Contribution of zinc accumulation to ischemic brain injury and its mechanisms about oxidative stress, inflammation, and autophagy: an update.

Ischemic stroke is a leading cause of death and disability worldwide, and presently, there is no effective neuroprotective therapy. Zinc is an essential trace element that plays important physiological roles in the central nervous system. Free zinc concentration is tightly regulated by zinc-related proteins in the brain under normal conditions. Disruption of zinc homeostasis, however, has been found to play an important role in the mechanism of brain injury following ischemic stroke. A large of free zinc releases from storage sites after cerebral ischemia, which affects the functions and survival of nerve cells, including neurons, astrocytes, and microglia, resulting in cell death. Ischemia-triggered intracellular zinc accumulation also disrupts the function of blood-brain barrier via increasing its permeability, impairing endothelial cell function, and altering tight junction levels. Oxidative stress and neuroinflammation have been reported to be as major pathological mechanisms in cerebral ischemia/reperfusion injury. Studies have showed that the accumulation of intracellular free zinc could impair mitochondrial function to result in oxidative stress, and form a positive feedback loop between zinc accumulation and reactive oxygen species production, which leads to a series of harmful reactions. Meanwhile, elevated intracellular zinc leads to neuroinflammation. Recent studies also showed that autophagy is one of the important mechanisms of zinc toxicity after ischemic injury. Interrupting the accumulation of zinc will reduce cerebral ischemia injury and improve neurological outcomes. This review summarizes the role of zinc toxicity in cellular and tissue damage following cerebral ischemia, focusing on the mechanisms about oxidative stress, inflammation, and autophagy.

Zinc accumulation aggravates cerebral ischemia/reperfusion injury by promoting inflammation.

Intracellular zinc accumulation has been shown to be associated with neuronal death after cerebral ischemia. However, the mechanism of zinc accumulation leading to neuronal death in ischemia/reperfusion (I/R) is still unclear. Intracellular zinc signals are required for the production of proinflammatory cytokines. The present study investigated whether intracellular accumulated zinc aggravates I/R injury through inflammatory response, and inflammation-mediated neuronal apoptosis. Male Sprague-Dawley rats were treated with vehicle or zinc chelator TPEN 15 mg/kg before a 90-min middle cerebral artery occlusion (MCAO). The expressions of proinflammatory cytokines TNF-α, IL-6, NF-κB p65, and NF-κB inhibitory protein IκB-α, as well as anti-inflammatory cytokine IL-10 were assessed at 6 or 24 h after reperfusion. Our results demonstrated that the expression of TNF-α, IL-6, and NF-κB p65 increased after reperfusion, while the expression of IκB-α and IL-10 decreased, suggesting that cerebral ischemia triggers inflammatory response. Furthermore, TNF-α, NF-κB p65, and IL-10 were all colocalized with the neuron-specific nuclear protein (NeuN), suggesting that the ischemia-induced inflammatory response occurs in neurons. Moreover, TNF-α was also colocalized with the zinc-specific dyes Newport Green (NG), suggesting that intracellular accumulated zinc might be associated with neuronal inflammation following cerebral I/R. Chelating zinc with TPEN reversed the expression of TNF-α, NF-κB p65, IκB-α, IL-6, and IL-10 in ischemic rats. Besides, IL-6-positive cells were colocalized with TUNEL-positive cells in the ischemic penumbra of MCAO rats at 24 h after reperfusion, indicating that zinc accumulation following I/R might induce inflammation and inflammation-associated neuronal apoptosis. Taken together, this study demonstrates that excessive zinc activates inflammation and that the brain injury caused by zinc accumulation is at least partially due to specific neuronal apoptosis induced by inflammation, which may provide an important mechanism of cerebral I/R injury.

Inhibition of the JAK2/STAT3 pathway and cell cycle re-entry contribute to the protective effect of remote ischemic pre-conditioning of rat hindlimbs on cerebral ischemia/reperfusion injury.

