BackgroundSepsis is a critical disease associated with extremely high mortality. Some severe forms of sepsis can induce brain injury, thus causing behavioral and cognitive dysfunction. Pyroptosis is a type of cell death that differs from apoptosis and plays an important role in the occurrence and development of infectious diseases, nervous system-related diseases. A recent study has found that there is pyroptosis in the hippocampus of sepsis-induced brain injury, but its mechanism and treatment scheme have not been evaluated.MethodsWe established immediately a septic rat model by cecal ligation and perforation (CLP) after administration with recombinant club cell protein (rCC16) and/or U46619 in different groups. The clinical performance, survival percentage, vital signs, and neurobehavioral scores were monitored at different time points. Cortical pathological changes were also examined. The expression of cortical nucleotide-binding domain leucine-rich repeat-containing pyrin domain-containing 3 (NLRP3), caspase-1, (p)-p38 mitogen-activated protein kinase (MAPK), and (p)-extracellular signal-related kinase (ERK) was detected by western blotting and immunofluorescence analysis. The levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha in the cortical supernatant were detected by enzyme-linked immunosorbent assay.ResultsCompared with the sham group, the clinical performance, survival percentage, vital signs, and severe cortical pathological changes in the CLP group were worse; NLRP3, caspase-1, and inflammatory factor levels were increased; and phosphorylation of p38 MAPK and ERK was also increased. Meanwhile, multiple indicators were deteriorated further after administration of U46619 in CLP rats. The clinical performance of CLP rats, however, was better after rCC16 administration; cortical pathological changes were attenuated; and NLRP3, caspase-1, and inflammatory factor levels and the phosphorylation of signaling pathway proteins (p38 MAPK and ERK) were reduced. Interestingly, the CLP rats showed the opposite changes in all indicators after administration with both rCC16 and U46619 when compared with those administered rCC16 alone.ConclusionsIn sepsis, rCC16 inhibits cortical pyroptosis through p38 MAPK and ERK signaling pathways. Meanwhile, rCC16 has a protective effect on newborn rats with sepsis, but it is not clear whether its mechanism is directly related to pyroptosis.

AimsSepsis‐associated encephalopathy (SAE) is a common complication of severe sepsis. Our goal was to investigate the role of immunity‐related GTPase M1 (IRGM1) in SAE and its underlying mechanism.MethodsA mouse sepsis model was established by cecal ligation and perforation. SAE was diagnosed by behavior, electroencephalography, and somatosensory evoked potentials. Wild‐type mice with SAE were treated with SB203580 to block the p38 mitogen‐activated protein kinase (MAPK) signaling pathway. We assessed hippocampal histological changes and the expression of IRGM1, interferon‐γ (IFN‐γ), and p38 MAPK signaling pathway‐related proteins.ResultsImmunity‐related GTPase M1 and IFN‐γ levels increased in the hippocampus, with apoptosis, autophagy, and the p38 MAPK signaling pathway activated in neurons. Administration of SB203580 to mice with SAE reduced apoptosis and autophagy. Relative to wild‐type mice with SAE, the general condition of Irgm1‐/‐ mice with SAE was worsened, the p38 MAPK signaling pathway was inhibited, and neuronal apoptosis and autophagy were reduced. The absence of IRGM1 exacerbated SAE, with higher p38 MAPK signaling pathway activity and increased apoptosis and autophagy.ConclusionsDuring SAE, IRGM1 can at least partially regulate apoptosis and autophagy in hippocampal neurons through the p38 MAPK signaling pathway.

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Brain and muscle aryl-hydrocarbon receptor nuclear translocator like protein1 (BMAL1), a core component of circadian oscillation, is involved in many physiological activities. Increasing evidence has demonstrated the essential role of BMAL1 in reproductive physiology. For instance, BMAL1-knockout (KO) mice were infertile, with impaired reproductive organs and gametes. Additionally, in BMAL1-KO mice, hormone secretion and signaling of hypothalamus-pituitary-gonadal (H-P-G) hormones were also disrupted, indicating that H-P-G axis was impaired in BMAL1-KO mice. Moreover, both BMAL1-KO mice and BMAL1-knockdown by small interfering RNA (siRNA) in vitro cultured steroidogenic cells showed that BMAL1 was associated with gonadal steroidogenesis and expression of related genes. Importantly, BMAL1 also participates in pathogenesis of human reproductive diseases. In this review, we elaborate on the impaired reproduction of BMAL1-KO mice including the reproductive organs, reproductive endocrine hormones, and reproductive processes, highlighting the vital role of BMAL1 in fertility and reproductive endocrinology.

