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Hypoglycemia has emerged as a prominent complication in anti-diabetic drug therapy or negative energy balance of animals, which causes brain damage, cognitive impairment, and even death. Brain injury induced by hypoglycemia is closely related to oxidative stress and the production of reactive oxygen species (ROS). The intracellular accumulation of ROS leads to neuronal damage, even death. Ketone body β-hydroxybutyrate (BHBA) not only serves as alternative energy source for glucose in extrahepatic tissues, but is also involved in cellular signaling transduction. Previous studies showed that BHBA reduces apoptosis by inhibiting the excessive production of ROS and activation of caspase-3. However, the effects of BHBA on apoptosis induced by glucose deprivation and its related molecular mechanisms have been seldom reported. In the present study, PC12 cells and primary cortical neurons were used to establish a low glucose injury model. The effects of BHBA on the survival and apoptosis in a glucose deficient condition and related molecular mechanisms were investigated by using flow cytometry, immunofluorescence, and western blotting. PC12 cells were incubated with 1 mM glucose for 24 h as a low glucose cell model, in which ROS accumulation and cell mortality were significantly increased. After 24 h and 48 h treatment with different concentrations of BHBA (0 mM, 0.05 mM, 0.5 mM, 1 mM, 2 mM), ROS production was significantly inhibited. Moreover, cell apoptosis rate was decreased and survival rate was significantly increased in 1 mM and 2 mM BHBA groups. In primary cortical neurons, at 24 h after treatment with 2 mM BHBA, the injured length and branch of neurites were significantly improved. Meanwhile, the intracellular ROS level, the proportion of c-Fos+ cells, apoptosis rate, and nuclear translocation of NF-κB protein after treatment with BHBA were significantly decreased when compared with that in low glucose cells. Importantly, the expression of p38, p-p38, NF-κB, and caspase-3 were significantly decreased, while the expression of p-ERK was significantly increased in both PC12 cells and primary cortical neurons. Our results demonstrate that BHBA decreased the accumulation of intracellular ROS, and further inhibited cell apoptosis by mediating the p38 MAPK signaling pathway and caspase-3 apoptosis cascade during glucose deprivation. In addition, BHBA inhibited apoptosis by activating ERK phosphorylation and alleviated the damage of low glucose to PC12 cells and primary cortical neurons. These results provide new insight into the anti-apoptotic effect of BHBA in a glucose deficient condition and the related signaling cascade.

Telocytes, a novel type of interstitial cells with very long and thin prolongations, have been identified in many organs in mammals. At present, the ultrastructural, immunocytochemical and electrophysiological properties of telocytes in multiple organs have been understood. However, telocytes in spleen, especially their roles in spleen have not been reported. The aim of this study was to investigate the ultrastructure, distribution and immunophenotypes of splenic telocytes. Rat spleen was harvested for the ultrastructure analysis by transmission electron microscopy (TEM). The primary culture of telocytes was performed after combined enzymatic digestion. The characteristic morphology was analyzed by a scanning electron microscopy (SEM). It was shown that telocytes displayed a piriform/spindle/triangular shape with long and slender telopods and extremely long prolongation contracting with surrounding cells in the spleen. Their dynamic profiles of cytoplasmic separation were recorded by the Live Cell Imaging System. The length of telopods was mostly distributing in 20-30 μm, in accordance with normal distribution. Most telocytes had three or two telopods (28.71% and 22.58% respectively). Immunostaining indicated that these cells were positive for vimentin, CD34, nanog and sca-1, but negative for c-kit. These data prove the existence of telocytes in the spleen, which may serve as the experimental base for exploring their roles in the spleen.

Cancer remains the foremost cause of mortality on a global scale. Immunotherapy has yielded remarkable outcomes in the fight against cancer and is regarded as one of the most crucial and promising therapeutic modalities. PCSK9, a critical target for plasma lipids control, has been extensively and deeply studied in multiple diseases. Currently, the functions of PCSK9 in cancer, particularly its immunomodulatory role, have been progressively revealed. PCSK9 is capable of modulating a variety of immune response throughout tumor progression by orchestrating lipid metabolism. Moreover, PCSK9 governs the cell fate of diverse immune cells, such as inflammatory factor signals, MHC signals, and TCR signals. This review comprehensively summarizes the current state of knowledge regarding the role and underlying mechanisms of PCSK9 in tumorigenesis, progression, immune escape, and drug resistance.

