Chinese herbal medicine for the treatment of diabetic nephropathy: From clinical evidence to potential mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic nephropathy (DN) is a typical chronic microvascular complication of diabetes, characterized by proteinuria and a gradual decline in renal function. At present, there are limited clinical interventions aimed at preventing the progression of DN to end-stage renal disease (ESRD). However, Chinese herbal medicine presents a distinct therapeutic approach that can be effectively combined with conventional Western medicine treatments to safeguard renal function. This combination holds considerable practical implications for the treatment of DN. AIM OF THE STUDY: This review covers commonly used Chinese herbal remedies and decoctions applicable to various types of DN, and we summarize the role played by their active ingredients in the treatment of DN and their mechanisms, which includes how they might improve inflammation and metabolic abnormalities to provide new ideas to cope with the development of DN. MATERIALS AND METHODS: With the keywords "diabetic nephropathy," "Chinese herbal medicine," "clinical effectiveness," and "bioactive components," we conducted an extensive literature search of several databases, including PubMed, Web of Science, CNKI, and Wanfang database, to discover studies on herbal formulas that were effective in slowing the progression of DN. The names of the plants covered in the review have been checked at MPNS (http://mpns.kew.org). RESULTS: This review demonstrates the superior total clinical effective rate of combining Chinese herbal medicines with Western medicines over the use of Western medicines alone, as evidenced by summarizing the results of several clinical trials. Furthermore, the review highlights the nephroprotective effects of seven frequently used herbs exerting beneficial effects such as podocyte repair, anti-fibrosis of renal tissues, and regulation of glucose and lipid metabolism through multiple signaling pathways in the treatment of DN. CONCLUSIONS: The potential of herbs in treating DN is evident from their excellent effectiveness and the ability of different herbs to target various symptoms of the condition. However, limitations arise from the deficiencies in interfacing with objective bioindicators, which hinder the integration of herbal therapies into modern medical practice. Further research is warranted to address these limitations and enhance the compatibility of herbal therapies with contemporary medical standards.

Buccal acupuncture combined with ultrasound-guided dry needle-evoked inactivation of trigger points to treat cervical and shoulder girdle myofascial pain syndrome.

BACKGROUND: Myofascial pain syndrome (MPS) is a common disease with easy persistence and recurrence. In clinical practice, although many methods have been adopted to prevent and treat MPS, the control of MPS is still not satisfactory. OBJECTIVE: To compare the safety and effectiveness of buccal acupuncture, inactivation of trigger points (MTrPs), and their combination in the treatment of MPS. METHODS: Two hundred MPS patients in the pain clinic were randomly divided into four groups (n= 50) to receive oral drugs (Group A), oral drugs + buccal needle (Group B), oral drugs + MTrP inactivation (Group C), or oral drugs + buccal needle + MTrP inactivation (Group D). RESULTS: The visual analogue scale (VAS) and cervical range of motion (ROM) of Group D were significantly lower than those of the other three groups, and the pressure pain threshold (PPT) value of labelled MTrPs was significantly higher than those of the other three groups (P< 0.05). The excellent rate and total effective rate of Group D were significantly higher than those of the other three groups. Group C had the highest pain score and the lowest acceptance score. The results showed that buccal acupuncture combined with ultrasound-guided dry needle-evoked inactivation of MTrPs can significantly reduce the VAS score of MPS patients, improve the range of motion of the cervical spine, and improve patient satisfaction. CONCLUSIONS: This study provides a highly accepted and satisfactory treatment for MPS, which is worthy of clinical promotion.

Electroacupuncture at ST 36 ameliorates cognitive impairment and beta-amyloid pathology by inhibiting NLRP3 inflammasome activation in an Alzheimer's disease animal model.

Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder leading to cognitive impairment in the elderly, and no effective treatment exists. Increasing evidence has demonstrated that physical therapy and electroacupuncture (EA) effectively improve spatial learning and memory abilities. Nevertheless, the mechanism underlying the effects of EA on AD pathology is largely unexplored. Acupuncture at Zusanli (ST 36) has previously been shown to improve cognitive impairment in AD, but the mechanism is unclear. According to recent studies, EA drives the vagal-adrenal axis from the hindlimb ST 36 acupoint but not from the abdominal Tianshu (ST 25) to curb severe inflammation in mice. This study examined whether ST 36 acupuncture improves cognitive dysfunction in AD model mice by improving neuroinflammation and its underlying mechanism. Methods: Male 5xFAD mice (aged 3, 6, and 9 months) were used as the AD animal model and were randomly divided into three groups: the AD model group (AD group), the electroacupuncture at ST 36 acupoint group (EA-ST 36 group), and the electroacupuncture at ST 25 acupoint group (EA-ST 25 group). Age-matched wild-type mice were used as the normal control (WT) group. EA (10 Hz, 0.5 mA) was applied to the acupoints on both sides for 15 min, 5 times per week for 4 weeks. Motor ability and cognitive ability were assessed by the open field test, the novel object recognition task, and the Morris water maze test. Thioflavin S staining and immunofluorescence were used to mark Aß plaques and microglia. The levels of NLRP3, caspase-1, ASC, interleukin (IL)-1ß, and IL-18 in the hippocampus were assayed by Western blotting or qRT-PCR. Results: EA at ST 36, but not ST 25, significantly improved motor function and cognitive ability and reduced both Aß deposition and microglia and NLRP3 inflammasome activation in 5×FAD mice. Conclusion: EA stimulation at ST 36 effectively improved memory impairment in 5×FAD mice by a mechanism that regulated microglia activation and alleviated neuroinflammation by inhibiting the NLRP3 inflammatory response in the hippocampus. This study shows that ST 36 may be a specific acupoint to improve the condition of AD patients.

Zinc Water Prevents Autism-Like Behaviors in the BTBR Mice.

This study aims to explore the effects of zinc water on autism-like behavior, convulsion threshold, and neurogenesis in ASD model animals. This study used the young BTBR ASD mouse model to explore the effect of a 6-week zinc water supplementation on ASD-like behaviors such as repetitive behavior and social communication disorder, seizure threshold, and the correlation with excitability regulation. The mice were divided into four groups of normal controls (B6) and models (BTBR) who did and did not receive zinc supplementation in water (B6, B6 + zinc, BTBR, and BTBR + zinc). For morphological changes in the hippocampus, we selected two indicators: hippocampal mossy fiber sprouting and neurogenesis. ASD-like behavior testing, seizure threshold determination, Timm staining, and neurogenesis-related assays-represented by Ki67 and DCX-were performed after 6 weeks of zinc supplementation. Our results show that zinc water can prevent autism-like behavior, reduce susceptibility to convulsions, and increase the proliferation of hippocampal progenitor cells in BTBR mice but has less effect on mossy fiber sprouting and neural progenitor cell differentiation. Zinc water reduces autism-like behavior in a partially inherited autism model mice-BTBR-which may be associated with hippocampal neural precursor cell proliferation and reversed hyperexcitability.

Transcriptional profiling and network pharmacology analysis identify the potential biomarkers from Chinese herbal formula Huosu Yangwei Formula treated gastric cancer in vivo.

Huosu Yangwei (HSYW) Formula is a traditioanl Chinese herbal medicine that has been extensively used to treat chronic atrophic gastritis, precancerous lesions of gastric cancer and advanced gastric cancer. However, the effective compounds of HSYW and its related anti-tumor mechanisms are not completely understood. In the current study, 160 ingredients of HSYW were identified and 64 effective compounds were screened by the ADMET evaluation. Furthermore, 64 effective compounds and 2579 potential targets were mapped based on public databases. Animal experiments demonstrated that HSYW significantly inhibited tumor growth in vivo. Transcriptional profiles revealed that 81 mRNAs were differentially expressed in HSYW-treated N87-bearing Balb/c mice. Network pharmacology and PPI network showed that 12 core genes acted as potential markers to evaluate the curative effects of HSYW. Bioinformatics and qRT-PCR results suggested that HSYW might regulate the mRNA expression of DNAJB4, CALD, AKR1C1, CST1, CASP1, PREX1, SOCS3 and PRDM1 against tumor growth in N87-bearing Balb/c mice.

