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Purpose: The nephrotoxicity caused by cisplatin severely limits the application and affects related platinum-based therapeutics. Neferine is a dibenzylisoquinoline alkaloid extracted from a Chinese medicinal herb (Nelumbo nucifera Gaertn), which can decrease cisplatin-induced apoptosis of NRK-52E cells by activating autophagy in vitro in our previous study. In this article, we aimed to further investigate the protective effect of neferine, against to the cispltain-induced kidney damage in mice., Methods: Six groups were designed in our study. Renal index, mice serum creatinine and blood urea nitrogen levels were detected after the mice were killed. HE staining was used to observe the pathological changes of each group. The apoptosis of mouse kidney tissue was detected by TUNEL. Immunofluorescence and Western blot were used to detect the expression of cleaved-caspase3 and LC3. The transmission electron microscope was used to reveal the changes of apoptosis and autophagy of renal tubular epithelial cells in different groups., Results: In our findings, the pathological changes of acute kidney injury were easily observed in cisplatin-treated mice while those in the neferine-pretreated groups were significantly alleviated. The apoptosis induced by cisplatin in mice increased evidently compared with the control group, which was decreased in the mice with neferine pretreatment. What' more, we found that autophagy increased obviously in mice pretreated by neferine contrast to the cisplatin-treated mice., Conclusion: In our study, neferine can effectively alleviate cisplatin-induced renal injury in mice, as well act as an autophagy-regulator in kidney protection., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

The incidence and progression of type 2 diabetes are closely related to pancreatic β-cell damage. Oxidative stress may be one of the key factors contributing to β-cell apoptosis. Opuntia milpa alta polysaccharides (MAPs) are water-soluble macromolecular polysaccharides that have antidiabetic effects in vivo. Therefore, we hypothesized that MAPs might effectively prevent β-cell apoptosis via the inhibition of oxidative damages. In this study, INS-1 cells were exposed to alloxan with different concentrations of MAPs in vitro, and the cell viability, oxidative enzyme activities, nitric oxide production, reactive oxygen species production, apoptosis, and the expression of proteins in the antioxidant nucleus transcription factor NF-E2-related factor 2 (Nrf2) pathway and proteins related to apoptosis were measured to assess oxidative stress responses and apoptosis. The results indicated that INS-1 cell viabilities and superoxide dismutase and reduced glutathione activities were significantly restored, whereas lactate dehydrogenase releases and reactive oxygen species, nitric oxide, and malondialdehyde levels were greatly decreased after MAPs treatment. We found that MAPs could attenuate alloxan-induced apoptosis by increasing the expression of Bcl-2 and decreasing the expression of Bax and the activities of caspase-3 and caspase-9. The results of Western blot revealed that MAPs suppressed the expression of cleaved caspase-3 and cleaved PARP and upregulated the expression of nucleus Nrf2 and its downstream protein. These findings indicated that MAPs could alleviate alloxan-induced β-cell apoptosis by reducing oxidative stress and upregulating Nrf2 expression., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Methamphetamine (METH) exposure can cause severe effects to the nervous system; however, the underlying molecular mechanism of neurotoxicity caused by METH is still unclear. Oxidative stress and apoptosis are linked in the pathophysiology of many neurodegenerative diseases. Krill oil (KO) benefits human health via its strong antioxidant ability. Therefore, we hypothesized that KO supplementation might effectively prevent METH-induced neurotoxicity via the inhibition of apoptotic responses and oxidative damages. In this study, PC12 cells were exposed to both METH (3 mmol/L) and KO (0.1, 0.2, 0.4, 0.8 μg/mL) in vitro for 24 h, and the following parameters were measured to detect apoptosis and oxidative stress responses that were triggered by METH: cell viability, the oxidative enzyme system, NO production, ROS production, apoptosis, mitochondrial membrane potential and protein expression of cleaved caspase-3. The results indicate that KO mitigates the apoptotic response post-METH exposure in PC 12 cells by increasing cell viability, decreasing protein expression of cleaved caspase-3, reducing apoptotic rates, and decreasing dissipation of mitochondrial membrane potential. In addition, the study revealed increases in SOD and GSH activity, and decreases in MDA content, NO and ROS production, suggesting that KO is beneficial in reducing oxidative stress, which may also play a role in the regulation of METH-triggered apoptotic response. Consequently, these data indicate that KO could potentially alleviate METH-induced neurotoxicity via the reduction of apoptotic responses and oxidative damages., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Accumulating evidence has demonstrated that voltage-gated potassium channels (Kv channels) were associated with regulating cell proliferation and apoptosis in tumor cells. Our previous study proved that the Kv channel blocker 4-aminopyridine (4-AP) could inhibit cell proliferation and induce apoptosis in glioma. However, the precise mechanisms were not clear yet. MicroRNAs (miRNAs) are small noncoding RNAs that act as key mediators in the progression of tumor, so the aim of this study was to investigate the role of miRNAs in the apoptosis-promoting effect of 4-AP in glioma cells. Using a microRNA array, we found that 4-AP altered the miRNA expression in glioma cells, and the down-regulation of miR-10b-5p induced by 4-AP was verified by real-time PCR. Transfection of miR-10b-5p mimic significantly inhibited 4-AP-induced caspases activation and apoptosis. Moreover, we verified that apoptosis-related molecule Apaf-1 was the direct target of miR-10b-5p. Furthermore, miR-10b-5p mimic significantly inhibited 4-AP-induced up-regulation of Apaf-1 and its downstream apoptosis-related proteins, such as cleaved caspase-3. In conclusion, Kv channel blocker 4-AP may exert its anti-tumor effect by down-regulating the expression of miR-10b-5p and then raised expression of Apaf-1 and its downstream apoptosis-related proteins. Current data provide evidence that miRNAs play important roles in Kv channels-mediated cell proliferation and apoptosis.