AIMS: Remote ischemic pre-conditioning (RIPC) protects against ischemia/reperfusion (I/R) injury. However, the mechanisms underlying this protection remain unclear. In the present study, we investigated the role of Janus-activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway and cell cycle arrest, and their relationship with neuronal apoptosis following RIPC. METHODS: A rat cerebral I/R injury model was induced by middle cerebral artery occlusion (MCAO), and AG490 was used to investigate the mechanisms of RIPC. p-JAK2-, p-STAT3-, cyclin D1-, and cyclin-dependent kinase 6 (CDK6) expression was assessed by Western blotting and immunofluorescence staining. RESULTS: RIPC reduced the infarct volume, improved neurological function, and increased neuronal survival. Furthermore, p-JAK2 and p-STAT3 were detected during the initial phase of reperfusion; the expression levels were significantly increased at 3 and 24 h after reperfusion and were suppressed by RIPC. Additionally, the MCAO-induced upregulation of the cell cycle regulators cyclin D1 and CDK6 was ameliorated by RIPC. Meanwhile, cyclin D1 and CDK6 were colocalized with p-STAT3 in the ischemic brain. CONCLUSION: RIPC ameliorates the induction of the JAK2/STAT3 pathway and cell cycle regulators cyclin D1 and CDK6 by MCAO, and this net inhibition of cell cycle re-entry by RIPC is associated with downregulation of STAT3 phosphorylation.

Nitric oxide promotes cerebral ischemia/reperfusion injury through upregulating hypoxia-inducible factor1-α-associated inflammation and apoptosis in rats.

Nitric oxide (NO) was one of the key factors to sustain hypoxia-inducible factor-1- α (HIF-1α) activation during hypoxia. However, the mechanism by which NO production promotes upregulation of HIF-1α to cause cerebral ischemia/reperfusion (I/R) injury remains unclear. The present study investigated whether eliminating NO would decrease HIF-1α level, and then reduce the subsequent inflammatory actions as well as neuronal apoptotic death in middle cerebral artery occlusion (MCAO) rats. Our results revealed that HIF-1α was correlated with 3-NT, a marker for nitrosative/oxidative stress, in the brain of MCAO rats. Treatment with NOS inhibitor L-NAME suppressed HIF-1α/3-NT double-positive cells, suggesting that HIF-1α was correlated with NO overproduction during cerebral I/R. Furthermore, pro-inflammatory cytokines TNF-α, IL-1ß and NF-κB p65 were significantly increased and colocalized with HIF-1α in the brain of MCAO rats, all of which could be attenuated by NO inhibition, suggesting that eliminating NO reduced MCAO-induced HIF-1α upregulation, which in turn exerted anti-inflammatory actions. Accordingly, cleaved caspase-3, as well as HIF-1α and TUNEL double-positive cells in ischemic brain were also decreased by L-NAME treatment. These results suggest that NO accumulation after cerebral ischemia leads to HIF-1α upregulation, which may activate pro-inflammatory cytokines, resulting in neuronal apoptotic death. These findings demonstrate a novel mechanism of NO-induced cerebral I/R injury.

Behavior and physiology in female Cricetulus barabensis are associated with the expression of circadian genes.

The circadian clock regulates the behavior, physiology, and metabolism of mammals, and these characteristics, such as sleep-wake cycles, exercise capacity, and hormone levels, exhibit circadian rhythms. Light signaling is the main stimulator of the mammalian circadian system. The photoperiod regulates the reproductive cycle of seasonal breeding animals, and the circadian clock plays a pivotal role in this process. However, the role of the clock in coordinating animal behavior and physiology in response to photoperiodic changes needs further investigation. The present study investigated the changes and correlation of behavioral activities, physiological indicators, and gene expression in female striped hamsters (Cricetulus barabensis) within 24 h under a 12L:12D photoperiod. We found that the daily rhythms of sleep-wake and open field were significant in hamsters. The expression of clock genes, melatonin receptor genes, and genes involved in general metabolism oscillated significantly in central and peripheral tissues (brain, hypothalamus, liver, ovary, and thymus) and was significantly associated with behavior and physiology. Our results revealed that the neuroendocrine system regulated the rhythmicity of behavior and physiology, and central and peripheral clock genes (Bmal1, Clock, Per1, Per2, Cry1, and Cry2), melatonin receptor genes (MT1, MT2, and GPR50), and metabolizing genes (SIRT1, FGF21, and PPARα) played important roles. Our results suggest that central and peripheral circadian clocks, melatonin receptors, and genes involved in general metabolism may play key roles in maintaining circadian behavior and metabolic homeostasis in striped hamsters. Our results may have important implication for rodent pest control.