Trehalose activates hepatic transcription factor EB (TFEB) but fails to ameliorate alcohol-impaired TFEB and liver injury in mice.

BACKGROUND: Recent evidence demonstrates that alcohol activates the mechanistic target of rapamycin (mTOR) and impairs hepatic transcription factor EB (TFEB) reducing autophagy and contributing to alcohol-induced liver injury. Trehalose, a disaccharide, activates TFEB and protects against diet-induced nonalcoholic fatty liver disease in mice. The aim of the present study was to investigate whether trehalose would reverse the impairment of TFEB induced by alcohol and protect against alcohol-induced liver injury. METHODS: Male C57BL/6J mice were subjected to chronic-plus-binge (Gao-binge) alcohol feeding with and without trehalose supplementation. Some mice were also administrered Alda-1, an aldehyde dehydrogenase 2 agonist. RESULTS: We found that Alda-1 did not affect Gao-binge alcohol-induced mTOR activation and impaired TFEB in mouse livers. Trehalose increased TFEB nuclear translocation, elevated levels of LC3-II and lysosomal proteins in mouse livers and cultured AML12 cells, confirming the activation of TFEB by trehalose. However, trehalose did not improve the impairment in TFEB induced by Gao-binge alcohol. Both Alda-1 and trehalose failed to protect against Gao-binge alcohol-induced steatosis and liver injury, based on the serum levels of alanine aminotransferase (ALT), histological analysis, and levels of hepatic triglyceride. Interestingly, trehalose increased expression of pro-inflammatory genes in mouse macrophage RAW264.7 cells and slightly increased the infiltration of hepatic neutrophils and inflammatory cytokine gene expression in Gao-binge alcohol-fed mice livers. CONCLUSIONS: Trehalose fails to improve the impaired TFEB induced by Gao-binge alcohol and does not protect against alcohol-induced liver injury.

[Research progress of continuous manufacturing and process knowledge system of traditional Chinese medicine].

In the past few years, continuous manufacturing(CM) has been put forward by the FDA. Pharmaceutical enterprises are encouraged to promote the implementation of CM, which has become a hot research direction of pharmaceutical technology. In February 2019, the FDA issued a draft guideline for the implementation of CM, which greatly promoted the development of CM and provided reference for continuous manufacturing of traditional Chinese medicine(TCM). The production process of TCM is a complex system. With the innovation of production equipment and the promotion of automation and informatization of TCM production, the exis-ting policies, regulations and traditional production control capacity are difficult to meet the market demand for high-quality TCM pro-ducts. In this paper, we reviewed the new technologies and methods of quality control in accordance with the characteristics of TCM production by referring to modern manufacturing technology, information technology and quality control technology. Based on the "QbD" theory and "PAT" technology, process knowledge system(PKS), an advanced control strategy, was proposed to provide a reference for the implementation of CM in TCM production.

[Rapid determination of active components in Ginkgo biloba leaves by near infrared spectroscopy combined with genetic algorithm joint extreme learning machine].

Near-infrared spectroscopy(NIRS) combined with band screening method and modeling algorithm can be used to achieve the rapid and non-destructive detection of the traditional Chinese medicine(TCM) production process. This paper focused on the ginkgo leaf macroporous resin purification process, which is the key technology of Yinshen Tongluo Capsules, in order to achieve the rapid determination of quercetin, kaempferol and isorhamnetin in effluent. The abnormal spectrum was eliminated by Mahalanobis distance algorithm, and the data set was divided by the sample set partitioning method based on joint X-Y distances(SPXY). The key information bands were selected by synergy interval partial least squares(siPLS); based on that, competitive adaptive reweighted sampling(CARS), successive projections algorithm(SPA) and Monte Carlo uninformative variable(MC-UVE) were used to select wavelengths to obtain less but more critical variable data. With selected key variables as input, the quantitative analysis model was established by genetic algorithm joint extreme learning machine(GA-ELM) algorithm. The performance of the model was compared with that of partial least squares regression(PLSR). The results showed that the combination with siPLS-CARS-GA-ELM could achieve the optimal model performance with the minimum number of variables. The calibration set correlation coefficient R_c and the validation set correlation coefficient R_p of quercetin, kaempferol and isorhamnetin were all above 0.98. The root mean square error of calibration(RMSEC), the root mean square error of prediction(RMSEP) and the relative standard errors of prediction(RSEP) were 0.030 0, 0.029 2 and 8.88%, 0.041 4, 0.034 8 and 8.46%, 0.029 3, 0.027 1 and 10.10%, respectively. Compared with the PLSR me-thod, the performance of the GA-ELM model was greatly improved, which proved that NIRS combined with GA-ELM method has a great potential for rapid determination of effective components of TCM.