Objectives: The aim of the study has been to investigate the effect of the Standard Reference Material of fine particulate matter (SRM 2786) on cytotoxicity and apoptosis in human lung bronchial epithelial cells (16HBE cells). Whether the lipopolysaccharide (LPS)-induced inflammation could further accelerate cell apoptosis induced by SRM 2786 stimulation has also been determined., Material and Methods: 16HBE cells were exposed to various doses of SRM 2786 with or without LPS. The following parameters: cytotoxicity, apoptotic rate, Bax/Bcl-2 expression, nitric oxide (NO) production, and reactive oxygen species (ROS) generation were measured., Results: The results have shown that SRM 2786 induces cell damage and apoptosis of 16HBE cells as demonstrated by significant decrease in expression of Bcl-2 and increase in expression of Bax. When compared with the control cells, the apoptotic rate of cells treated by 500 μg/ml of SRM 2786 increased from 2.43±0.21% to 43.96±2.95% (p < 0.01). Further, there was an elevated production of NO and ROS post SRM 2786 treatment. The level of NO in cells treated with 500 μg/ml of SRM 2786 was 18.33±1.02 μmol/l whereas that of control cells was 1.58±0.31 μmol/l (p < 0.01). When compared with the control group, the level of intracellular ROS increased by 24% after treatment with 500 μg/ml of SRM 2786 (p < 0.05). In addition, LPS pre-treatment may accelerate cell apoptosis by increasing generation of NO and ROS followed by SRM 2786 stimulation. When compared to cells treated with 125 μg/ml of SRM 2786 alone, the levels of NO and ROS in cells pretreated with LPS increased by 28% and 11.6%, respectively (p < 0.05), and the apoptotic rate increased from 34.62±4.44% to 54.11±3.34% (p < 0.01)., Conclusions: These findings have suggested that in vitro exposure to SRM 2786 could induce 16HBE cells apoptosis probably by means of the mechanism involving the generation of free radicals, while the degree of apoptosis would be further aggravated under inflammation condition. Int J Occup Med Environ Health 2018;31(2):173-183., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

