Experimental Evidence of Buyang Huanwu Decoction and Related Modern Preparations (Naoxintong Capsule and Yangyin Tongnao Granule) in Treating Cerebral Ischemia: Intestinal Microorganisms and Transcriptomics in Rats.

Background: The traditional Chinese medicines of Buyang Huanwu decoction (BYHW), Naoxintong capsule (NXT), and Yangyin Tongnao granules (YYTN) have excellent effects in preventing and treating cerebrovascular disease and are widely tolerated by patients. However, their effects on middle cerebral artery occlusion (MCAO) remain unknown. Methods: We evaluated gut microbiota alterations, the brain transcriptome, and nerve cell responses in rats with MCAO. Results: Our results showed that BYHW, NXT, and YYTN not only effectively improved the damaged state of blood vessels in rats and restored nerve function, but also improved survival. Additional experiments showed that treatment with BYHW, NXT, and YYTN regulated the intestinal microflora. Transcriptome analyses showed that BYHW, NXT, and YYTN modulated the transcriptome of rats with MCAO. The common mechanism of the three prescriptions for the treatment of cerebral ischemia may be related to the intestinal flora regulation of 60S ribosomal protein L18 (Rpl18), eukaryotic translation initiation factor 3 subunit, Ras homolog family member C, G protein subunit gamma 13 (Gng13), and Gng10 genes, among which Rpl18 is the most important. In addition, the three prescriptions had great specificity as anticerebral ischemia targets. Moreover, BYHW, NXT, and YYTN mitigated MCAO-induced hyperactivation of microglia and astrocytes. Conclusion: This study provides a foundation for further research on the mechanisms and treatment of IS. The results strongly suggest that key gut microbiota can be used to study functional genomics of brain, leading to novel discoveries about key genes involved in important biological processes.

The relationship between physical exercise and mobile phone addiction among Chinese college students: Testing mediation and moderation effects.

Background: During the COVID-19 pandemic, suspensions of activities and long periods of self-isolation led to a sharp increase in excessive use of mobile phones, which sparked public concern about mobile phone addiction (MPA). In recent years, more and more attention has been paid to physical exercise as a protective effect of MPA. However, more studies are needed to reveal this relationship and the exact mechanisms, based on which this study tested the mediating and moderating roles of self-control, rumination, psychological distress, and loneliness between physical exercise and MPA. Methods: In this cross-sectional study, primary data was collected by questionnaire from 1,843 college students (19.75 ± 1.3) from five universities in Sichuan Province in Mainland China. Mobile Phone Addiction Tendency Scale (MPATS), Physical Activity Rating Scale-3 (PARS-3), Self-Control Scale (SCS), Ruminative Response Scale (RRS), Depression Anxiety Stress Scale-21 (DASS-21), and UCLA Loneliness Scale (UCLA-20) were investigated. The mediating models were examined using SPSS PROCESS macro 3.3 software, in which the mediation variables were self-control, rumination, and psychological distress, and the moderation was loneliness. Gender, major, and grade were included as control variables. Result: Self-control, rumination, and psychological distress played a simple mediating role between physical exercise and MPA. Moreover, not only self-control and rumination but also self-control and psychological distress played the chain mediating roles between physical exercise and MPA. The chain pathways were moderated by loneliness. Specifically, the effect was more substantial among college students with higher loneliness. Conclusion: The conclusions corroborate and clarify that self-control, rumination, and psychological distress mediated the association between physical exercise and MPA, and the mediation effects were moderated via loneliness. This present study advanced our understanding of how and when college students' physical exercise was related to MPA. It also illustrates that educators and parents should pay more attention to college students' physical exercise.

Danhong injection enhances the therapeutic effect of mannitol on hemispheric ischemic stroke by ameliorating blood-brain barrier disruption.