Chemical composition and uterine smooth muscle relaxant activity of essential oils from 10 kinds of blood-activating and stasis-resolving Chinese medicinal herbs.

ETHNOPHARMACOLOGICAL RELEVANCE: Dysmenorrhea is one of the most common gynecological problems among menstruating females. Blood-activating and stasis-resolving herbs (BASRHs) have been employed to be the first choice for treating dysmenorrhea in China. Especially, the essential oils of some BASRHs have been confirmed to play important roles in the treatment of dysmenorrhea, but the constituents and uterine smooth muscle relaxant activity of some commonly used BASRH essential oils have not been fully assessed, and whether there are differences in the constituents and anti-dysmenorrhea effect among BASRH essential oils has not been evaluated. AIM OF THE STUDY: This study aims to systematically investigate the chemical constituents of 10 BASRH essential oils and assess their uterine smooth muscle relaxant activity and the preliminary mechanism of the most effective essential oil. MATERIALS AND METHODS: The chemical constituents of 10 BASRH essential oils were analyzed by Gas Chromatography-Mass Spectrometer. A rat model of dysmenorrhea in vitro was established to investigate the uterine smooth muscle relaxant activity of 10 kinds of essential oils. Rat isolated uterus strips were given different dose of 10 kinds of essential oils (0.04, 0.08, 0.16 mg/mL). The contractile responses were recorded with Power Lab recording system, and contractile tension, contractile frequency, and contractile activity were evaluated. The preliminary mechanism of the essential oil of the rhizomes of Curcuma phaeocaulis Valeton (CPEO) was assessed using a rat model of dysmenorrhea in vivo and in vitro, and rats were given the CPEO (15, 30, and 60 mg/kg) by gavage. The level of Ca2+ in uterine tissue of rats was determined by methyl thyme phenol blue colorimetric and Bradford methods. The effects of CPEO on extracellular Ca2+ influx and intracellular Ca2+ release were evaluated using the isolated uterus. RESULTS: The results of Gas Chromatography-Mass Spectrometer analysis showed that more than 81 components (content: 1% max appearance) were identified. The main components of the 10 BASRH essential oils were found to be monoterpenoids, sesquiterpenoids, diterpenoids, aromatics, aliphatics, and phthalides. The study of in vitro smooth muscle relaxant activity demonstrated that all the essential oils except the essential oil of the roots of Cyathula officinalis K.C.Kuan markedly decrease the contractile activity, tension, and frequency (P < 0.05 or P < 0.01). Among these oils, CPEO has the most pronounced effect. Further in vivo studies indicated that CPEO can significantly decrease the level of Ca2+ in uterine tissue when compared with the model group (P < 0.05 or P < 0.01). In vitro studies indicated that CPEO can inhibit the extracellular Ca2+ influx and intracellular Ca2+ release in favor of uterine relaxation. CONCLUSIONS: BASRH essential oils play an important role in inhibiting uterine smooth muscle contractions, and sesquiterpenoids and phthalides in BASRH essential oils are important active compounds for relaxing uterine smooth muscle. CPEO is a favorable candidate for developing anti-dysmenorrhea drugs.

Pharmacokinetic interaction between a Chinese herbal formula Huosu Yangwei oral liquid and apatinib in vitro and in vivo.