Accumulating evidence has proved that potassium channels (K+ channels) are involved in regulating cell proliferation, cell cycle progression and apoptosis of tumor cells. However, the precise cellular mechanisms are still unknown. In the present study, we investigated the effect and mechanisms of quinidine, a commonly used voltage-gated K+ channel blocker, on cell proliferation and apoptosis of human glioma U87-MG cells. We found that quinidine significantly inhibited the proliferation of U87-MG cells and induced apoptosis in a dose-dependent manner. The results of caspase colorimetric assay showed that the mitochondrial pathway was the main mode involved in the quinidine-induced apoptotic process. Furthermore, the concentration range of quinidine, which inhibited voltage-gated K+ channel currents in electrophysiological assay, was consistent with that of quinidine inhibiting cell proliferation and inducing cell apoptosis. In U87-MG cells treated with quinidine (100 µmol/l), 11 of 2,042 human microRNAs (miRNAs) were upregulated and 16 were downregulated as detected with the miRNA array analysis. The upregulation of miR-149-3p and downregulation of miR-424-5p by quinidine treatment were further verified by using quantitative real-time PCR. In addition, using miRNA target prediction program, putative target genes related to cell proliferation and apoptosis for two differentially expressed miRNAs were predicted. Taken together, these data suggested that the anti-proliferative and pro-apoptosis effect of voltage-gated K+ channel blocker quinidine in human glioma cells was mediated at least partly through regulating expression of miRNAs, and provided further support for the mechanisms of voltage-gated K+ channels in mediating cell proliferation and apoptosis.

Alveolar macrophages (AM) are the predominant lung cells responsible for both ingestion and clearance of inhaled particulate matter (PM). The aims of this study were (1) to examine effects of fine PM on rat NR8383 cell line apoptosis, and (2) to determine whether NR8383 cell functions are further affected when exposed to fine PM in the presence of inflammation induced by lipopolysaccharide (LPS). Standard Reference Material 2786 (SRM 2786) for fine PM was used to measure the following parameters: cytotoxicity, apoptotic rate, Bax/Bcl-2 expression, nitric oxide (NO) production, and reactive oxygen species (ROS) generation in NR8383 cells. Data showed that SRM 2786 alone induced damage and apoptosis in NR8383 cells in a concentration-dependent manner as demonstrated by significant decrease in expression of Bcl-2 and increase in expression of Bax, suggesting fine PM might trigger apoptosis involving a mitochondria-mediated apoptotic pathway. In addition, there was elevated production of free radicals, such as NO and ROS, suggesting oxidative stress plays a role in the observed apoptotic responses. Further, LPS pretreatment enhanced apoptosis of NR8383 cells induced by SRM 2786. Consequently, data indicate that SRM 2786 triggered cell apoptosis in NR8383 cells, probably by mechanisms involving oxidative stress, as evidenced by elevated NO and ROS levels, while the degree of apoptosis was further aggravated by inflammation.

Oridonin, the main active component of Rabdosia rubescens, has antitumor activities in experimental and clinical settings. The aims of the current study were to explore the anticancer abilities of oridonin in hepatoblastoma (HB) HuH-6 cells and to investigate the underlying mechanisms. We found that oridonin inhibited HuH-6 cell in vitro growth in a dose- and time-dependent manner. Further, oridonin induced HuH-6 cell apoptosis and G2/M cell cycle arrest. Upon studying the mechanism, we found that oridonin treatment caused endoplasmic reticulum (ER) stress activation. Meanwhile, ER stress inhibitor salubrinal- or inositol-requiring enzyme 1 (IRE-1) shRNA silencing inhibited oridonin's anti-HuH-6 effects, while ER stress inducers thapsigargin (Tg) and tunicamycin (Tm) mimicked oridonin's actions on HuH-6 cells. Oridonin also activated apoptosis signal regulating kinase 1 (ASK1)-c-Jun N-terminal kinase 1 (JNK1) signaling in cultured HuH-6 cells, which was inhibited by IRE-1 silencing. Importantly, the JNK inhibitors suppressed oridonin-induced growth inhibition and apoptosis in HuH-6 cells. In conclusion, our results suggest that oridonin induces growth inhibition and apoptosis in cultured HuH-6 cells involving ER stress and ASK1/JNK signaling pathways, which enhances our understanding of the molecular mechanisms of oridonin in HB management.