Gossypol is a yellow polyphenolic compounds extracted from roots, stems and seeds of cotton plants. Excessive intake of gossypol induces severe pathological signs of toxicity in livestock and wildlife. Currently, gossypol has received widespread attention for its toxic effects on the reproductive system. However, reports of the effects of gossypol during corticogenesis and the development of the mouse cerebral cortex are unavailable. In the present study, gossypol was orally administrated at a dose of 0, 20, and 50 mg/kg body weight/day to pregnant mice from embryonic day 6.5 to the time of sample collection. We used electroporation and immunofluorescence to demonstrate that gossypol impaired cortical neuronal migration. Furthermore, labeling with 5-bromo-2-deoxyuridine and western blot analysis revealed that gossypol disturbed the balance between proliferation and differentiation of neural progenitors, inhibited neural progenitor cell proliferation, neuronal differentiation, and maturation. Additionally, cortical progenitor apoptotic cell death increased in the developing gossypol-treated cortex, which was associated with NF-κB and MAPK pathways. In conclusion, our findings indicate that gossypol exposure disrupted neurogenesis in the developing neocortex, suggesting the potentially harmful impact of gossypol on the cerebral cortex development of humans and livestock.

In the present study, the immuno-enhancing effect of Eucommia ulmoides leaf polysaccharide (ELP) was investigated in immunosuppressed mice induced by cyclophosphamide (CTX). To evaluate the immune enhancement mechanism of ELP, the immunoregulation effect of ELP was evaluated in vitro and in vivo. ELP is primarily composed of arabinose (26.61%), galacturonic acid (25.1%), galactose (19.35%), rhamnose (16.13%), and a small amount of glucose (12.9%). At 1000~5000 μg·mL−1, ELP could significantly enhance the proliferation and the phagocytosis of macrophages in vitro. Additionally, ELP could protect immune organs, reduce pathological damage, and reverse the decrease in the hematological indices. Moreover, ELP significantly increased the phagocytic index, enhanced the ear swelling response, augmented the production of inflammatory cytokines, and markedly up-regulated the expression of IL-1β, IL-6, and TNF-α mRNA levels. Furthermore, ELP improved phosphorylated p38, ERK1/2, and JNK levels, suggesting that MAPKs might be involved in immunomodulatory effects. The results provide a theoretical foundation for exploring the immune modulation function of ELP as a functional food.

Ischemic stroke ranks as the second leading cause of global mortality. The limited time for effective thrombolytic treatment has prompted the exploration of alternative prevention approaches. Eucommia ulmoides (E. ulmoides) Oliv. bark has shown multiple pharmacological effects, including neuroprotection, anti-inflammation and autophagy modulation. This study aims to elucidate the neuroprotective effects of water extract of E. ulmoides (WEU) supplementation in a middle cerebral artery occlusion (MCAO) mouse model and to further explore the underlying molecular mechanisms. Seven bioactive compounds in WEU—aucubin, chlorogenic acid, geniposidic acid, quercetin, protocatechuic acid, betulin and pinoresinol diglucoside—were identified using HPLC-MS. Our results showed that WEU supplementation significantly decreased infarct volume and ameliorated neurological dysfunction in mice following MCAO/reperfusion (MCAO/R) injury. Furthermore, the administration of WEU significantly attenuated microglia activation induced by cortical ischemia in mice and inhibited the production of pro-inflammatory mediators, including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Importantly, in contrast with the vehicle group, the protein expression levels of Toll-like receptor 4 (TLR4), phospho-p38 (p-p38) and nuclear factor kappa B (NF-κB) were reduced in the WEU group. Therefore, this present study provides evidence that E. ulmoides improves neurological behaviors by suppressing neuroinflammation and inhibiting the activation of the TLR4/ p38 MAPK and NF-κB pathways in mice after ischemia, which indicates that E.ulmoides is a promising candidate for alleviating gray matter ischemic change.

