Malignant melanoma is a fatal cancer. Signal transducer and activator of transcription 3 (STAT3) has been proposed as a therapeutic target of melanoma. An herbal formula Huai-Hua-San (HHS) comprising ...Sophorae Flos (SF) and Gardeniae Fructus (GF) is traditionally used for treating cancers including melanoma, but the pharmacological basis is unknown.
This study aimed to investigate the anti-melanoma effects of an ethanolic extract of HHS (HHSE), and explore the involvement of STAT3 signaling in the effects.
An UPLC-TOF/MS method was developed to control the quality of HHSE. A B16F10 allograft mouse model and three melanoma cell lines (B16F10, A375 and A2058) were used to determine the anti-melanoma effects of HHSE. Dacarbazine (DTIC) and Stattic were used as positive controls. Cell viability was detected using MTT and crystal violet staining assays. Cell apoptosis was analyzed by flow cytometry after the cells were stained with Annexin-V/PI. Cell invasive ability was examined using the transwell assay. Protein levels were determined by Western blotting.
The contents of crocin I, crocin II, quercetin and kaempferol in HHSE were 0.59%, 0.98%, 4.66% and 1.15%, respectively. A clinically relevant dose of HHSE (0.1 g/kg/day, i.g. for 15 consecutive days) significantly suppressed B16F10 tumor growth in mice. HHSE dose-dependently reduced cell viability and dampened invasion of, and induced apoptosis in, melanoma cells. Mechanistic studies revealed that HHSE inhibited the phosphorylation/activation of STAT3 in B16F10 allografts and in cultured melanoma cells. In cell models, HHSE also inhibited the phosphorylation of STAT3 upstream kinases, JAK2 (Tyr1007/1008) and Src (Tyr416), lowered STAT3 nuclear levels, and down-regulated the protein levels of STAT3-targeted molecules. Over-activation of STAT3 in A375 cells significantly attenuated the cytotoxic effects of HHSE.
HHSE exhibits anti-melanoma effects in cell and mouse models. Inhibition of STAT3 signaling contributes to the anti-melanoma mechanisms of HHSE. Our findings lay a groundwork for developing HHSE as a modern agent for melanoma management, and provide pharmacological justifications for the traditional use of HHS in treating melanoma.
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Biological foaming (or biofoaming) is a frequently occurring problem in wastewater treatment plants (WWTPs) and is attributed to the overwhelming growth of filamentous bulking and foaming bacteria ...(BFB). Biological foaming has been intensively investigated, with BFB like
and
having been identified from WWTPs and implicated in foaming. Nevertheless, studies are still needed to improve our understanding of the microbial diversity of WWTP biofoams and how microbial activities contribute to foaming. In this study, sludge foaming at the Qinghe WWTP of China was monitored, and sludge foams were investigated using culture-dependent and culture-independent microbiological methods. The foam microbiomes exhibited high abundances of
, Mycobacterium,
, and
. A previously unknown bacterium,
Kaistella beijingensis, was cultivated from foams, its genome was sequenced, and it was phenotypically characterized.
. K. beijingensis exhibits hydrophobic cell surfaces, produces extracellular polymeric substances (EPS), and metabolizes lipids.
. K. beijingensis abundances were proportional to EPS levels in foams. Several proteins encoded by the
. K. beijingensis genome were identified from EPS that was extracted from sludge foams.
. K. beijingensis populations accounted for 4 to 6% of the total bacterial populations in sludge foam samples within the Qinghe WWTP, although their abundances were higher in spring than in other seasons. Cooccurrence analysis indicated that
. K. beijingensis was not a core node among the WWTP community network, but its abundances were negatively correlated with those of the well-studied BFB Skermania piniformis among cross-season Qinghe WWTP communities.
Biological foaming, also known as scumming, is a sludge separation problem that has become the subject of major concern for long-term stable activated sludge operation in decades. Biological foaming was considered induced by foaming bacteria. However, the occurrence and deterioration of foaming in many WWTPs are still not completely understood. Cultivation and characterization of the enriched bacteria in foaming are critical to understand their genetic, physiological, phylogenetic, and ecological traits, as well as to improve the understanding of their relationships with foaming and performance of WWTPs.
Background and aim
Previous studies have reported an association between gut microbiota and cirrhosis. However, the causality between intestinal flora and liver cirrhosis still remains unclear. In ...this study, bi-directional Mendelian randomization (MR) analysis was used to ascertain the potential causal effect between gut microbes and cirrhosis.
Methods
Large-scale Genome Wide Association Study (GWAS) data of cirrhosis and gut microbes were obtained from FinnGen, Mibiogen consortium, and a GWAS meta-analysis of Alcoholic cirrhosis (ALC). Two-sample MR was performed to determine the causal relationship between gut microbiota and cirrhosis. Furthermore, a bi-directional MR analysis was employed to examine the direction of the causal relations.