OBJECTIVES: This study aimed to evaluate the inhibitory effects of Huosu Yangwei oral liquid (HSYW) on cytochrome P450 enzymes (CYPs) and to investigate whether this herbal medicine could modulate the pharmacokinetic behaviour of the co-administered CYP-substrate drug apatinib. METHODS: Cytochrome P450 enzymes inhibition assays were conducted in human liver microsomes (HLM) by a LC-MS/MS method for simultaneous determination of the oxidative metabolites of eight probe substrates for hepatic CYPs. The modulatory effects of HSYW on the oxidative metabolism of apatinib were investigated in both HLM and rat liver microsomes (RLM). The influences of HSYW on the pharmacokinetic behaviour of apatinib were investigated in rats. KEY FINDINGS: Huosu Yangwei oral liquid inhibited all tested CYPs in human liver preparations, with the IC50 values ranged from 0.3148 to 2.642 mg/ml. HSYW could also inhibit the formation of two major oxidative metabolites of apatinib in liver microsomes from both human and rat. In-vivo assays demonstrated that HSYW could significantly prolong the plasma half-life of apatinib by 7.4-fold and increase the AUC0-inf (nm·h) of apatinib by 43%, when HSYW (10 ml/kg) was co-administered with apatinib (10 mg/kg) in rats. CONCLUSIONS: Huosu Yangwei oral liquid could inhibit mammalian CYPs and modulated the metabolic half-life of apatinib both in vitro and in vivo.

Long-Term Effects of Zinc Deficiency and Zinc Supplementation on Developmental Seizure-Induced Brain Damage and the Underlying GPR39/ZnT-3 and MBP Expression in the Hippocampus.

We previously illustrated that long-term upregulated expression of ZnT-3 in the hippocampus of rats that underwent neonatal seizures was restored by pretreatment with a ketogenic diet. It was recently demonstrated that upregulated expression of ZnT-3 was associated with increased concentrations of intracellular free zinc ions in an in vitro model of glutamate-induced hippocampal neuronal excitotoxic damage. However, there is still a lack of research on the effects of different concentrations of zinc in the diet on developmental convulsive brain injury. The aim of this study was to investigate the effects of different zinc concentrations in the diet on long-term neurobehavioral and seizure thresholds following lithium chloride-pilocarpine-induced developmental seizures. Sprague-Dawley rats (postnatal day 27, P27) were randomly assigned to one of six dietary groups for 4 weeks: normal zinc control group (Control group, 44 mg/kg Zn), Zn-deficient control group (ZD group, 2.7 mg/kg Zn), Zn supplemented control group (ZS group, 246 mg/kg Zn), pilocarpine-induced seizure plus regular zinc diet group (SE group, 44 mg/kg Zn), seizure plus low-zinc diet group (SE + ZD group, 2.7 mg/kg Zn), and seizure plus high-zinc diet group (SE + ZS group, 246 mg/kg Zn). Novel object recognition and passive avoidance tests were performed on rats at P42 and P56. After routine seizure threshold detection and Timm staining procedures at P57, expression of GPR39, ZnT-3, and MBP were detected in the hippocampus by Western blot analysis. The results revealed that the Zinc-deficient diet for 4 weeks aggravated the long-term adverse effects of developmental seizures, evidenced by weight, cognition, seizure threshold and serum zinc concentrations, which were paralleled by expression changes in hippocampal GPR39 and ZnT-3. In contrast, zinc supplementation for 4 weeks significantly improved damage-related changes described above and rescued the abnormal expression of GPR39, ZnT-3, and MBP in the hippocampus. Similar alterations between the expression pattern of MBP and aberrant sprouting of mossy fibers in the hippocampus may indicate that sprouting is a secondary pathological change caused by developmental brain damage rather than the cause of epileptogenesis. Up-regulation of MBP protein levels in the high zinc diet-treated seizure group as well as the corresponding improvement of cognitive impairment and reduced hippocampal mossy fiber regenerative sprouting, may represent a compensatory mechanism for neuronal membrane damage and repair.

A whole-brain map of long-range inputs to GABAergic interneurons in the mouse medial prefrontal cortex.

