Schisandrin A alleviates renal fibrosis by inhibiting PKCß and oxidative stress.

BACKGROUND: Renal fibrosis is a common pathway that drives the advancement of numerous kidney maladies towards end-stage kidney disease (ESKD). Suppressing renal fibrosis holds paramount clinical importance in forestalling or retarding the transition of chronic kidney diseases (CKD) to renal failure. Schisandrin A (Sch A) possesses renoprotective effect in acute kidney injury (AKI), but its effects on renal fibrosis and underlying mechanism(s) have not been studied. STUDY DESIGN: Serum biochemical analysis, histological staining, and expression levels of related proteins were used to assess the effect of PKCß knockdown on renal fibrosis progression. Untargeted metabolomics was used to assess the effect of PKCß knockdown on serum metabolites. Unilateral Ureteral Obstruction (UUO) model and TGF-ß induced HK-2 cells and NIH-3T3 cells were used to evaluate the effect of Schisandrin A (Sch A) on renal fibrosis. PKCß overexpressed NIH-3T3 cells were used to verify the possible mechanism of Sch A. RESULTS: PKCß was upregulated in the UUO model. Knockdown of PKCß mitigated the progression of renal fibrosis by ameliorating perturbations in serum metabolites and curbing oxidative stress. Sch A alleviated renal fibrosis by downregulating the expression of PKCß in kidney. Treatment with Sch A significantly attenuated the upregulated proteins levels of FN, COL-I, PKCß, Vimentin and α-SMA in UUO mice. Moreover, Sch A exhibited a beneficial impact on markers associated with oxidative stress, including MDA, SOD, and GSH-Px. Overexpression of PKCß was found to counteract the renoprotective efficacy of Sch A in vitro. CONCLUSION: Sch A alleviates renal fibrosis by inhibiting PKCß and attenuating oxidative stress.

Translocated HMGB3 is involved in papillary thyroid cancer progression by activating cytoplasmic TLR3 and transmembrane TREM1.

The family of high mobility group box (HMGB) proteins participates in various biological processes including immunity, inflammation, as well as cancer formation and progression. However, its role in thyroid cancer remains to be clarified. We performed quantitative RT-PCR (qRT-PCR), western blot, enzyme-linked immunosorbent, immunohistochemistry, and immunofluorescence assays to evaluate the expression level and subcellular location of HMGB3. The effects of HMGB3 knockdown on malignant biological behaviors of thyroid cancer were determined by cell proliferation assays, cell cycle and apoptosis assays, and transwell chamber migration and invasion assays. Differential expression genes (DEGs) altered by HMGB3 were analyzed using the Ingenuity Pathway Analysis (IPA) and TRRUST v2 database. HMGB3 correlated pathways predicted by bioinformatic analysis were then confirmed using western blot, co-immunoprecipitation, dual-luciferase reporter assay, and flow cytometry. We found that HMGB3 is overexpressed and its downregulation inhibits cell viability, promotes cell apoptosis and cell cycle arrest, and suppresses cell migration and invasion in thyroid cancer. In PTC, both tissue and serum levels of HMGB3 are elevated and are correlated with lymph node metastasis and advanced tumor stage. Mechanistically, we observed the translocation of HMGB3 in PTC, induced at least partially by hypoxia. Cytoplasmic HMGB3 activates nucleic-acid-mediated TLR3/NF-κB signaling and extracellular HMGB3 interacts with the transmembrane TREM1 receptor in PTC. This study demonstrates the oncogenic role of HMGB3 cytoplasmic and extracellular translocation in papillary thyroid cancers; we recommend its future use as a potential circulating biomarker and therapeutic target for PTC.

Baicalin ameliorates neuroinflammation-induced depressive-like behavior through inhibition of toll-like receptor 4 expression via the PI3K/AKT/FoxO1 pathway.