Glucocorticoid (GC) are stress hormones, whose cytotoxicity has been shown in various cells. The imbalance of calcium homeostasis is believed to be associated with the dexamethasone (DEX, a synthetic GC)-induced apoptosis. Here we show that in C2C12 myoblasts, DEX markedly up-regulated the expression of inositol 1,4,5-triphosphate receptor 1 (IP3R1) and down-regulated the expression of SERCA1 (sarcoendoplasmic reticulum Ca(2+)-ATPase 1), leading to calcium overload. Furthermore, the imbalance of calcium homeostasis increased the level of BAX, decreased the level of Bcl-2, induced cytochrome c release and activated caspase-3, leading to intranucleosomal DNA fragmentation and plasma membrane damage, eventually resulting in cell apoptosis. Taken together, by using C2C12 myoblasts as a model system, we demonstrated a novel mechanism for stress hormone-induced apoptosis: it is dependent on the induction of intracellular calcium overload via the alterations of IP3R1 and SERCA1 expressions., ((c) 2009 Elsevier Inc. All rights reserved.)

Ambient fine particulate matter (PM2.5) is a threat to public health. The P2 X 7purinergic receptor (P2X7R) is a modulator that responds to inflammation. Yet the role of P2X7R in the mediation of PM2.5-induced pulmonary cytotoxicity is rarely investigated. In this study, the expression of P2X7R and its effect on cell viability, oxidative damage, apoptosis, mitochondrial dysfunction and underlying mechanism following PM2.5 treatment in rat alveolar macrophages (NR8383) were analyzed. The outcome indicated that PM2.5 exposure significantly increased the expression of P2X7R, while P2X7R antagonist oATP markedly alleviate the production of reactive oxygen species (ROS), Nitrite Oxidation (NO), mitochondrial membrane potential, apoptosis rate, and release of inflammatory cytokines. In contrast, P2X7 agonist BzATP showed opposite effect in PM2.5-treated NR8383 cells. Therefore, these results demonstrated that P2X7R participated in PM2.5-induced pulmonary toxicity, while the blockade of P2X7R is a promising therapeutic approach of treating PM2.5-induced lung diseases. [ABSTRACT FROM AUTHOR]