The medial prefrontal cortex (mPFC) contains populations of GABAergic interneurons that play different roles in cognition and emotion. Their local and long-range inputs are incompletely understood. We used monosynaptic rabies viral tracers in combination with fluorescence micro-optical sectioning tomography to generate a whole-brain atlas of direct long-range inputs to GABAergic interneurons in the mPFC of male mice. We discovered that three subtypes of GABAergic interneurons in two areas of the mPFC are innervated by same upstream areas. Input from subcortical upstream areas includes cholinergic neurons from the basal forebrain and serotonergic neurons (which co-release glutamate) from the raphe nuclei. Reconstruction of single-neuron morphology revealed novel substantia innominata-anteromedial thalamic nucleus-mPFC and striatum-anteromedial thalamic nucleus-mPFC circuits. Based on the projection logic of individual neurons, we classified cortical and hippocampal input neurons into several types. This atlas provides the anatomical foundation for understanding the functional organization of the mPFC.

Impaired TFEB-mediated lysosomal biogenesis promotes the development of pancreatitis in mice and is associated with human pancreatitis.

Impaired macroautophagy/autophagy has been implicated in experimental and human pancreatitis. However, the transcriptional control governing the autophagy-lysosomal process in pancreatitis is largely unknown. We investigated the role and mechanisms of TFEB (transcription factor EB), a master regulator of lysosomal biogenesis, in the pathogenesis of experimental pancreatitis. We analyzed autophagic flux, TFEB nuclear translocation, lysosomal biogenesis, inflammation and fibrosis in GFP-LC3 transgenic mice, acinar cell-specific tfeb knockout (KO) and tfeb and tfe3 double-knockout (DKO) mice as well as human pancreatitis samples. We found that cerulein activated MTOR (mechanistic target of rapamycin kinase) and increased the levels of phosphorylated TFEB as well as pancreatic proteasome activities that led to rapid TFEB degradation. As a result, cerulein decreased the number of lysosomes resulting in insufficient autophagy in mouse pancreas. Pharmacological inhibition of MTOR or proteasome partially rescued cerulein-induced TFEB degradation and pancreatic damage. Furthermore, genetic deletion of tfeb specifically in mouse pancreatic acinar cells increased pancreatic edema, necrotic cell death, infiltration of inflammatory cells and fibrosis in pancreas after cerulein treatment. tfeb and tfe3 DKO mice also developed spontaneous pancreatitis with increased pancreatic trypsin activities, edema and infiltration of inflammatory cells. Finally, decreased TFEB nuclear staining was associated with human pancreatitis. In conclusion, our results indicate a critical role of impaired TFEB-mediated lysosomal biogenesis in promoting the pathogenesis of pancreatitis. Abbreviations: AC: acinar cell; AMY: amylase; ATP6V1A: ATPase, H+ transporting, lysosomal V1 subunit A; ATP6V1B2: ATPase, H+ transporting, lysosomal V1 subunit B2; ATP6V1D: ATPase, H+ transporting, lysosomal V1 subunit D; ATP6V1H: ATPase, H+ transporting, lysosomal V1 subunit H; AV: autophagic vacuole; CDE: choline-deficient, ethionine-supplemented; CLEAR: coordinated lysosomal expression and regulation; CQ: chloroquine; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; EM: electron microscopy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; H & E: hematoxylin and eosin; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK1/ERK2: mitogen-activated protein kinase 1; MTORC1: mechanistic target of rapamycin kinase complex 1; ND: normal donor; NEU: neutrophil; PPARGC1A/PGC1α: peroxisome proliferator-activated receptor, gamma, coactivator 1 alpha; RIPA: radio-immunoprecipitation; RPS6: ribosomal protein S6; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TM: tamoxifen; WT: wild-type; ZG: zymogen granule.

p53 Up-regulated Modulator of Apoptosis Induction Mediates Acetaminophen-Induced Necrosis and Liver Injury in Mice.