[Impact of land use pattern on water quality under different riparian buffer zone scales in Gaya River Basin, Northeast China]. / 不同河岸缓冲区尺度下土地利用方式对嘎呀河流域水质的影响.

River water quality is influenced by land use and landscape distribution patterns. Quantifying the relationship between land use, landscape pattern and water quality factor at different riparian buffer zone scales is of great significance for rational land use planning and water quality improvement. Based on water quality data from 91 sites in May 2021 in the Gaya River Basin, we analyzed the spatial characteristics of land use types and landscape patterns at the riparian buffer zone scales. With redundancy analysis (RDA) and generalized additive models (GAM), we examined the effects of land use and landscape patterns on river water quality. The results showed that water quality was primarily impacted by total nitrogen (TN). Farmland was the dominant land use type at riparian buffer zone of 50, 100 and 500 m. The sampling sites were classified into farmland dominant group and farmland other group. Forest was dominant at riparian buffer zone of 1000, 1500, 2000 m, and the sampling sites were classified into forest dominant group and forest other group. 100 m riparian buffer zone was the strongest scale in the Gaya River, and 1000 m was the second. Land use types in the forest dominant group were closely related with electrical conductivity, dissolved oxygen, phosphate, permanganate index and ammonium (NH4+-N) of water. NH4+-N was positively correlated with proportion of forest and farmland area. Phosphate was significantly affected by Shannon diversity index (SHDI). SHDI and largest patch index (LPI) was the key landscape indices affecting permanganate index. TN was significantly impacted by area proportion of forest, grassland and LPI in farmland dominant group, showing decreasing trend with the area proportion of forest increasing from 8% to 40%. Total suspended solids in farmland other group were significantly correlated with proportion of farmland area, while negatively correlated with proportion of forest area. Water quality in the Gaya River was mainly affected by proportion of forest area, followed by proportion of farmland area. The combined effects of LPI, SHDI and other land use types played an important role in affecting water quality.

Effect of combined wet alkaline mechanical pretreatment on enzymatic hydrolysis of corn stover and its mechanism.

BACKGROUND: To further optimize the mechanochemical pretreatment process, a combined wet alkaline mechanical pretreatment of corn stover was proposed with a short time and less chemical consumption at room temperature. RESULTS: The combined alkaline mechanical pretreatment significantly enhanced enzymatic hydrolysis resulting a highest glucose yield (YG) of 91.9% with 3% NaOH and ball milling (BM) for 10 min. At this optimal condition, 44.4% lignin was removed and major portion of cellulose was retained (86.6%). The prehydrolysate contained by-products such as monosaccharides, oligosaccharides, acetic acid, and lignin but no furfural and 5-HMF. The alkaline concentration showed a significant impact on glucose yield, while the BM time was less important. Quantitative correlation analysis showed that YG (%) = 0.68 × BM time (min) + 19.27 × NaOH concentration (%) + 13.71 (R2 = 0.85), YG = 6.35 × glucan content - 231.84 (R2 = 0.84), and YG = - 14.22 × lignin content + 282.70 (R2 = 0.87). CONCLUSION: The combined wet alkaline mechanical pretreatment at room temperature had a boosting effect on the yield of enzymatic hydrolysis with short treatment time and less chemical consumption. The impact of the physical and chemical properties of corn stover pretreated with different BM times and/or different NaOH concentrations on the subsequent enzymatic hydrolysis was investigated, which would be beneficial to illustrate the effective mechanism of the mechanochemical pretreatment method.

A Rare Case of Cutaneous Intravascular NK/T-Cell Lymphoma.

BACKGROUND: Cutaneous intravascular NK/T cell lymphoma (CIVNKTC) is a rare form of extranodal non-Hodgkin's lymphoma with its unique histological and immunophenotypic characteristics. METHODS: We report a case presenting with an over 2-month history of nodules on the extremities and trunk with intermittent fever. Skin biopsy was taken from the patient and a histopathological examination was made from the material. RESULTS: The histopathological examination showed some expanding vessels filled with atypical lymphoid cells in the dermis and subcutaneous tissue. The tumor cells had large nuclei and one or two small nucleoli, with the expression of CD3, cytotoxic protein, and Epstein-Barr virus (EBV)-encoded messenger RNAs (EBER), and without the expression of tumor cytokeratin (CK), CD20, CD79A, CD4, and CD8. After being diagnosed as CIVNKTC and treated with a CHOP regimen 6 times, the patient died of this disease 1 year later. CONCLUSIONS: The clinical course is dangerous and the prognosis is extremely poor.