Background: The ovary is highly sensitive to radiation, and patients receiving radiotherapy are at significant risk of premature ovarian failure (POF). This study aimed to explore the radioprotective effect of honokiol (HKL) on ionizing radiation (IR)‐induced POF. Methods: Female C57BL/6 mice were administered intraperitoneally with vehicle or HKL once daily for 7 days. On day 7, the mice in the IR and HKL+IR groups were exposed to 3.2 Gy whole‐body radiation for one hour after the intraperitoneal injection and sacrificed 12 or 72 h after radiation exposure. The gonadosomatic index (GSI) was calculated. Blood samples were collected for enzyme‐linked immunosorbent assay (ELISA). Ovaries were harvested for histological examination, immunohistochemistry, immunofluorescence, TUNEL, western blot, and qPCR. The fertility assessment was evaluated by calculating live offspring number. Results: The optimum dose of HKL against radiation was 10 mg/kg via intraperitoneal injection. POF was induced 72 h after irradiation with significantly downregulated proliferating cell nuclear antigen (PCNA). The numbers of primordial and preantral follicles decreased significantly after irradiation (p <.001), whereas the number of atretic follicles increased (p <.001). The serum levels of estradiol (E2) and anti‐Müllerian hormone (AMH) decreased to 50% of the control group after irradiation (p <.05). Moreover, the GSI after irradiation was 27% lower than in the control group (p <.05). The number of offspring in the IR group dropped by 50% compared with the control group (p <.05). HKL pretreatment protected the animals' fertility, GSI, PCNA, serum levels of E2 and AMH, and the number of primordial and preantral follicles. Significant upregulation of apoptosis‐related proteins such as Pho‐P53, Bax, Cyto C, C‐caspase‐3, C‐PARP, and pyroptosis‐related proteins such as Pho‐NF‐κB p65, NLRP3, caspase‐1, IL‐1β, and IL‐18 was observed after irradiation, while the expression of Bcl‐2 decreased. HKL pretreatment prevented these changes. After irradiation, malondialdehyde (MDA), Nrf2, and HO‐1 were upregulated. HKL treatment activated the expression of Nrf2 and HO‐1 and promoted the nucleus translocation of Nrf2. Furthermore, HKL did not affect ovarian reserves under physiological conditions. Conclusions: HKL ameliorated IR‐induced POF by inhibiting apoptosis and pyroptosis by enhancing Nrf2 expression and translocation. [ABSTRACT FROM AUTHOR]

PM2.5 exposure has been demonstrated to correlate with neurological disorders recently. Ferroptosis is recognized as a newly found programmed form of cell death associated with neurodegenerative diseases, while glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis. However, the relationship between PM2.5‐induced neurotoxicity and ferroptosis is still unclear. The current study aims to investigate if ferroptosis is involved in neurotoxicity post PM2.5 exposure and its underlying mechanism. The PM2.5‐treated neuronal Neuro‐2a (N2A) and SH‐SY5Y cells were applied to the current study. The results showed that PM2.5 significantly increased the neuronal cell death, yet the ferroptosis antagonist Ferrostain‐1 (Fer‐1) markedly decreased the cell death induced by PM2.5. Western blot further confirmed that ferroptosis was triggered post PM2.5 treatment in N2A cells by decreasing expressions of GPX4 and ferritin heavy chain (FTH), as well as enhancing expressions of ferritin light chain (FTL) and transferrin receptor protein (TFRC). Meanwhile, PM2.5 treatment augmented neuronal oxidative damage and mitochondrial dysfunction. The bioinformatic analysis indicated that CREB could be the regulator of GPX4, and our results showed that ERK/CREB pathway was down‐regulated in N2A cells post PM2.5 treatment. The addition of ERK1/2 agonist post PM2.5 treatment significantly inhibit ferroptosis via increasing the expression of GPX4. Taken together, the present study demonstrated that PM2.5‐induced ferroptosis via inhibiting ERK/CREB pathway, and these findings will advance our knowledge of PM2.5‐induced cytotoxicity in the nervous system. [ABSTRACT FROM AUTHOR]