BACKGROUND: Baicalin, which is isolated from Radix Scutellariae, possesses strong biological activities including an anti-inflammation property. Recent studies have shown that the anti-inflammatory effect of baicalin is linked to toll-like receptor 4 (TLR4), which participates in pathological changes of central nervous system diseases such as depression. In this study, we explored whether baicalin could produce antidepressant effects via regulation of TLR4 signaling in mice and attempted to elucidate the underlying mechanisms. METHODS: A chronic unpredictable mild stress (CUMS) mice model was performed to explore whether baicalin could produce antidepressant effects via the inhibition of neuroinflammation. To clarify the role of TLR4 in the anti-neuroinflammatory efficacy of baicalin, a lipopolysaccharide (LPS) was employed in mice to specially activate TLR4 and the behavioral changes were determined. Furthermore, we used LY294002 to examine the molecular mechanisms of baicalin in regulating the expression of TLR4 in vivo and in vitro using western blot, ELISA kits, and immunostaining. In the in vitro tests, the BV2 microglia cell lines and primary microglia cultures were pretreated with baicalin and LY292002 for 1 h and then stimulated 24 h with LPS. The primary microglial cells were transfected with the forkhead transcription factor forkhead box protein O 1 (FoxO1)-specific siRNA for 5 h and then co-stimulated with baicalin and LPS to investigate whether FoxO1 participated in the effect of baicalin on TLR4 expression. RESULTS: The administration of baicalin (especially 60 mg/kg) dramatically ameliorated CUMS-induced depressive-like symptoms; substantially decreased the levels of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) in the hippocampus; and significantly decreased the expression of TLR4. The activation of TLR4 by the LPS triggered neuroinflammation and evoked depressive-like behaviors in mice, which were also alleviated by the treatment with baicalin (60 mg/kg). Furthermore, the application of baicalin significantly increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and FoxO1. The application of baicalin also promoted FoxO1 nuclear exclusion and contributed to the inhibition of the FoxO1 transactivation potential, which led to the downregulation of the expression of TLR4 in CUMS mice or LPS-treated BV2 cells and primary microglia cells. However, prophylactic treatment of LY294002 abolished the above effects of baicalin. In addition, we found that FoxO1 played a vital role in baicalin by regulating the TLR4 and TLR4-mediating neuroinflammation triggered by the LPS via knocking down the expression of FoxO1 in the primary microglia. CONCLUSION: Collectively, these results demonstrate that baicalin ameliorated neuroinflammation-induced depressive-like behaviors through the inhibition of TLR4 expression via the PI3K/AKT/FoxO1 pathway.

Baicalin exerts neuroprotective effects via inhibiting activation of GSK3ß/NF-κB/NLRP3 signal pathway in a rat model of depression.

Chronic stress can provoke depressive-like behaviors through activation of inflammation and apoptosis, leading to a reduction of neurons. Antidepressant therapy may contribute to inhibiting inflammation responses and have neuroprotective effects. Baicalin (BA) has an antidepressant effect in the chronic unpredictable mild stress (CUMS) animal model and exerts anti-inflammation, anti-apoptosis, as well as neuroprotective effects in many central nervous system (CNS)-related diseases. But the effects of BA on neuroprotection, apoptosis, and neuroinflammation and the potential mechanisms in depression are unclear. Here, we focused on examining the therapeutic effects of BA in CUMS-induced depression rats and investigating the molecular mechanisms. Results showed that administration of BA improved depressive-like behaviors and significantly increased the levels of doublecortin (DCX), Neuron-specific enolase (NSE), and Brain-derived neurotrophic factor (BDNF) in hippocampus. Furthermore, administration of BA increased the cell survival by reducing the level of malondialdehyde (MDA) and increasing the level of superoxide dismutase (SOD). Finally, administration of BA significantly decreased CUMS-induced apoptosis and inflammatory cytokines (caspase-1 and IL-1ß) in hippocampus. These responses were mediated by Glycogen synthase kinase-3 (GSK3) ß/Nuclear factor-κB (NF-κB)/Nucleotide-binding domain, leucine-rich repeat, pyrin domain containing protein 3 (NLRP3) signal pathway. Taken together, these results indicate that BA could promote neuronal maturation and rescue neurons from apoptosis via inhibiting activation of GSK3ß/NF-κB/NLRP3 signal pathway that is known to be associated with inflammation, thus exerting neuroprotective effects and preventing CUMS-induced depressive-like behaviors.

[Platelet-rich plasma combined with demineralized freeze-dried bone allografts for periodontal regeneration in the treatment of periodontal defects: a meta-analysis].

PURPOSE: The aim of this meta analysis was to assess the influence of platelet-rich plasma (PRP)combined with demineralized freeze-dried bone allografts(DFDBA) on regeneration of periodontal periodontal defects by means of evaluating clinical and radiographic outcomes in prospective human clinical trials. METHODS: The following databases such as PubMed, The Cochrane Library, EMbase, CNKI, Wanfang data and VIP data were searched on computer from inception to December, 2016. According to the inclusion and exclusion criteria, two reviewers independently extracted the data，assessed the methodological quality of the included studies. RevMan 5.2 was applied for meta analysis. RESULTS: Six papers were obtained reviewed which included 205 periodontal bone defect sites. Six articles showed that there was no significant difference in probing depth decrease between PRP combined with DFDBA and PRP or DFBDA group[MD=0.35, 95%CI（-0.09，0.79), P=0.12], but there was significant difference in clinical attachment loss increase between the two groups［MD= 0.68，95%CI（0.41，0.94），P<0.00001]. Three articles were included for evaluating bone filling, there was significant difference in the distance from the cemento-enamel junction(CEJ) to the vertical bone defect(BD)(CEJ-BD)[MD=0.71，95%CI（0.46，0.95），P<0.00001]between the two groups; there was also significant difference in the distance from the alveolar crest to the vertical bone defect(AC-BD)[MD=0.64，95%CI（0.41，0.87)，P<0.00001]between the two groups. but there was no significant difference in the distance from the cemento-enamel junction(CEJ)to the alveolar crest (AC)(CEJ-AC)[MD=0.03，95%CI（-0.10，0.16），P=0.68] between the two groups. CONCLUSIONS: Within the limitations of this meta analysis, PRP combined with DFDBA is superior to PRP or DFDBA alone in clinical attachment loss and bone filling ,but there was no significant difference in probing depth. However, given the limited sample size and quantity of included studies, the above findings still need to be further proved by conducting more high-quality and large-scale RCTs.