Mannitol, a representative of hyperosmolar therapy, is indispensable for the treatment of malignant cerebral infarction, but its therapeutic effect is limited by its exacerbation of blood-brain barrier (BBB) disruption. This study was to explore whether Danhong injection (DHI), a standardized product extracted from Salvia miltiorrhiza Bunge and Carthamus tinctorius L., inhibits the destructive effect of mannitol on BBB and thus enhancing the treatment of hemispheric ischemic stroke. SD rats were subjected to pMCAO followed by intravenous bolus injections of mannitol with/without DHI intervention. Neurological deficit score, brain edema, infarct volume at 24 h after MCAO and histopathology, microvascular ultrastructure, immunohistochemistry and immunofluorescence staining of endothelial cell junctions, energy metabolism in the ischemic penumbra were assessed. Intravenous mannitol after MCAO resulted in a decrease in 24 h mortality and cerebral edema, whereas no significant benefit on neurological deficits, infarct volume and microvascular ultrastructure. Moreover, mannitol led to the loss of endothelial integrity, manifested by the decreased expression of occludin, junctional adhesion molecule-1 (JAM-1) and zonula occluden-1 (ZO-1) and the discontinuity of occludin staining around the periphery of endothelial cells. Meanwhile, after mannitol treatment, energy-dependent vimentin and F-actin, ATP content, and ATP5D expression were down-regulated, while MMP2 and MMP9 expression increased in the ischemic penumbra. All the insults after mannitol treatment were attenuated by addition of intravenous DHI. The results suggest DHI as a potential remedy to attenuate mannitol-related BBB disruption, and the potential of DHI to upregulate energy metabolism and inhibit the activity of MMPs is likely attributable to its effects observed.

Danhong injection alleviates cerebral ischemia/reperfusion injury by improving intracellular energy metabolism coupling in the ischemic penumbra.

Danhong injection (DHI) is a compound Chinese medicine widely used in China for treatment of ischemic cardio-cerebrovascular diseases. However, limited data are available regarding the protective effect of DHI on the ischemic penumbra in ischemic stroke. This study aimed to investigate the effect of intravenous DHI on neuronal injure in the ischemic penumbra after cerebral ischemia/reperfusion (CI/R), focusing especially on the involvement of intracellular energy metabolism coupling. Male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion for 60 min followed by reperfusion with or without intravenous DHI (0.5, 1.0, or 2.0 mL/kg) once daily for 7 days. Post-treatment with DHI ameliorated neurological defects, diminished cerebral infarction, alleviated cerebral edema, improved microcirculatory perfusion after 7days of reperfusion, and inhibited apoptosis and enhanced neuronal survival in the ischemic penumbra. In addition, DHI significantly ameliorated oxidative stress, reduced DNA damage, and inhibited the activation of PARP1/AIF pathway, thereby restoring cytoplasmic glycolytic activity. Furthermore, this drug increased PDH activity by inhibiting the HIF1α/PDK1 signaling pathway, thus eliminating the inhibitory effect of CI/R on mitochondrial metabolism. The results of this study suggest that DHI can alleviate cerebral edema after CI/R and rescue the ischemic penumbra, and these protective effects are due to the regulation of intracellular energy metabolic coupling.

Protocatechudehyde improves mitochondrial energy metabolism through the HIF1α/PDK1 signaling pathway to mitigate ischemic stroke-elicited internal capsule injury.

ETHNOPHARMACOLOGICAL RELEVANCE: The internal capsule is vulnerable to ischemia, and mild ischemic stroke often results in lesion of the internal capsule, manifested as contralateral hemiplegia. Protocatechudehyde (PCA), a potential neuroprotective agent, has shown therapeutic effects in the study of a variety of nervous system diseases, including ischemic stroke. AIM OF THE STUDY: The aim of this study was to evaluate the effects of PCA on cerebral ischemia reperfusion (CI/R)-elicited internal capsule injury and to elucidate the role of mitochondrial energy metabolism in the underlying mechanism of neuroprotective effects on ischemic stroke. MATERIALS AND METHODS: A rat tMCAO model was established to investigate the therapeutic effects of intravenous PCA (20, 40, and 80 mg/kg, once per day, continued for 7 days) on CI/R-induced internal capsule injury and the regulation of PCA on molecules related to mitochondrial energy metabolism. In vitro, an OGD/R model of PC12 cells was established to further verify the therapeutic mechanism of PCA. RESULTS: Results showed that PCA dose-dependently attenuated neurological deficit, reduced cerebral infarction, alleviated histopathological damage, and improved mitochondrial ultrastructure of the internal capsule after CI/R. Moreover, PCA reversed the upregulation of HIF1α, PDK1 and pPDHA1 expression induced by CI/R and significantly increased the content of acetyl-CoA, ATP, and the activity of ATP synthase. In vitro, PCA treatment promoted cell survival, inhibited apoptosis, attenuated the dissipation of mitochondrial membrane potential in OGD/R-treated PC12 cells, and these therapeutic effects were reversed by the combination of cobalt chloride (CoCl2), a specific pharmacological inducer of HIF1a expression. CONCLUSIONS: These results indicate that PCA exerts a protective effect against CI/R-induced internal capsule injury and improves mitochondrial energy metabolism in the internal capsule, and the mechanism is associated with the inhibition of HIF1α/PDK1 signaling pathway.