Methamphetamine (METH) abuse produces serious neurotoxicity to the central nervous system along with long‐term cognitive dysfunction. Resveratrol, a natural polyphenol, has broad application prospects in the treatment of neurodegenerative diseases. Therefore, this study was conducted to investigate whether resveratrol might alleviate METH‐induced memory deficits in vivo. We found that multiple exposures to METH significantly impaired cognitive functions and caused long‐lasting memory deficits (p <.05). Pretreatment of resveratrol (10 or 100 mg/kg) remarkably attenuated METH‐induced memory impairment in mice (p <.05). Bioinformatics analysis results showed that resveratrol might alleviate memory deficits by inhibiting METH‐induced oxidative damage and apoptosis. Molecular docking showed that resveratrol had hydrogen bonding interactions with Kelch‐like ECH associated protein 1 (Keap1), a repressor protein of the classic antioxidant Keap1‐Nrf2 pathway. Further results validated oxidative stress parameters, apoptosis, and expression of Keap1 were significantly increased, while the translocation and activation of nuclear factor erythroid 2‐related factor 2 (Nrf2) into the nucleus and expression of its downstream proteins were greatly decreased in the hippocampus after METH exposure (p <.05). These changes caused by METH could be prevented by resveratrol (p <.05). Therefore, these findings suggested that the prevention of resveratrol on memory dysfunction induced by METH was possibly related to the activation of the Keap1‐Nrf2 pathway and reduction of apoptosis. Supplementation of resveratrol could be a potential treatment for preventing the neurotoxicity of METH in the future. Practical applications: As one of the worst commonly abused psychostimulants, methamphetamine (METH) addiction produces serious complications including cognitive impairment and memory deficits. Resveratrol is a natural polyphenol that has important nutritional supplements and protective effects in the treatment of many neurodegenerative diseases. In this study, the results of bioinformatics prediction and experimental validation showed that resveratrol might effectively prevent memory impairment via the interaction with Keap1, activation of the Keap1‐Nrf2 pathway, and inhibition of DNA damage and apoptotic responses post METH exposure. Therefore, these findings provide new ideas and insights into the application of resveratrol in the treatment of nervous system damage caused by METH. [ABSTRACT FROM AUTHOR]

This research was designed to investigate if antioxidant sulforaphane (SFN) alleviates methamphetamine (METH)-induced neurotoxicity by activation of the Nrf2-mediated pathway. Oxidative damage, apoptosis and mitochondrial membrane potential were evaluated in PC12 cells or the prefrontal cortex of SD rats post METH treatment with/without SFN. In addition, knockdown of Nrf2 expression in PC12 cells was used to further study the underlying mechanism. The results showed that METH exposure induced increased oxidative damage and apoptosis accompanied by decreased expressions of Nrf2, HO-1 and GCS in PC12 cells and the prefrontal cortex of SD rats. Meanwhile SFN effectively prevented METH-induced cell oxidative damage, apoptosis and mitochondrial membrane potential; however, the knockdown of Nrf2 expression partly reversed the protective effect of SFN in reducing METH-induced oxidative damage and apoptosis in PC12 cells. These results indicate that SFN might be a promising functional food-derived compound for preventing METH-induced neurotoxicity via the Nrf2-mediated pathway. [ABSTRACT FROM AUTHOR]