Geraniol produces antidepressant-like effects in a chronic unpredictable mild stress mice model.

Geraniol (GE), which has neuroprotection and anti-inflammation activities, is mostly abundant in the essential oils of rose, ginger, lemon, orange, lavender etc. However, its antidepressant-like effect has not been reported before. The present study was designed to investigate whether GE confers an antidepressant effect in mice exposed to a chronic unpredictable mild stress (CUMS) model of depression and to explore its possible mechanisms. The results showed that GE treatments for 3 weeks significantly alleviated the depression-related behaviors of CUMS-exposed mice, as indicated by restored decreased sucrose preference and shortened immobile time in both the forced swimming tests (FST) and tail suspension tests (TST). And these ameliorative effects of GE treatment were involved with regulating CUMS-induced pro-inflammatory cytokine interleukin-1 beta (IL-1ß) related neuro-inflammation. We further found that GE treatment reversed CUMS-induced IL-1ß elevation, possibly by inhibiting nuclear factor kappa B (NF-κB) pathway activation and regulating nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome expression. Taken together, our findings suggested that GE exerted a potential antidepressant-like effect in CUMS mice model of depression, which may provide an insight into the potential of GE in therapeutic implications for depression.

Cardioprotective effects of timosaponin B II from Anemarrhenae asphodeloides Bge on isoproterenol-induced myocardial infarction in rats.

The aim of the present study was to investigate the cardioprotective effects of Timosaponin B II (TB), a main bioactive constituent from Anemarrhenae asphodeloides Bge, on an isoproterenol (ISO)-induced myocardial infarction model in rats and explore its underlying mechanisms. Rats were treated with TB (50 mg/kg, 100 mg/kg) or diltiazem hydrochloride (DH, 5 mg/kg) by gastric gavage for five days. At the 4th and 5th days, myocardial injury was induced by ISO injection (85 mg/kg) at an interval of 24 h for 2 consecutive days. After the induction, rats were anaesthetized with pentobarbital sodium (30 mg/kg) to record the electrocardiogram. Our research showed that ISO administration resulted in significant elevations in the ST-segment, the levels of cardiac injury biomarkers creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), and concentrations of serum proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Pretreatment with TB significantly reversed these alterations induced by ISO challenge. The cardioprotective effects of TB were further proved by the histopathological examination. Exploration of the underlying mechanisms of its actions revealed that TB pretreatment restored the ISO-induced decrease of super oxide dismutase (SOD) and the increase of malondialdehyde (MDA). Meanwhile, we found that the enhancement of antioxidant defense system might be associated with the increased heme oxygenase isoform 1 (HO-1) induction and activated nuclear respiratory factor 2 (Nrf-2) translocation. Furthermore, the present research also demonstrated that nuclear translocation of Nrf-2 and subsequent HO-1 expression might be associated with nuclear factor kappa B (NF-κB) pathway activation. Taken together, our finding demonstrated that TB might have a potential benefit in preventing ischemic heart diseases like myocardial infarction.

Thymol produces an antidepressant-like effect in a chronic unpredictable mild stress model of depression in mice.

Thymol, a bioactive monoterpene isolated from Thymus vulgaris, has displayed inspiring neuroprotective properties. The present study was designed to evaluate the antidepressant-like effects of thymol on a chronic unpredictable mild stress (CUMS) model of depression in mice and explore the underlying mechanisms. It was observed that thymol treatment (15 mg/kg and 30 mg/kg) significantly reversed the decrease of sucrose consumption, the loss of body weight, the reduction of immobile time in the tail suspension tests (TST) and forced swimming tests (FST) induced by CUMS paradigm. The levels of norepinephrine (NE) and serotonin (5-HT) in the hippocampus decreased in the CUMS-treated mice. Chronic treatments with thymol significantly restored the CUMS-induced alterations of monoamine neurotransmitters in the hippocampus. Our results further demonstrated that thymol administration negatively regulated the induction of proinflammatory cytokines including interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α in CUMS mice. Furthermore, thymol inhibited the activation of nod-like receptor protein 3 (NLRP3) inflammasome and its adaptor, and subsequently decreased the expression of caspase-1. In sum, our findings suggested that thymol played a potential antidepressant role in CUMS mice model through up-regulating the levels of central neurotransmitters and inhibiting the expressions of proinflammatory cytokines, which might provide potential for thymol in the light of opening up new therapeutic avenues for depression.