The interaction between m⁶A-methylated RNA and chromatin modification remains largely unknown. We found that targeted inhibition of bromodomain-containing protein 4 (BRD4) by siRNA or its inhibitor (JQ1) significantly decreases mRNA m⁶A levels and suppresses the malignancy of breast cancer (BC) cells via increased expression of demethylase AlkB homolog 5 (ALKBH5). Mechanistically, inhibition of BRD4 increases the mRNA stability of ALKBH5 via enhanced binding between its 3' untranslated regions (3'UTRs) with RNA-binding protein RALY. Further, BRD4 serves as a scaffold for ubiquitin enzymes tripartite motif containing-21 (TRIM21) and ALKBH5, resulting in the ubiquitination and degradation of ALKBH5 protein. JQ1-increased ALKBH5 then demethylates mRNA of extra spindle pole bodies like 1 (ESPL1) and reduces binding between ESPL1 mRNA and m⁶A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leading to decay of ESPL1 mRNA. Animal and clinical studies confirm a critical role of BRD4/ALKBH5/ESPL1 pathway in BC progression. Further, our study sheds light on the crosstalks between histone modification and RNA methylation.

OBJECTIVE: To evaluate the effect of Shilajit, a medicine of Ayurveda, on the serum changes in cytokines and adipokines caused by non-alcoholic fatty liver disease (NAFLD). METHODS: After establishing fatty liver models by feeding a high-fat diet (HFD) for 12 weeks, 35 Wistar male rats were randomly divided into 5 groups, including control (standard diet), Veh (HFD + vehicle), high-dose Shilajit [H-Sh, HFD + 250 mg/(kg·d) Shilajit], low-dose Shilajit [L-Sh, HFD + 150 mg/(kg·d) Shilajit], and pioglitazone [HFD + 10 mg/(kg·d) pioglitazone] groups, 7 rats in each group. After 2-week of gavage administration, serum levels of glucose, insulin, interleukin 1beta (IL-1β), IL-6, IL-10, tumor necrosis factor-alpha (TNF-α), adiponectin, and resistin were measured, and insulin resistance index (HOMA-IR) was calculated. RESULTS: After NAFLD induction, the serum level of IL-10 significantly increased and serum IL-1β, TNF-α levels significantly decreased by injection of both doses of Shilajit and pioglitazone (P<0.05). Increases in serum glucose level and homeostasis model of HOMA-IR were reduced by L-Sh and H-Sh treatment in NAFLD rats (P<0.05). Both doses of Shilajit increased adiponectin and decreased serum resistin levels (P<0.05). CONCLUSION The probable protective role of Shilajit in NAFLD model rats may be via modulating the serum levels of IL-1β, TNF-α, IL-10, adipokine and resistin, and reducing of HOMA-IR.
Adiponectin ; Animals ; Cytokines ; Diet, High-Fat ; Glucose ; Insulin Resistance ; Interleukin-10 ; Liver ; Male ; Minerals ; Non-alcoholic Fatty Liver Disease/pathology* ; Pioglitazone/therapeutic use* ; Rats ; Rats, Wistar ; Resins, Plant ; Resistin/therapeutic use* ; Tumor Necrosis Factor-alpha

Background & Objective: This study aimed to find a biomarker to predict the development of multiple sclerosis (MS). Serum levels of vitamin D3, C-reactive protein (CRP) and melatonin and their ratio were evaluated to find the valuable cut-off point. Methods: Serum levels of vitamin D3, CRP and melatonin were evaluated using commercial ELISA kit in newly diagnosed MS patients and compared with healthy controls. Results: Serum CRP level significantly increased and serum melatonin level significantly decreased in MS patients in comparison to controls. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy for the cut-off point of CRP/melatonin ratio ≥ 78.29087 were 80%. Conclusion: CRP/melatonin ratio ≥ 78.29087 may be used for prediction of MS in an at risk population