Acetaminophen (APAP) overdose is one of the leading causes of hepatotoxicity and acute liver failure in the United States. Accumulating evidence suggests that hepatocyte necrosis plays a critical role in APAP-induced liver injury (AILI). However, the mechanisms of APAP-induced necrosis and liver injury are not fully understood. In this study, we found that p53 up-regulated modulator of apoptosis (PUMA), a B-cell lymphoma-2 (Bcl-2) homology domain 3 (BH3)-only Bcl-2 family member, was markedly induced by APAP in mouse livers and in isolated human and mouse hepatocytes. PUMA deficiency suppressed APAP-induced mitochondrial dysfunction and release of cell death factors from mitochondria, and protected against APAP-induced hepatocyte necrosis and liver injury in mice. PUMA induction by APAP was p53 independent, and required receptor-interacting protein kinase 1 (RIP1) and c-Jun N-terminal kinase (JNK) by transcriptional activation. Furthermore, a small-molecule PUMA inhibitor, administered after APAP treatment, mitigated APAP-induced hepatocyte necrosis and liver injury. Conclusion: Our results demonstrate that RIP1/JNK-dependent PUMA induction mediates AILI by promoting hepatocyte mitochondrial dysfunction and necrosis, and suggest that PUMA inhibition is useful for alleviating acute hepatotoxicity attributed to APAP overdose.

Leptin Maintained Zinc Homeostasis Against Glutamate-Induced Excitotoxicity by Preventing Mitophagy-Mediated Mitochondrial Activation in HT22 Hippocampal Neuronal Cells.

Developmental seizure-induced long-term neuronal hyperexcitation is partially mediated by regenerative mossy fiber sprouting in hippocampus. Yet, there are no effective drugs available to block this pathological process. Recently, leptin has been shown to prevent the sprouting of hippocampal mossy fibers and abnormalities in the neurobehavioral parameters. However, their underlying molecular mechanisms are largely unknown. The purpose of this study was to determine the effect of glutamate on the parameters of zinc homeostasis, mitochondrial functions, and mitophagy regulating factors, as well as to investigate the protective effects of leptin against cytotoxicity of glutamate in murine HT22 hippocampal neuronal cells. Cells were assigned to one of the four groups as follows: control group, leptin alone group, glutamate injury group, and leptin pretreatment group. Our results demonstrated that glutamate induced a decrease in superoxide dismutase, GSH (glutathione), and mitochondrial membrane potential and an increase in GSSG (oxidized glutathione), mitochondrial reactive oxygen species, and supplementation of leptin blocked the toxic effect of glutamate on cell survival. The glutamate-induced cytotoxicity was associated with an increase in mitophagy and intracellular zinc ion levels. Furthermore, glutamate activated the mitophagy markers PINK1, Parkin, and the ratio of LC3-II/LC3-I, as well as increased the expression of zinc transporter 3 (ZnT3). Leptin corrected these glutamate-caused alterations. Finally, the mitophagy inhibitor, CsA, significantly reduced intracellular zinc ion content and ZnT3 expression. These results suggest that mitophagy-mediated zinc dyshomeostasis and mitochondrial activation contributed to glutamate-induced HT22 neuronal cell injury and that leptin treatment could counteract these detrimental effects, thus highlighting mitophagy-mediated zinc homeostasis via mitochondrial activation as a potential strategy to counteract neuroexcitotoxicity.

Arsenite Effects on Mitochondrial Bioenergetics in Human and Mouse Primary Hepatocytes Follow a Nonlinear Dose Response.

Arsenite is a known carcinogen and its exposure has been implicated in a variety of noncarcinogenic health concerns. Increased oxidative stress is thought to be the primary cause of arsenite toxicity and the toxic effect is thought to be linear with detrimental effects reported at all concentrations of arsenite. But the paradigm of linear dose response in arsenite toxicity is shifting. In the present study we demonstrate that arsenite effects on mitochondrial respiration in primary hepatocytes follow a nonlinear dose response. In vitro exposure of primary hepatocytes to an environmentally relevant, moderate level of arsenite results in increased oxidant production that appears to arise from changes in the expression and activity of respiratory Complex I of the mitochondrial proton circuit. In primary hepatocytes the excess oxidant production appears to elicit adaptive responses that promote resistance to oxidative stress and a propensity to increased proliferation. Taken together, these results suggest a nonlinear dose-response characteristic of arsenite with low-dose arsenite promoting adaptive responses in a process known as mitohormesis, with transient increase in ROS levels acting as transducers of arsenite-induced mitohormesis.

