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Diabetes mellitus (DM) is a multifaceted pathological condition, which at present is being considered an epidemic disease keeping the rampant rate of its increase in almost all population groups of the world in consideration. Out of the two types of DM described, T1D is characterized as an autoimmune condition that leads to the destruction of pancreatic ß-cells by macrophages and T-cells, thereby, adversely affecting the production of insulin. On the other hand, T2D, often caused by insulin resistance, is commonly related to unhealthy habits, and therefore, it can be prevented in most cases. In both of the conditions, high levels of proinflammatory cytokines like IL-6, TNF-α, and INF-Æ´, lead to chronic inflammation, and elevated oxidative stress resulting in apoptosis and destruction of tissues. Although several treatments are available to treat the symptoms, the underlying causes are not well addressed. One of the most promising approaches to tackle the ill effects and the primary causes of DM is mesenchymal stem cell (MSC) therapy. The use of MSC therapy, because of the immunomodulatory and regenerative properties recorded in this type of cells in a number of experiments carried out in animal models and clinical trials of the disease, has reported positive outcomes. This review covers the principal mechanisms of action induced during MSC therapy in reference to the described pathophysiological pathways of both T1D and T2D. In addition, how this therapeutic intervention can counteract the ill effects of this condition leading to the promotion of tissue regeneration has been covered.

Assuntos

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OBJECTIVE: Trastuzumab is the preferred drug for the treatment of breast cancer. However, research on the cellular mechanisms of trastuzumab's potential cardiotoxicity is insufficient. The purpose of this study was to explore the toxic effects and potential mechanism of action of trastuzumab on cardiomyocytes. METHOD: Human Cardiomyocyte (HCM) viability was assessed using the MTT method. HCM apoptosis was detected using the Hoechst33342/PI Fluorescent staining. The LDH and CK activities of the cell were measured using commercially available LDH and CK assay kits. The expression levels of Notch2, JAK2, STAT3, cleaved caspase 3, bax, and bcl 2 in HCMs were detected using western blotting. RESULTS: The results showed that 250 mg/L trastuzumab induced cardiomyocyte injury and apoptosis, inhibited viability, activated the Notch2 receptor, and inhibited JAK2/STAT3 expression in HCM. Inhibition of Notch2 expression in HCM by targeted siNotch2 transfection reversed the trastuzumab-induced injury and apoptosis, and the expression of JAK2/STAT3 returned to normal levels. CONCLUSIONS: Trastuzumab induces Notch2 expression by inhibiting the JAK2/STAT3 pathway of HCMs, promotes cell apoptosis, and causes cardiomyocyteinjury. Notch2 may be a potential target of trastuzumab-inducedmyocardial injury. This experiment reveals the mechanism of trastuzumab-induced cardiotoxicity, providing a theoretical basis for the application of trastuzumab.

Assuntos

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BACKGROUND: The main features of polycystic ovary syndrome (PCOS) are abnormal follicular development and ovulatory dysfunction, which are caused by excessive apoptosis of ovarian granulosa cells. Acupuncture has been shown to improve follicular development abnormalities in patients with PCOS, but its mechanism is unknown. This study hypothesized that the mechanism of acupuncture on follicular development abnormalities in PCOS patients is the inhibition of granulosa cell apoptosis through LncMEG3-mediated regulation of miR-21-3p. METHODS: A PCOS-like rat model was established using subcutaneous injection of dehydroepiandrosterone (DHEA). Acupuncture was performed on rats for 15 d (CV-4, RN-3, CV-6, SP-6 and EX-CA 1). Ovarian morphology was observed by HE staining, and sex hormone and AMH levels were detected by ELISA. Primary granulosa cells were isolated from each group of rats to assess the association of acupuncture treatment, LncMEG3, miR-21-3p, and granulosa cell apoptosis in rats with PCOS. RESULTS: LncMEG3 and miR-21-3p were highly expressed in the ovarian granulosa cells of rats with PCOS, and LncMEG3-mediated regulation of miR-21-3p was involved in the development of PCOS in rats. Silencing of MEG3 attenuated sex hormone dysregulation and ovarian histopathological changes in PCOS rats and promoted follicle cell development and maturation. In addition, silencing MEG3 increased the viability and number of granulosa cells. In addition, silencing MEG3 further inhibited early and late apoptosis of ovarian granulosa cells in PCOS rats. Acupuncture improved polycystic ovarian morphology and sex hormone levels in PCOS rats. Acupuncture intervention increased the viability and number of granulosa cells. Acupuncture intervention inhibited early and late apoptosis of ovarian granulosa cells in PCOS rats by targeting miR-21-3p via LncMEG3. CONCLUSION: These results suggest that acupuncture can downregulate LncMEG3, thereby targeting and regulating miR-21-3p to suppress early and late granulosa cell apoptosis and normalize their proliferation. These factors ultimately compensate for abnormal follicular development. These findings shed light on the clinical potential of acupuncture as a safe treatment for follicular developmental abnormalities in PCOS.