Result
In MR analysis, we found that 21 gut microbiotas were potentially associated with cirrhosis. In reverse MR analysis, 11 gut microbiotas displayed potentially associations between genetic liability in the gut microbiome and cirrhosis. We found that the family
Lachnospiraceae
(OR: 1.59, 95% CI:1.10–2.29) might be harmful in cirrhotic conditions (ICD-10: K74). Furthermore, the genus
Erysipelatoclostridium
might be a protective factor for cirrhosis (OR:0.55, 95% CI:0.34–0.88) and PBC (OR:0.68, 95% CI:0.52–0.89). Combining the results from the MR analysis and reverse MR analysis, we firstly identified the
Genus Butyricicoccus
had a bi-directional causal effect on PBC (Forward: OR: 0.37, 95% CI:0.15–0.93; Reverse: OR: 1.03, 95% CI:1.00–1.05).
Conclusion
We found a new potential causal effect between cirrhosis and intestinal flora and provided new insights into the role of gut microbiota in the pathological progression of liver cirrhosis.
•Disparities in sad face processing exist among different patients with major depressive disorder.•Major depressive disorder is associated with brain function activation of multiple brain areas.•The ...disruption patterns of brain function differ according to Traditional Chinese Medicine-defined syndromes.•Clinical syndromes of major depressive disorder are associated with abnormalities of functional activation.
Objective:Patients with major depressive disorder (MDD) may experience a series of emotional and mental problems accompanied by characteristic clinical symptoms. Depressive patients often have emotional recognition disorders, but the reasons remain unclear. Though a great many functional abnormalities have been observed in the brains of depressed patients, such abnormalities are not often related to clinical symptoms. Currently in Traditional Chinese Medicine (TCM), syndrome differentiation for the MDD mainly consists of excess pattern (EP), and deficiency pattern (DP). EP and DP emphasize balance-regulation thought processes, and are widely used in diagnosis of diseases including depression, anxiety, insomnia, and other emotional disorders. We hope that syndrome differentiation in TCM can combine clinical symptoms and brain function more effectively. The present study investigated altered patterns and different association of brain activation in MDD patients with EP and DP during a facial emotion discrimination task with fMRI.
Methods:A total of 45 patients (20 with EP and 25 with DP) and 18 normal controls participated in this study. Whole-brain functional scans were collected for each subject. Different patterns of brain activation and association during the facial emotion discrimination task were analyzed statistically.
Results:Comparing all the MDD patients with the normal controls, there were no significant differences for sad vs. neutral condition or for happy vs. neutral condition (corrected p > 0.05). One-way ANCOVA showed significant differences in the left inferior frontal gyrus, the left insula, and the left caudate for sad vs. neutral condition across the DP, EP and NC groups (corrected p < 0.05). The whole brain activation comparison for sad vs. neutral condition between the EP MDD subtype and the DP MDD subtype further verified these differences in the left insula and left inferior frontal gyrus, discovering that these regions showed increased activation in EP MDD subtype compared with the DP MDD subtype (corrected p < 0.05). There were no significant differences in brain activation between each MDD subtype and the normal controls.
Conclusion:Disparities in sad face processing exist between MDD patients with different TCM syndrome types, suggesting that TCM syndrome differentiation may provide a biological basis for negativity bias in depression, and may determine both symptom formation and social dysfunction.
Venous malformations (VMs), featuring localized dilated veins, are the most common developmental vascular anomalies. Aberrantly organized perivascular extracellular matrix (ECM) is one of the ...prominent pathological hallmarks of VMs, accounting for vascular dysfunction. Although previous studies have revealed various proteins involved in ECM remodeling, the detailed pattern and molecular mechanisms underlying the endothelium-ECM interplay have not been fully elucidated. Our previous studies revealed drastically elevated extracellular vesicle (EV) secretion in VM lesions. Here, we identified increased EV-carried MMP14 in lesion fluids of VMs and culture medium of TIE2-L914F mutant endothelial cells (ECs), along with stronger ECM degradation. Knockdown of
RAB27A
, a required regulator for vesicle docking and fusion, led to decreased secretion of EV-carried MMP14 in vitro. Histochemical analysis further demonstrated a highly positive correlation between RAB27A in the endothelium and MMP14 in the perivascular environment. Therefore, our results proved that RAB27A-regulated secretion of EV-MMP14, as a new pattern of endothelium-ECM interplay, contributed to the development of VMs by promoting ECM degradation.
