that NTRK1 inhibits MnCl2-induced apoptosis in SH-SY5Y cells. NTRK1 overexpression significantly upregulated IGF2 expression, and subsequent siRNA- IGF2 experiments confirmed IGF2 's pivotal role in NTRK1 -mediated neuroprotection. Notably, the study identifies that NTRK1 regulates the expression of IGF2 in the neuroprotective mechanism with the involvement of ER stress pathways. The study reveals NTRK1 's neuroprotective role via IGF2 against Mn-induced neurotoxicity and ER stress modulation in SH-SY5Y cells. These findings offer insights into potential therapies for neurodegenerative disorders related to Mn exposure and NTRK1 dysfunction, driving future research in this domain. [Display omitted] • NTRK1 Shields Nerve Cells from Manganese-Induced Neurotoxicity and Apoptosis. • IGF2-Mediated Neuroprotection: NTRK1 Safeguards Against MnCl2-Induced Neuronal Damage. • Precision in Stress Management: NTRK1 Coordinates ER Stress Alleviation via IGF2 Modulation During MnCl2 Treatment. • Decoding NTRK1's Intricate Role: Unraveling Mechanisms for Manganese-Induced Neuronal Preservation and ER Stress Mitigation. [ABSTRACT FROM AUTHOR]

Excessive mechanical loads on the temporomandibular joint (TMJ) can cause mandibular cartilage degradation and subchondral bone erosion, but the treatment of these conditions remains challenging. Salubrinal, which target eukaryotic translation initiation factor 2 alpha, has been shown to have multiple beneficial effects on skeletal tissue. Here, we examined the effect of a Salubrinal injection on the mandibular cartilage and subchondral bone of the TMJ under various compressive stresses. We conducted in vivo analyses in rat models using various compressive stresses (40 g and 80 g), and we observed time-related degeneration and pathological changes in the cartilage and subchondral bone of the TMJ at days 1, 3 and 7 through histological measurements, subcellular observation, and changes in proliferation and apoptosis. After the Salubrinal injection, the thickness of the cartilage recovered, and the pathological change was alleviated. In the Salubrinal/light (Sal/light) compressive stress group, the drug altered the proliferation and apoptosis of chondrocytes most significantly at day 1. In the Salubrinal/heavy (Sal/heavy) compressive stress group, the drug increased the proliferation of chondrocytes most significantly at day 1 and reduced the apoptosis of chondrocytes most significantly at day 7. Salubrinal also increased the area of the bone trabeculae and suppressed inflammatory responses and pathological change in the subchondral bone of the TMJ. Together, these results indicate that the administration of Salubrinal reduces apoptosis and strengthens the proliferation of chondrocyte to varying degrees at days 1, 3 and 7 under various compressive mechanical stresses, both of which contribute to the recovery of cartilage thickness and the alleviation of pathological change. Salubrinal also suppresses inflammatory responses and pathological change in the subchondral bone of the TMJ. [ABSTRACT FROM AUTHOR]

Abstract: To increase the efficacy of currently used anti-cancer genotoxins, one of the current efforts is to find agents that can sensitize cancer cells to genotoxins so that the efficacious doses of genotoxins can be lowered to reduce deleterious side-effects. In this study, we reported that a synthetic RasGAP-derived peptide GAP159 could enhance the effect of chemotherapeutic agent cisplatin (CDDP) in human colon carcinoma HCT116 cells. Our results showed that GAP159 significantly increased the CDDP-induced cytotoxicity and apoptosis in HCT116 cells. This synergistic effect was associated with the inhibitions of phospho-AKT, phospho-ERK and NF-κB. In mouse colon tumor CT26 animal models, GAP159 combined with CDDP significantly suppressed CT26 tumor growth, and GAP159 alone showed slight inhibitory effect. Our data suggests that co-treatment of GAP159 and chemotherapeutics will become a potential therapeutic strategy for colon cancers. [Copyright &y& Elsevier]

Highlights: [•] siN-ras and U0126 enhanced the cytotoxicity of SKI II in hepatoma cells. [•] U0126 enhanced SKI II-induced apoptosis through Akt/NF-κB signaling pathway. [•] Combing U0126 and SKI II led to enhanced migratory inhibition via FAK/MLC-2 pathway. [ABSTRACT FROM AUTHOR]