Assuntos

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Apiculate yeasts belonging to the genus Hanseniaspora are predominant on grapes and other fruits. While some species, such as Hanseniaspora uvarum, are well known for their abundant presence in fruits, they are generally characterized by their detrimental effect on fermentation quality because the excessive production of acetic acid. However, the species Hanseniaspora vineae is adapted to fermentation and currently is considered as an enhancer of positive flavour and sensory complexity in foods. Since 2002, we have been isolating strains from this species and conducting winemaking processes with them. In parallel, we also characterized this species from genes to metabolites. In 2013, we sequenced the genomes of two H. vineae strains, being these the first apiculate yeast genomes determined. In the last 10 years, it has become possible to understand its biology, discovering very peculiar features compared to the conventional Saccharomyces yeasts, such as a natural and unique G2 cell cycle arrest or the elucidation of the mandelate pathway for benzenoids synthesis. All these characteristics contribute to phenotypes with proved interest from the biotechnological point of view for winemaking and the production of other foods.

Assuntos

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Abstract EphrinB2 plays a critical role in tumor growth. In this study, we studied the antitumor activity of imperatorin derivative IMP-1 in renal cell carcinoma (RCC) by regulating EphrinB2 pathway.. Results showed that IMP-1 inhibited the proliferation of 786-O cells in a dose- and time-dependent manner. More importantly, knockdown and transfection of EphrinB2 altered the inhibitory effect of IMP-1 on the activity of 786-O cells. IMP-1 arrested 786-O cell cycle at G0/G1 phase by decreasing the expression of cyclin D1 and cyclin E. Moreover, IMP-1 regulated Bcl-2 family proteins' expression, thus inducing apoptosis of 786-O cells. IMP-1 down-regulated the expression of EphrinB2, Syntenin1 and PICK1. Then, IMP-1 decreased the phosphorylation of Erk1/2 and AKT. In all, IMP-1 could regulate the EphrinB2 pathway in order to inhibit 786-O cell growth by arresting the cell cycle at G0/G1 phase and inducing cell apoptosis. Thus, IMP-1 may present as a potential strategy for RCC treatment.

Assuntos

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Abstract Objective Trastuzumab is the preferred drug for the treatment of breast cancer. However, research on the cellular mechanisms of trastuzumab's potential cardiotoxicity is insufficient. The purpose of this study was to explore the toxic effects and potential mechanism of action of trastuzumab on cardiomyocytes. Method Human Cardiomyocyte (HCM) viability was assessed using the MTT method. HCM apoptosis was detected using the Hoechst33342/PI Fluorescent staining. The LDH and CK activities of the cell were measured using commercially available LDH and CK assay kits. The expression levels of Notch2, JAK2, STAT3, cleaved caspase 3, bax, and bcl 2 in HCMs were detected using western blotting. Results The results showed that 250 mg/L trastuzumab induced cardiomyocyte injury and apoptosis, inhibited viability, activated the Notch2 receptor, and inhibited JAK2/STAT3 expression in HCM. Inhibition of Notch2 expression in HCM by targeted siNotch2 transfection reversed the trastuzumab-induced injury and apoptosis, and the expression of JAK2/STAT3 returned to normal levels. Conclusions Trastuzumab induces Notch2 expression by inhibiting the JAK2/STAT3 pathway of HCMs, promotes cell apoptosis, and causes cardiomyocyteinjury. Notch2 may be a potential target of trastuzumab-inducedmyocardial injury. This experiment reveals the mechanism of trastuzumab-induced cardiotoxicity, providing a theoretical basis for the application of trastuzumab.

