Chronic high-dose alcohol consumption impairs bone remodeling, reduces bone mass, and increases the risk of osteoporosis and bone fracture. However, the mechanisms underlying alcohol-induced osteoporosis are yet to be elucidated. In this study, we showed that excess intake of ethyl alcohol (EtOH) resulted in osteopenia and osteoblast necroptosis in mice that led to necrotic lesions and reduced osteogenic differentiation in bone marrow mesenchymal stem cells (BMMSCs). We found that EtOH treatment led to the activation of the RIPK1/RIPK3/MLKL signaling, resulting in increased osteoblast necroptosis and decreased osteogenic differentiation and bone formation both in vivo and in vitro. We further discovered that excessive EtOH treatment-induced osteoblast necroptosis might partly depend on reactive oxygen species (ROS) generation; concomitantly, ROS contributed to necroptosis of osteoblasts through a positive feedback loop involving RIPK1/RIPK3. In addition, blocking of the RIPK1/RIPK3/MLKL signaling by necrostatin-1 (Nec-1), a key inhibitor of RIPK1 kinase in the necroptosis pathway, or antioxidant N-acetylcysteine (NAC), an inhibitor of ROS, could decrease the activation of osteoblast necroptosis and ameliorate alcohol-induced osteopenia both in vivo and in vitro. Collectively, we demonstrated that chronic high-dose alcohol consumption induced osteopenia via osteoblast necroptosis and revealed that RIPK1 kinase may be a therapeutic target for alcohol-induced osteopenia.

In 2020, a group of experts officially suggested metabolic dysfunction associated with fatty liver disease “MAFLD” as a more appropriate overarching term than NAFLD, indicating the key role of metabolism in fatty liver disease. Bdh1, as the rate-limiting enzyme of ketone metabolism, acts as an important metabolic regulator in liver. However, the role of Bdh1 in MAFLD is unclear. In this study, we used the transgenic db/db mice as a MAFLD mouse model and observed the downregulated expression of Bdh1 in fatty liver. In addition, expression of Bdh1 was also reduced by palmitic acid (PA) treatment in LO2 cells. Bdh1 knockdown led to ROS overproduction and ROS-induced inflammation and apoptosis in LO2 cells, while Bdh1 overexpression protected LO2 cells from lipotoxicity by inhibiting ROS overproduction. Mechanistically, Bdh1-mediated βOHB metabolism inhibits ROS overproduction by activation of Nrf2 through enhancement of metabolic flux composed of βOHB-AcAc-succinate-fumarate. Notably, adeno-associated virus (AAV)-mediated Bdh1 overexpression successfully reversed the hepatic function indexes, fibrosis, inflammation, and apoptosis in fatty livers from db/db mice. In conclusion, our study revealed a Bdh1-mediated molecular mechanism in pathogenesis of metabolic dysfunction related liver disease and identified Bdh1 as a novel potential therapeutic target for MAFLD.

The present study assessed biochemical endpoints indicative of acrylamide toxicity in astrocyte cultures derived from neonatal rat pups. Given earlier reports on the possible ability of acrylamide to induce astrocytomas in the Fischer 344 rat, we performed studies in neonatal rat astrocyte cultures from the Fischer 344 to assess the ability of acrylamide to induce astrocytic proliferation. Measurements on astrocytic proliferation included [3H]‐leucine incorporation, [3H]‐thymidine incorporation, and changes in proliferating cell nuclear antigen (PCNA). Although acrylamide (0.1 and 1 mM for 7, 11, 15, or 20 days) did not significantly (P > 0.05) affect [3H]‐leucine or [3H]‐thymidine incorporation, it significantly (P < 0.05) increased PCNA protein expression in astrocytes exposed to acrylamide for 15 and 20 days. Additional studies revealed that this effect on PCNA protein expression was not associated with activation of dopamine‐2 (D2) receptors, given that quinpirole (10 μM added to cultures for the last hour of 7, 11, 15, or 20 days in culture), a selective D2 receptor agonist, did not produce results analogous to those seen with acrylamide treatment. Cotreatment of astrocytes with acrylamide (7, 11, 15, or 20 days) and the D2 receptor antagonist, sulpiride (1 μM for the last 6 h of exposure), also failed to reverse acrylamide's effect on PCNA protein induction. Taken together, these studies suggest that acrylamide promotes astrocytic cell proliferation in the CNS even though DNA synthesis did not appear stimulated.

RA treatment induces autophagy and Beclin1 may play an important role in endometriosis progression.