Neuronal apoptosis is one of the main pathological processes of hypoxic‐ischemic brain damage (HIBD) and is involved in the development of hypoxic‐ischemic encephalopathy (HIE) in neonates. Atorvastatin has been found to have neuroprotective effects in some nervous system diseases, but its role in regulating the pathogenesis of neonatal HIBD remains elusive. Thus, this study aimed to explore the effects and related mechanisms of atorvastatin on the regulation of neuronal apoptosis after HIBD in newborn rats. The rat HIBD model and the neuronal oxygen glucose deprivation (OGD) model were established routinely. Atorvastatin, cAMP inhibitor (SQ22536), and BDNF inhibitor (ANA‐12) were used to treat HIBD rats and OGD neurons. Cerebral infarction, learning and memory ability, cAMP/PKA/p‐CREB/BDNF signaling molecules, and apoptosis‐related indicators (TUNEL, cleaved caspase‐3, and Bax/Bcl2) were then examined. In vivo, atorvastatin reduced cerebral infarction, improved learning and memory ability, decreased the number of TUNEL‐positive neurons, inhibited the expression of cleaved caspase‐3 and Bax/Bcl2, and activated the cAMP/PKA/p‐CREB/BDNF pathway in the cerebral cortex after HIBD. In vitro, atorvastatin also decreased the apoptosis‐related indicators and activated the cAMP/PKA/p‐CREB/BDNF pathway in neurons after OGD. Furthermore, inhibition of cAMP or BDNF attenuated the effect of atorvastatin on the reduction of neuronal apoptosis, suggesting that atorvastatin inhibits HIBD‐induced neuronal apoptosis and alleviates brain injury in neonatal rats mainly by activating the cAMP/PKA/p‐CREB/BDNF pathway. In conclusion, atorvastatin may be developed as a potential drug for the treatment of neonatal HIE.

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Background: Sepsis, a serious condition with high mortality, usually causes sepsis associated encephalopathy (SAE) that involves neuronal cell death. However, the cell death programs involved and their underlying mechanisms are not clear. This study aimed to explore the regulatory mechanisms of different cell death programs in SAE. Methods: A neonatal rat model of SAE was established by cecal ligation and perforation. Survival rate and vital signs (mean arterial pressure and heart rate) were monitored, nerve reflexes were evaluated, and cortical pathological changes were observed by hematoxylin and eosin staining. The expression of pyroptosis, apoptosis, and necroptosis (PANoptosis)-related proteins, mitogen- activated protein kinase (MAPK), and its upstream regulator toll-like receptor 9 (TLR9) were detected. The expression of TLR9 in neurons was observed by immunofluorescence staining. The ultrastructure of neurons was observed by transmission electron microscope. Results: First, PANoptosis was found in cortical nerve cells of the SAE rats. Meanwhile, the subunits of MAPKs, p38 MAPK, Jun N- terminal kinase, and extracellular signal-regulated kinase (ERK) were activated. After pharmacologically inhibiting each of the subunits, only p38 MAPK was found to be associated with PANoptosis. Furthermore, blocking the p38 MAPK signaling pathway activated necroptosis but inhibited apoptosis and pyroptosis. When necroptosis was pharmacologically inhibited, apoptosis and pyroptosis were reactivated. Finally, we found that the expression of TLR9, a regulator of MAPKs, was significantly increased in this model. After down-regulation of TLR9, p38 MAPK, and ERK signaling pathways were inhibited, which led to the inhibition of PANoptosis. Further analysis found that down-regulation of TLR9 improved the survival rate and reduced the pathological changes in SAE rats. Conclusions: Our study showed that the programs comprising PANoptosis are activated simultaneously in SAE rats. TLR9 activated PANoptosis through the p38 MAPK signaling pathway. TLR9 may work as a potential target for SAE treatment.

Background: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by sepsis.Pyroptosis and autophagy are important mechanisms in the pathogenesis of sepsis, and also pannexin-1 is involved in the occurrence of sepsis. However, role of pannexin-1 in SAE and its relationship with pyroptosis and autophagy are unclear. This study examined the relationship between pannexin-1 and pyroptosis, and further explore the relationship between pyroptosis and autophagy in SAE mice. Methods: A SAE mouse model was established by cecal ligation and puncture (CLP). Different groups of mice were administrated probenecid (PRB), 3-methyladenine (3-MA), or a vehicle control and the survival rates were monitored at different time points. Cortical pathological changes were examined by hematoxylin and eosin (HE) staining. The expression of cortical pannexin-1 and adenosine monophosphate-activated protein kinase (AMPK), as well as pyroptosis and autophagy related proteins, was detected by Western blotting and immunofluorescence analysis. The ultrastructure of neurons was observed by transmission electron microscopy.Results: Septic mice showed significantly higher rates of mortality and cortical pathological change compared to control mice. In addition, the pannexin-1 and AMPK signaling pathway were activated in the cerebral cortex of the septic mice, coupled with the activation of pyroptosis and incomplete activation of autophagy. Inhibition of pannexin-1 expression reduce the rates of mortality and the cortical pathological changes in the mice, further activated the AMPK signaling pathway, inhibited pyroptosis, and completely activated autophagy. The inhibition of autophagy may cause pyroptosis to reactivate. Conclusions:The present findings suggested that in SAE mice, pannexin-1 may regulate neuronal pyroptosis through autophagy. Moreover, the regulation of autophagy may be related to the AMPK signaling pathway. Inhibiting pannexin-1 expression in SAE mice may have a neuroprotective effect.