Domesticated and optimized mitochondria: Mitochondrial modifications based on energetic status and cellular stress.

Mitochondria are the main source of energy and play an important role in coupling intracellular and intercellular metabolic cooperation. Cellular stress and energetic status can affect various mitochondrial behaviors, including mitochondrial biogenesis, mitophagy, assembly of respiratory chain supercomplexes and mitochondrial distribution. These modifications usually result in adaptive adjustment of mitochondrial output and resistance to cellular stress. However, when the pro-death signals triggered by excessive damage converge to mitochondria, mitochondrial reserve and functional status can profoundly determine the direction of cell death, and even affect the survival and death of surrounding or distant tissues. In this review, we discuss multiple mitochondrial modifications in eukaryotes based on metabolic status and cellular stress, and review the emerging knowledge about the effects of mitochondrial dysfunction on the fate of cells and surrounding tissues.

Output Regulation and Function Optimization of Mitochondria in Eukaryotes.

The emergence of endosymbiosis between aerobic alpha-proteobacterium and anaerobic eukaryotic cell precursors opened the chapter of eukaryotic evolution. Multiple functions of mitochondria originated from the ancient precursors of mitochondria and underwent remodeling in eukaryotic cells. Due to the dependence on mitochondrial functions, eukaryotic cells need to constantly adjust mitochondrial output based on energy demand and cellular stress. Meanwhile, eukaryotes conduct the metabolic cooperation between different cells through the involvement of mitochondria. Under some conditions, mitochondria might also be transferred to nearby cells to provide a protective mechanism. However, the endosymbiont relationship determines the existence of various types of mitochondrial injury, such as proteotoxic stress, mutational meltdown, oxidative injure, and immune activation caused by released mitochondrial contents. Eukaryotes have a repertoire of mitochondrial optimization processes, including various mitochondrial quality-control proteins, regulation of mitochondrial dynamics and activation of mitochondrial autophagy. When these quality-control processes fail, eukaryotic cells can activate apoptosis to intercept uncontrolled cell death, thereby minimizing the damage to extracellular tissue. In this review, we describe the intracellular and extracellular context-based regulation of mitochondrial output in eukaryotic cells, and introduce new findings on multifaceted quality-control processes to deal with mitochondrial defects.

Complete Nucleotide Sequence of a Partitivirus from Rhizoctonia solani AG-1 IA Strain C24.

The complete genome of a novel double-stranded (ds) RNA mycovirus, named as Rhizoctonia solani partitivirus 5 (RsPV5), isolated from rice sheath blight fungus R. solani AG-1 IA strain C24, was sequenced and analysed. RsPV5 consists of two segments, dsRNA-1 (1899 nucleotides) and dsRNA-2 (1787 nucleotides). DsRNA-1 has an open reading frame (ORF) 1 that potentially codes for a protein of 584 amino acid (aa) containing the conserved motifs of a RNA-dependent RNA polymerase (RdRp), and dsRNA-2 also contains a ORF 2, encoding a putative capsid protein (CP) of 513 aa. Phylogenetic analysis revealed that RsPV5 clustered together with six other viruses in an independent clade of the genus Alphapartitivirus, indicating that RsPV5 was a new member of the genus Alphapartitivirus, within the family Partitiviridae.