DNA integrity plays a crucial role in cell survival. Methamphetamine (METH) is an illegal psychoactive substance that is abused worldwide, and repeated exposure to METH could form mass free radicals and induce neuronal apoptosis. It has been reported that free radicals generated by METH treatment can oxidize DNA and hence produce strand breaks, but whether oxidative DNA damage is involved in the neurotoxicity caused by METH remains unclear. Tea polyphenols exert bioactivities through antioxidant-related mechanisms. However, the potential neuroprotective effect of tea polyphenols on METH-induced nerve cell damage and the underlying mechanism remain to be clarified. In this study, oxidative stress, DNA damage, and cell apoptosis were increased after METH exposure, and the expressions of DNA repair-associated proteins, including the phosphorylation of ataxia telangiectasia mutant (p-ATM) and checkpoint kinase 2 (p-Chk2), significantly declined in PC12 cells after high-dose or long-time METH treatment. Additionally, tea polyphenols could protect PC12 cells against METH-induced cell viability loss, reactive oxide species and nitric oxide production, and mitochondrial dysfunction and suppress METH-induced apoptosis. Furthermore, tea polyphenols could increase the antioxidant capacities and expressions of p-ATM and p-Chk2 and then attenuate DNA damage via activating the DNA repair signaling pathway. These findings indicate that METH is likely to induce neurotoxicity by inducing DNA damage, which can be reversed by tea polyphenols. Supplementation with tea polyphenols could be an effective nutritional prevention strategy for METH-induced neurotoxicity and neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study has been to investigate the effect of the Standard Reference Material of fine particulate matter (SRM 2786) on cytotoxicity and apoptosis in human lung bronchial epithelial cells (16HBE cells). Whether the lipopolysaccharide (LPS)-induced inflammation could further accelerate cell apoptosis induced by SRM 2786 stimulation has also been determined.Material and Methods: 16HBE cells were exposed to various doses of SRM 2786 with or without LPS. The following parameters: cytotoxicity, apoptotic rate, Bax/Bcl-2 expression, nitric oxide (NO) production, and reactive oxygen species (ROS) generation were measured.Results: The results have shown that SRM 2786 induces cell damage and apoptosis of 16HBE cells as demonstrated by significant decrease in expression of Bcl-2 and increase in expression of Bax. When compared with the control cells, the apoptotic rate of cells treated by 500 μg/ml of SRM 2786 increased from 2.43±0.21% to 43.96±2.95% (p < 0.01). Further, there was an elevated production of NO and ROS post SRM 2786 treatment. The level of NO in cells treated with 500 μg/ml of SRM 2786 was 18.33±1.02 μmol/l whereas that of control cells was 1.58±0.31 μmol/l (p < 0.01). When compared with the control group, the level of intracellular ROS increased by 24% after treatment with 500 μg/ml of SRM 2786 (p < 0.05). In addition, LPS pre-treatment may accelerate cell apoptosis by increasing generation of NO and ROS followed by SRM 2786 stimulation. When compared to cells treated with 125 μg/ml of SRM 2786 alone, the levels of NO and ROS in cells pretreated with LPS increased by 28% and 11.6%, respectively (p < 0.05), and the apoptotic rate increased from 34.62±4.44% to 54.11±3.34% (p < 0.01).Conclusions: These findings have suggested that in vitro exposure to SRM 2786 could induce 16HBE cells apoptosis probably by means of the mechanism involving the generation of free radicals, while the degree of apoptosis would be further aggravated under inflammation condition. Int J Occup Med Environ Health 2018;31(2):173-183. [ABSTRACT FROM AUTHOR]

Estrogen plays an important role in inhibiting osteoclast differentiation and protecting against bone loss from osteoporosis, especially in postmenopausal women. However, the precise mechanisms underlying the effect of estrogen on osteoclasts are not well known. In the present study, we performed proteomics analysis and bioinformatics analysis to comprehensively compare the differential expression of proteins in receptor activator of nuclear factor-κB ligand RANKL-induced osteoclasts in the presence and absence of estrogen. We identified 6403 proteins, of which 124 were upregulated and 231 were downregulated by estrogen. Bioinformatics analysis showed that estrogen treatment interfered with 77 intracellular pathways, including both confirmed canonical and unconfirmed pathways of osteoclast formation. Our findings validate the inhibitory effect of estrogen on osteoclasts via the promotion of apoptosis and suppression of differentiation and polarization and suggest that estrogen might inhibit osteoclast formation via other pathways, which requires further investigation and verification. [ABSTRACT FROM AUTHOR]

Abstract: Glucocorticoid (GC) are stress hormones, whose cytotoxicity has been shown in various cells. The imbalance of calcium homeostasis is believed to be associated with the dexamethasone (DEX, a synthetic GC)-induced apoptosis. Here we show that in C2C12 myoblasts, DEX markedly up-regulated the expression of inositol 1,4,5-triphosphate receptor 1 (IP3R1) and down-regulated the expression of SERCA1 (sarcoendoplasmic reticulum Ca2+-ATPase 1), leading to calcium overload. Furthermore, the imbalance of calcium homeostasis increased the level of BAX, decreased the level of Bcl-2, induced cytochrome c release and activated caspase-3, leading to intranucleosomal DNA fragmentation and plasma membrane damage, eventually resulting in cell apoptosis. Taken together, by using C2C12 myoblasts as a model system, we demonstrated a novel mechanism for stress hormone-induced apoptosis: it is dependent on the induction of intracellular calcium overload via the alterations of IP3R1 and SERCA1 expressions. [Copyright &y& Elsevier]