RESUMO

BACKGROUND: The main features of polycystic ovary syndrome (PCOS) are abnormal follicular development and ovulatory dysfunction, which are caused by excessive apoptosis of ovarian granulosa cells. Acupuncture has been shown to improve follicular development abnormalities in patients with PCOS, but its mechanism is unknown. This study hypothesized that the mechanism of acupuncture on follicular development abnormalities in PCOS patients is the inhibition of granulosa cell apoptosis through LncMEG3-mediated regulation of miR-21-3p. METHODS: A PCOS-like rat model was established using subcutaneous injection of dehydroepiandrosterone (DHEA). Acupuncture was performed on rats for 15 d (CV-4, RN-3, CV-6, SP-6 and EX-CA 1). Ovarian morphology was observed by HE staining, and sex hormone and AMH levels were detected by ELISA. Primary granulosa cells were isolated from each group of rats to assess the association of acupuncture treatment, LncMEG3, miR-21-3p, and granulosa cell apoptosis in rats with PCOS. RESULTS: LncMEG3 and miR-21-3p were highly expressed in the ovarian granulosa cells of rats with PCOS, and LncMEG3-mediated regulation of miR-21-3p was involved in the development of PCOS in rats. Silencing of MEG3 attenuated sex hormone dysregulation and ovarian histopathological changes in PCOS rats and promoted follicle cell development and maturation. In addition, silencing MEG3 increased the viability and number of granulosa cells. In addition, silencing MEG3 further inhibited early and late apoptosis of ovarian granulosa cells in PCOS rats. Acupuncture improved polycystic ovarian morphology and sex hormone levels in PCOS rats. Acupuncture intervention increased the viability and number of granulosa cells. Acupuncture intervention inhibited early and late apoptosis of ovarian granulosa cells in PCOS rats by targeting miR-21-3p via LncMEG3. CONCLUSION: These results suggest that acupuncture can downregulate LncMEG3, thereby targeting and regulating miR-21-3p to suppress early and late granulosa cell apoptosis and normalize their proliferation. These factors ultimately compensate for abnormal follicular development. These findings shed light on the clinical potential of acupuncture as a safe treatment for follicular developmental abnormalities in PCOS. Highlights LncMEG3-mediated inhibition of miR-21-3p regulates ovarian granulosa cell apoptosis. LncMEG3 and miR-21-3p are involved in the occurrence and development of PCOS-related abnormal follicular development. CuONPs induce co-occurrence of autophagy activation and autophagic flux blockade. Acupuncture can improve the sex hormone levels and follicular development in the context of PCOS. The underlying mechanism of acupuncture in the treatment of PCOS abnormal follicular development was revealed.

Assuntos

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Colorectal cancer (CRC) is one type of cancer with high morbidity and mortality worldwide. Photodynamic therapy (PDT), a promising new therapeutic approach for cancer, induces tumor damage through photosensitizer-mediated oxidative cytotoxicity. Hypericin is a powerful photosensitizer with pronounced tumor-localizing properties. In this study, we investigated the phototoxic effects of hypericin-mediated PDT (HYP-PDT) in HCT116 and SW620 cells. We validated that HYP-PDT inhibited cell proliferation, triggered intracellular reactive oxygen species generation, induced S phase cell cycle arrest and apoptosis of HCT116 and SW620 cells. Mechanistically, the results of western blot showed that HYP-PDT downregulated CDK2 expression through decreasing the CDC25A protein, which resulted in the decrease of CDK2/Cyclin A complex. Additionally, HYP-PDT induced DNA damage as evidenced by ATM activation and upregulation of p-H2AX. Further investigation showed that HYP-PDT significantly increased Bax expression and decreased Bcl-2 expression, and then, upregulated the expression of cleaved caspase-9, cleaved caspase-3 and cleaved PARP, thereby inducing apoptosis in HCT116 and SW620 cells. In conclusion, our results indicated that the CDC25A/CDK2/Cyclin A pathway and the mitochondrial apoptosis pathway were involved in HYP-PDT induced S phase cell cycle arrest and apoptosis in colorectal cancer cells, which shows HYP could be a probable candidate used for treating colorectal cancer.