Abstract Background Neurogenesis in the neonatal period involves the proliferation and differentiation of neuronal stem/progenitor cells and the establishment of synaptic connections. This process plays a critical role in determining the normal development and maturation of the brain throughout life. Exposure to certain physical or chemical factors during the perinatal period can lead to many neuropathological defects that cause high cognitive dysfunction and are accompanied by abnormal hippocampal neurogenesis and plasticity. As an endocrine disruptor, gossypol is generally known to exert detrimental effects in animals exposed under experimental conditions. However, it is unclear whether gossypol affects neurogenesis in the hippocampal dentate gyrus during early developmental stages. Methods Pregnant Institute of Cancer Research mice were treated with gossypol at a daily dose of 0, 20, and 50 mg/kg body weight from embryonic day 6.5 to postnatal day (P) 21. The changes of hippocampal neurogenesis as well as potential mechanisms were investigated by 5-bromo-2-deoxyuridine labeling, behavioral tests, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western-blot analyses. Results At P8, maternal gossypol exposure impaired neural stem cell proliferation in the dentate gyrus and decreased the number of newborn cells as a result of reduced proliferation of BLBP+ radial glial cells and Tbr2+ intermediate progenitor cells. At P21, the numbers of NeuN+ neurons and parvalbumin+ γ-aminobutyric acid-ergic interneurons were increased following 50 mg/kg gossypol exposure. In addition, gossypol induced hippocampal neuroinflammation, which may contribute to behavioral abnormalities and cognitive deficits and decrease synaptic plasticity. Conclusions Our findings suggest that developmental gossypol exposure affects hippocampal neurogenesis by targeting the proliferation and differentiation of neuronal stem/progenitor cells, cognitive functions, and neuroinflammation. The present data provide novel insights into the neurotoxic effects of gossypol on offspring.

In the present study, the immuno-enhancing effect of Eucommia ulmoides leaf polysaccharide (ELP) was investigated in immunosuppressed mice induced by cyclophosphamide (CTX). To evaluate the immune enhancement mechanism of ELP, the immunoregulation effect of ELP was evaluated in vitro and in vivo. ELP is primarily composed of arabinose (26.61%), galacturonic acid (25.1%), galactose (19.35%), rhamnose (16.13%), and a small amount of glucose (12.9%). At 1000~5000 μg·mL[sup.−1] , ELP could significantly enhance the proliferation and the phagocytosis of macrophages in vitro. Additionally, ELP could protect immune organs, reduce pathological damage, and reverse the decrease in the hematological indices. Moreover, ELP significantly increased the phagocytic index, enhanced the ear swelling response, augmented the production of inflammatory cytokines, and markedly up-regulated the expression of IL-1β, IL-6, and TNF-α mRNA levels. Furthermore, ELP improved phosphorylated p38, ERK1/2, and JNK levels, suggesting that MAPKs might be involved in immunomodulatory effects. The results provide a theoretical foundation for exploring the immune modulation function of ELP as a functional food.

Bedaquiline has recently been approved for the treatment of multidrug-resistant tuberculosis. Carvedilol is a cardiovascular medication extensively used in the treatment of heart failure and hypertension. In this study, Sprague-Dawley rats, rat liver microsomes (RLM), human liver microsomes (HLM), and recombinant human CYP3A4 were used to explore the effect of carvedilol on the metabolism of bedaquiline. Ultra-performance liquid chromatography-tandem mass spectrometry was used to facilitate the quantification of the analyte concentrations. In vitro, carvedilol did not exhibit time-dependent inhibition of bedaquiline, which aligns with the half-maximal inhibitory concentration (IC 50 ) shift results. The IC 50 values of carvedilol were 15.35 ± 0.43 µM in RLM, 7.55 ± 0.74 µM in HLM, and 0.79 ± 0.05 µM in CYP3A4. Besides, the inhibition type of carvedilol was found to be mixed, un-competitive, and mixed in RLM, HLM, and CYP3A4, respectively. In vivo , the co-administration of carvedilol with bedaquiline resulted in a significant increase in the area under the plasma concentration-time curve (AUC) (0 −  t ) , AUC (0 − ∞), and C max of bedaquiline while decreasing its CL z/F . Lay summary : Carvedilol could inhibit the metabolism of bedaquiline in vitro and in vivo , with different mechanisms in different enzymatic reaction systems. Hence, caution should be exercised when combining bedaquiline with carvedilol.