Research progress in hypoglycemic effect and mechanism of heat-clearing and detoxifying Chinese materia medica / 中草药

Heat-toxin stagnation is regarded to be an important pathologic mechanism of diabetes mellitus (DM) in terms of traditional Chinese medicine. Treating DM with heat-clearing and detoxifying principle on the basis of syndrome differentiation proves to be effective. Heat-clearing and detoxifying Chinese materia medica can decrease blood sugar by protecting islet β-cell, improving insulin resistance, regulating glucose metabolism and lipid metabolism, regulating GLP-1, inflammatory cytokines, and intestinal microflora.

Relationship between autophagy and T2DM and intervention effect of traditional Chinese medicine / 中国中药杂志

Insulin resistance and insulin secretion deficiency are main machanisms in inducing type 2 diabetes mellitus (T2DM), and mitochondria damage plays an important role in them. Research shows that autophagy is a self-protective mechanism of cells, which plays an important role in maintaining the normal structure and function of pancreatic β cells and improving insulin resistance. Previous studies show that traditional Chinese medicine can regulate cell autophagy to influence β cells and insulin resistance, type 2 diabetes mellitus and its complications. Thus this review will talk about the process of the relationship between autophagy and T2DM and the intervention effect of traditional Chinese medicine.

Fabrication and properties of TiO2 nanofilms on different substrates by a novel and universal method of Ti-ion implantation and subsequent annealing.

We report a new, novel and universal method to fabricate high-quality titanium dioxide (TiO2) nanofilms on different substrates by a solid phase growth process of ion implantation and subsequent annealing in oxygen atmosphere. Ti ions were implanted into fused silica, soda lime glass, Z-cut quartz, or (0001) α-sapphire by a metal vapor vacuum arc (MEVVA) ion source implanter to fluences of 0.75, 1.5 and 3 × 10(17) ions cm(-2) with a nominal accelerating voltage of 20 kV. To understand the influence of the annealing temperature, time, and substrate on the formation and phase transformation of the TiO2 nanofilms, the Ti-ion-implanted substrates were annealed in oxygen atmosphere from 500 to 1000 °C for 1-6 h. The formation of TiO2 nanofilms resulted from the slow out-diffusion of implanted Ti ions from the substrates which were then oxidized at the surfaces. The thickness and phase of the nanofilms can be tailored by controlling the implantation and annealing parameters. Since the TiO2 nanofilms are formed under high temperature and low growth rate, they show good crystallinity and antibacterial properties, with good film adhesion and stability, suggesting that the TiO2 nanofilms formed by this method have great potential in applications such as antibacterial and self-cleaning transparent glass.

Suppressing Erwinia carotovora pathogenicity by projecting N-acyl homoserine lactonase onto the surface of Pseudomonas putida cells.

N-Acyl homoserine lactones (AHLs) serve as the vital quorum-sensing signals that regulate the virulence of the pathogenic bacterium Erwinia carotovora. In the present study, an approach to efficiently restrain the pathogenicity of E. carotovora-induced soft rot disease is described. Bacillus thuringiensis-derived N-acyl homoserine lactonase (AiiA) was projected onto the surface of Pseudomonas putida cells, and inoculation with both strains was challenged. The previously identified N-terminal moiety of the ice nucleation protein, InaQ-N, was applied as the anchoring motif. A surface display cassette with inaQ-N/ aiiA was constructed and expressed under the control of a constitutive promoter in P. putida AB92019. Surface localization of the fusion protein was confirmed by Western blot analysis, flow cytometry, and immunofluorescence microscopy. The antagonistic activity of P. putida MB116 expressing InaQ-N/AiiA toward E. carotovora ATCC25270 was evaluated by challenge inoculation in potato slices at different ratios. The results revealed a remarkable suppressing effect on E. carotovora infection. The active component was further analyzed using different cell fractions, and the cell surface-projected fusion protein was found to correspond to the suppressing effect.