Oxidative stress plays an important role in the progression of cardiac diseases, including acute myocardial infarction, ischemia/reperfusion (I/R) injury and heart failure. Growing evidence indicates that thyroid hormone has protective properties against cardiovascular diseases. However, little is known about its effect on oxidative stress in cardiomyocytes or the underlying mechanisms. This study showed that T3 pretreatment in vivo significantly reduced cardiac dysfunction by increasing the left ventricular ejection function and ameliorating the pathological changes induced by I/R-induced injury. In an in vitro experiment, T3 inhibited apoptosis in H 2 O 2 -treated cardiomyocytes, as evidenced by the decreased expression of Bax, cleaved caspase 3 and 9, and increased expression of Bcl-2. In addition, oxidative stress observed in hearts of mice with I/R injury was significantly alleviated by T3 pretreatment, intracellular ROS and mitochondrial ROS overproduction were effectively inhibited, and similar results were also detected in H 2 O 2 -treated cardiomyocytes in vitro. T3 significantly increased antioxidant protein (Nrf2 and HO-1) expression levels, and inhibited NOX2 and NOX4 protein expression levels in H 2 O 2 -treated cardiomyocytes. Moreover, T3 preserved mitochondrial functions upon H 2 O 2 -induced oxidative stress by increasing mitochondrial membrane potential and promoting the expression of mitochondrial biogenesis genes. Notably, the PI3K/AKT signaling was significantly activated by T3 pretreatment in H 2 O 2 -induced cardiomyocytes. Together, these findings revealed that T3 could be served as potential therapeutic target for protection against cardiac oxidative stress injury through its antioxidant and anti-apoptosis effects, which are mediated by the activation of the PI3K/AKT signaling pathway. • T3 improved mouse cardiac function after I/R injury in vivo. • T3 prevented cardiomyocytes apoptosis from H 2 O 2 -induced injury in vitro. • T3 protected myocardium against oxidative stress both in vivo and in vitro. • T3 prevented mitochondrial dysfunction caused by H 2 O 2 -induced oxidative stress. • T3 protected cardiomyocytes via regulating PI3K/AKT signaling pathway. [ABSTRACT FROM AUTHOR]

Temporomandibular joint osteoarthritis (TMJ OA) is a common degenerative joint disease that has multiple causes. The abnormal stress distribution is known to be an important trigger of TMJ OA. This article explored the pathological changes of the condylar cartilage under 60 g mechanical force and whether the inhibition of Receptor-interacting protein 1 (RIP1) can protect stress-induced TMJ OA. We used a compressive mechanical force-induced-TMJ OA model and Lenti-virus targeting RIP1 to perform this study. A total of 72 male rats were used in the animal experiment. Each rat was injected with a negative control Lenti-shRNA in the right TMJ and Lenti-siRIP1 in the left TMJ and euthanized after 4 and 7 days, respectively. Quantitative real-time PCR, immunohistochemistry, Tunnel staining and Micro-CT were used to detect cartilage pathological changes and one way ANOVA with LSD analysis was used to determine statistical significance between groups. The results identified the characteristics of the spatio-temporal changes in stress-induced TMJ OA. Under mechanical force, inflammation and apoptosis, which occur in the whole layer of mandibular cartilage, appear on the 4th day and persist till the 7th day. Necroptosis arises in the later stage of mechanical force and is mainly located in the transition layer. RIP1 inhibition through Lenti-virus could protect stress-induced mandibular cartilage thinning by inhibiting persisted apoptosis and later-stage necroptosis in the transition layer. RIP1 plays an essential role in the destruction of mandibular cartilage under mechanical force. RIP1 inhibition through Lenti-virus could protect mechanical stress-induced TMJ OA. • Receptor-interacting protein 1 plays an essential role in the pathological change of mandibular cartilage under 60 g mechanical force. • Inflammation and apoptosis are continuous in the pathological changes of mandibular cartilage and necroptosis appears on the later stage. • Receptor-interacting protein 1 inhibition through Lenti-virus could protect mechanical stress-induced mandibular cartilage thinning. [ABSTRACT FROM AUTHOR]

Severe cardiovascular diseases, such as myocardial infarction or heart failure, can alter thyroid hormone (TH) secretion and peripheral conversion, leading to low triiodothyronine (T3) syndrome. Accumulating evidence suggests that TH has protective properties against cardiovascular diseases and that treatment with TH can effectively reduce myocardial damage after myocardial infarction (MI). Our aim is to investigate the effect of T3 pretreatment on cardiac function and pathological changes in mice subjected to MI and the underlying mechanisms. Adult male C57BL/6 mice underwent surgical ligation of the left anterior descending coronary artery (LAD) (or sham operation) to establish MI model. T3, BMS-754807 (inhibitor of insulin-like growth factor-1 receptor (IGF-1R)) or vehicle was administered before surgery. Compared with the MI group, the T3 pretreatment group exhibited significant attenuation of the myocardial infarct area, inhibition of cardiomyocyte apoptosis and fibrosis, and improved left ventricular function after MI. In addition, T3 exhibited an enhanced potency to stimulate angiogenesis and exert anti-inflammatory effects by reducing the levels of serum inflammatory cytokines after MI. However, all of these protective effects were inhibited by the IGF-1R inhibitor BMS-754807. Moreover, the protein expression of IGF-1/PI3K/AKT signaling-related proteins, such as IGF-1, IGF-1R, phosphorylated PI3K (p-PI3K) and p-AKT was significantly upregulated in MI mice that received T3 pretreatment, and BMS-754807 pretreatment blocked the upregulation of the expression of these signaling-related proteins. T3 pretreatment can protect the heart against dysfunction post-MI, which may be mediated by the activation of the IGF-1/PI3K/AKT signaling pathway. • T3 pretreatment can reduce the area of myocardial infarction, inhibit myocardial cell apoptosis and fibrosis, stimulate angiogenesis and prevent cardiac dysfunction after MI. • The protective mechanism of T3 after myocardial infarction involves the activation of IGF-1 / PI3K / AKT signaling pathway. • T3 pretreatment is a promising approach for treating postinfarction cardiac dysfunction and cardiac remodeling. [ABSTRACT FROM AUTHOR]