Animal studies indicate that gonadal steroids have prominent neuroprotective effects in several models of experimental traumatic brain injury (TBI). Neuromedin U (NMU) and neuromedin S (NMS) are regulatory peptides involved in inflammatory and stress responses, and modulation of the gonadotropic axis. Since steroid hormone levels change during the estrous cycle, we sought to determine whether variations in ovarian hormones would affect blood-brain barrier (BBB) permeability and brain levels of NMS, NMU, and neuromedin S receptor 2 in experimental TBI. Two groups (proestrus and nonproestrus) of female rats underwent diffuse TBI. At 24 hrs after TBI, results showed a significantly decrease in BBB permeability in traumatic-proestrus animals (TBI-P) in comparison to traumatic nonproestrus (TBI-NP) rats. Western blot analyzes demonstrated an enhanced expression of prepro-NMS in TBI-P compared with that in the TBI-NP group. Likewise, TBI-P rats exhibited significantly higher NMUR2 gene expression compared with those of TBI-NP, whereas no significant difference in brain NMU content was seen between sham and traumatic animals. Our findings indicate that diffuse TBI induces an increase in prepro-NMS and neuromedin S receptor 2 expression in traumatic-proestrus rats which may mediate the anti-edematous effects of gonadal hormones in proestrus rats following trauma.

Animal studies indicate that gonadal steroids have prominent neuroprotective effects in several models of experimental traumatic brain injury (TBI). Neuromedin U (NMU) and neuromedin S (NMS) are regulatory peptides involved in inflammatory and stress responses, and modulation of the gonadotropic axis. Since steroid hormone levels change during the estrous cycle, we sought to determine whether variations in ovarian hormones would affect blood-brain barrier (BBB) permeability and brain levels of NMS, NMU, and neuromedin S receptor 2 in experimental TBI. Two groups (proestrus and nonproestrus) of female rats underwent diffuse TBI. At 24 hrs after TBI, results showed a significantly decrease in BBB permeability in traumatic-proestrus animals (TBI-P) in comparison to traumatic nonproestrus (TBI-NP) rats. Western blot analyzes demonstrated an enhanced expression of prepro-NMS in TBI-P compared with that in the TBI-NP group. Likewise, TBI-P rats exhibited significantly higher NMUR2 gene expression compared with those of TBI-NP, whereas no significant difference in brain NMU content was seen between sham and traumatic animals. Our findings indicate that diffuse TBI induces an increase in prepro-NMS and neuromedin S receptor 2 expression in traumatic-proestrus rats which may mediate the anti-edematous effects of gonadal hormones in proestrus rats following trauma.
Neuropeptides ; Receptors, Neuropeptide

It has been shown that some opium derivatives promote cell death via apoptosis. This study was designed to examine the influence of opium addiction on brain and liver cells apoptosis in male and female diabetic and non-diabetic Wistar rats. This experimental study was performed on normal, opium-addicted, diabetic and diabetic opium-addicted male and female rats. Apoptosis was evaluated by TUNEL and DNA fragmentation assays. Results of this study showed that apoptosis in opium-addicted and diabetic opium-addicted brain and liver cells were significantly higher than the both normal and diabetic rats. In addition, we found that apoptosis in brain cells of opium-addicted and diabetic opium-addicted male rats were significantly higher than opium-addicted and diabetic opium-addicted female, whereas apoptosis in liver cells of opium-addicted and diabetic opium-addicted female rats were significantly higher than opium-addicted and diabetic opium-addicted male. Overall, these results indicate that opium probably plays an important role in brain and liver cells apoptosis, therefore, leading neurotoxicity and hepatotoxicity. These findings also in away possibly means that male brain cells are more susceptible than female and interestingly liver of females are more sensitive than males in induction of apoptosis by opium.
Animals ; Apoptosis ; Brain ; Cell Death ; DNA Fragmentation ; Female ; Humans ; In Situ Nick-End Labeling ; Liver ; Male ; Opium ; Rats ; Rats, Wistar