Psoriasis is a chronic autoimmune disease that is predominantly mediated by T-lymphocytes and keratinocytes. Tacrolimus is T cell-targeted immunosuppression drug that has been widely used in topical ...therapy of psoriasis; however, the pharmacologic effect of tacrolimus on human keratinocytes has not been fully clarified. This study aimed to investigate the potential regulatory effect of tacrolimus on TNF-α/ IL-17A-costimulated human keratinocytes in the mimic psoriatic microenvironment. The cultured normal human keratinocytes (NHKs) were divided into the following groups: control, TNF-α/IL-17A, tacrolimus, and TNF-α/IL-17A + tacrolimus. Cultured cells and supernatant were collected after 24 h, and then real-time quantitative PCR, western blot, and ELISA analysis were performed. Foreskin tissues were treated by using TNF-α, IL-17A, and tacrolimus 0.03% ointment and then cultured for 24 h, and immunohistochemistry was performed. NHKs expressed significant IL-36γ, CCL-20, IL-1β, S100-A9, and CXCL-1 mRNA after TNF-α/IL-17A treatment. Tacrolimus significantly inhibited TNF-α/IL-17A-induced IL-36γ, CCL-20, IL-1β, and S100-A9 expression at gene level and IL-36γ and CCL-20 expression at protein level. We further discovered TNF-α/IL-17A induced significant IκBζ mRNA and protein expression in NHKs, which could be inhibited by tacrolimus. Tacrolimus can inhibit pro-inflammatory synergistic action of TNF-α/IL-17A on human keratinocytes by regulating IκBζ expression.
Purpose
To assess the associations of corneal biomechanical properties as measured by the Corvis ST with refractive errors and ocular biometry in an unselected sample of young adults.
Methods
A total ...of 1645 healthy university students underwent corneal biomechanical parameters measurement by the Corvis ST. The refractive status of the participants was measured using an autorefractor without cycloplegia. Ocular biometric parameters were measured using the IOL Master.
Results
After adjusting for the effect of age, sex, biomechanical-corrected intraocular pressure and central corneal thickness, axial length was significantly associated with A1 velocity (A1v,
β
= -10.47), A2 velocity (A2v,
β
= 4.66), A2 deflection amplitude (A2DeflA,
β
= -6.02), HC deflection amplitude (HC-DeflA,
β
= 5.95), HC peak distance (HC-PD,
β
= 2.57), deformation amplitude ratio max (DA Rmax,
β
= -0.36), Ambrósio′s relational thickness to the horizontal profile (ARTh,
β
= 0.002). For axial length / corneal radius ratio, only A1v (
β
= -2.01), A1 deflection amplitude (A1DeflA,
β
= 2.30), HC-DeflA (
β
= 1.49), HC-PD (
β
= -0.21), DA Rmax (
β
= 0.07), stress–strain index (SSI,
β
= -0.29), ARTh (
β
< 0.001) were significant associates. A1v (
β
= 23.18), HC-DeflA (
β
= -15.36), HC-PD (
β
= 1.27), DA Rmax (
β
= -0.66), SSI (
β
= 3.53), ARTh (
β
= -0.02) were significantly associated with spherical equivalent.
Conclusion
Myopic eyes were more likely to have more deformable corneas and corneas in high myopia were easier to deform and were even softer compared with those in the mild/moderate myopia.
Heart failure (HF) has been proposed as a potential indication of renal denervation (RDN). However, the mechanisms enabling RDN to attenuate HF are not well understood, especially the central effects ...of RDN. The aim of this study was to decipher the mode of operation of RDN in the treatment of HF using a canine model of right ventricular rapid pacing-induced HF. Accordingly, 24 Chinese Kunming dogs were randomly grouped to receive sham procedure (sham-operated group), bilateral RDN (RDN group), rapid pacing to induce HF (HF-control group), and bilateral RDN plus rapid pacing (RDN + HF group). Echocardiography, plasma brain natriuretic peptide (BNP), and norepinephrine (NE) concentrations of randomized dogs were measured at baseline and 4 weeks after interventions, followed by histological and molecular analyses. Twenty dogs completed the research successfully and were enrolled for data analyses. Results showed that the average optical density of renal efferent and afferent nerves were significantly lower in the RDN and RDN + HF groups than in the sham-operated group, with a significant reduction of renal NE concentration. Rapid pacing in the RDN + HF and HF-control groups, compared with the sham-operated group, induced a significant increase in left ventricular end-diastolic volume and decrease in left ventricular ejection fraction and correspondingly resulted in cardiac fibrosis and dysfunction. Cardiac fibrosis evaluated by Masson's trichrome staining and the expression of transforming growth factor-β1 (TGF-β1) were significantly higher in the HF-control group than in the sham-operated group, which were remarkably attenuated by the application of the RDN technique in the RDN + HF group. In terms of central renin-angiotensin system (RAS), the expression of angiotensin II (AngII)/angiotensin-converting enzyme (ACE)/AngII type 1 receptor (AT1R) in the hypothalamus of dogs in the HF-control group, compared with the sham-operated group, was upregulated and that of the angiotensin-(1-7) Ang-(1-7)/ACE2 was downregulated. Furthermore, both of them were significantly attenuated by the RDN therapy in the RDN + HF group. In conclusion, the RDN technique could damage renal nerves and suppress the cardiac remodeling procedure in canine with HF while concomitantly attenuating the overactivity of central RAS in the hypothalamus.
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