Assuntos

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A few Bacillus thuringiensis Cry proteins, known as parasporins, have demonstrated cell proliferation inhibition of human cancer cells in vitro after protease activation. In this work, eight peptides derived from the Cry11Bb protoxin produced by B. thuringiensis subsp. medellin were selected and evaluated to investigate their membrane permeabilization and cytolytic activities, using red blood cells and cancer cell lines A549, MCF-7 and Caco-2, respectively. The most active peptides permeabilized red blood cells in a membrane potential-dependent manner. Half maximal inhibitory concentration in cancer cells was in the range 0.78-7.63 µM. At the same time, at peptides concentration of 25 µM, the hemolysis percentage varied in the range of 4.6-32.4%. The peptides BTM-P1 and BTM-P4 in D form had the lowest IC50 values on the MCF-7 cell line and they are considered as the most promising peptides among the evaluated. Fluorescence microscopy using AnnexinV-FLUOS staining indicates that the possible cause of MCF-7 cell death by peptide BTM-P1, is apoptosis. Real time PCR analysis showed an increased transcription of p53 in MCF-7 cells, thus confirming the probable pro-apoptotic effect of the peptide BTM-P1. In general, this study suggests that the cytolytic activity of the polycationic peptides derived from the Cry11Bb protoxin could be mediated by a pro-apoptotic mechanism that might include potential-dependent membrane permeabilization. Further studies might be accomplished to establish whether the peptides are cytolytic to other cancer cell lines and to solid tumors.

Assuntos

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The occurrence of cadmium (Cd) in feed is a major problem in animal health and production. Studies have confirmed that Cd depresses egg production of laying hens, which is closely related to follicular atresia. This study aimed to assess the toxic impacts of Cd on the ovarian tissue, and to examine the mechanism of Cd-induced granulosa cell proliferation and apoptosis. Results from the nitric oxide (NO) and malondialdehyde (MDA) content, total superoxide dismutase (T-SOD), glutathione peroxide (GSH-Px), total nitric oxide synthase (T-NOS) and adenosine triphosphatase (ATPase) activities, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, and hematoxylin-eosin (H & E) staining indicated that excess Cd induced oxidative stress, granulosa cell apoptosis and follicular atresia in the layer ovary. Low-dose Cd exposure (1 µM) induced the granulosa cell proliferation, upregulated the mRNA levels of RSK1 and RHEB, activated FoxO3a, AKT, ERK1/2, mTOR and p70S6K1 phosphorylation, and promoted cell cycle progression from phase G1 to S. However, high-dose Cd exposure (15 µM) induced reactive oxygen species (ROS) generation and cell apoptosis, upregulated the mRNA levels of the inflammatory factors, ASK1, JNK, p38 and TAK1, downregulated the expressions of RSK1 and RHEB genes, and inhibited the phosphorylation of ERK1/2, mTOR and p70S6K1 proteins, and the cell cycle progression. Rapamycin pre-treatment completely blocked the phosphorylation of mTOR and p70S6K1 proteins, and the cell cycle progression induced by 1 µM Cd, and accelerated 15 µM Cd-induced cell apoptosis and cell cycle arrest. The microRNA sequencing result showed that 15 µM Cd induced differential expression of microRNA genes, which may regulate AKT, ERK1/2 and mTOR signaling and cell cycle progression by regulating the activity of G proteins and cell cycle-related proteins. Conclusively, these results indicated that Cd can cause the ovarian damage and follicular atresia, and regulate cell cycle, cell proliferation or apoptosis of granulosa cells through MAPK, AKT/FoxO3a and mTOR pathways in laying hens.

Assuntos