Effects of photoperiod on morphology and function in testis and epididymis of Cricetulus barabensis.

Photoperiod regulates the seasonal reproductive rhythms of mammals by influencing the development and function of sexual organs; however, the underlying mechanism remains unclear. We examined the morphology and functioning of the main sex organs of striped dwarf hamsters (Cricetulus barabensis) under different photoperiods (short daylight [SD], moderate daylight [MD], and long daylight [LD]) and further investigated the underlying molecular mechanisms. There was an inverse correlation between blood melatonin levels and photoperiod in the order SD > MD > LD. Decreases in body and tissue weights were observed under SD, whereas testis and epididymis weights between MD and LD were comparable. The diameters of the spermatogenic tubules, thickness of the spermatogenic epithelium, and the number of spermatogonia and Sertoli cells decreased under SD, whereas the serum-luteinizing hormone, follicle-stimulating hormone, and fecal testosterone concentrations decreased under LD. In SD, bax/bcl2 protein expression increased in the testes and decreased in the epididymides, whereas LC3II/LC3I remained unchanged in the testes and increased in the epididymides compared with the MD group. In LD, bax/bcl2 and LC3II/LC3I protein expression levels were unchanged in the testes but were decreased in the epididymides. In SD and LD, adenosine triphosphate synthase and citrate synthase protein expression levels were unchanged in the testes but were decreased in the epididymides. Drp1 and Mff protein expression increased in the testes and decreased in the epididymides. Overall, different regulatory mechanisms in the testis and epididymis led to degeneration under SD and maintenance under LD, preferentially protecting mitochondrial function in the testis by regulating mitochondrial fission.

Partial Perforation of the Bladder by an Intrauterine Device in a Pregnant Woman: A Case Report.

BACKGROUND: Perforation by intrauterine devices (IUDs) can involve. neighboring organs such as the bladder. CASE: A 29-year-old woman with 2 previous cesarean section deliveries was diagnosed in the early stage of pregnancy with an IUD that had partially perforated the bladder. The exact location of the migrated IUD was determined with pelvic ultrasonography and endoscopic techniques, and the IUD was successfully retrieved with a hysteroscope. CONCLUSION: The use of imaging studies and endoscopic techniques such as ultrasonic examination, hysteroscopy, and cystoscopy are essential for identifying the location of an IUD that has partially perforated the bladder. Depending on the application of the correct treatment method, good results can be achieved following partial perforation of the bladder by an IUD.

Exploration of essential gene functions via titratable promoter alleles.

Nearly 20% of yeast genes are required for viability, hindering genetic analysis with knockouts. We created promoter-shutoff strains for over two-thirds of all essential yeast genes and subjected them to morphological analysis, size profiling, drug sensitivity screening, and microarray expression profiling. We then used this compendium of data to ask which phenotypic features characterized different functional classes and used these to infer potential functions for uncharacterized genes. We identified genes involved in ribosome biogenesis (HAS1, URB1, and URB2), protein secretion (SEC39), mitochondrial import (MIM1), and tRNA charging (GSN1). In addition, apparent negative feedback transcriptional regulation of both ribosome biogenesis and the proteasome was observed. We furthermore show that these strains are compatible with automated genetic analysis. This study underscores the importance of analyzing mutant phenotypes and provides a resource to complement the yeast knockout collection.

A panoramic view of yeast noncoding RNA processing.

Predictive analysis using publicly available yeast functional genomics and proteomics data suggests that many more proteins may be involved in biogenesis of ribonucleoproteins than are currently known. Using a microarray that monitors abundance and processing of noncoding RNAs, we analyzed 468 yeast strains carrying mutations in protein-coding genes, most of which have not previously been associated with RNA or RNP synthesis. Many strains mutated in uncharacterized genes displayed aberrant noncoding RNA profiles. Ten factors involved in noncoding RNA biogenesis were verified by further experimentation, including a protein required for 20S pre-rRNA processing (Tsr2p), a protein associated with the nuclear exosome (Lrp1p), and a factor required for box C/D snoRNA accumulation (Bcd1p). These data present a global view of yeast noncoding RNA processing and confirm that many currently uncharacterized yeast proteins are involved in biogenesis of noncoding RNA.