Follistatin-like 1 protects against doxorubicin-induced cardiotoxicity by preventing mitochondrial dysfunction through the SIRT6/Nrf2 signaling pathway.

Mitochondrial dysfunction and myocardial remodeling have been reported to be the main underlying molecular mechanisms of doxorubicin-induced cardiotoxicity. SIRT6 is a nicotinamide adenine dinucleotide-dependent enzyme that plays a vital role in cardiac protection against various stresses. Moreover, previous studies have demonstrated that FSTL1 could alleviate doxorubicin-induced cardiotoxicity by inhibiting autophagy. The present study investigated the probable mechanisms of FSTL1 on doxorubicin-induced cardiotoxicity in vivo and in vitro. We confirmed that FSTL1 exerted a pivotal protective role on cardiac tissue in vivo and on doxorubicin-induced cell injury in vitro. Furthermore, FSTL1 can alleviate doxorubicin-induced mitochondrial dysfunction by inhibiting autophagy and apoptosis. Further studies demonstrated that FSTL1 can activate SIRT6 signaling by restoring the SIRT6 protein expression in doxorubicin-induced myocardial injury. SIRT6 activation elevated the protein expression of Nrf2 in doxorubicin-induced H9C2 injury. Treatment with the Nrf2 inhibitor ML385 partially antagonized the cardioprotective role of SIRT6 on doxorubicin-induced autophagy or apoptosis. These results suggested that the protective mechanism of FSTL1 on doxorubicin-induced cardiotoxicity may be related with the inhibition of autophagy and apoptosis, partly through the activation of SIRT6/Nrf2.

An Innovative SbIII-WVI-Cotemplated Antimonotungstate with Potential in Sensing Paroxetine Electrochemically.

Advances in polyoxometalate (POM) self-assembly chemistry are always accompanied by new developments in molecular blocks. The exploration and discovery of uncommon building blocks offer great possibilities for generating unprecedented POM clusters. An intriguing SbIII-WVI-cotemplated antimonotungstate [H2N(CH3)2]11Na[SbW9O33]Er2(H2O)2Sb2[SbWVIW15O57]·22H2O (1) was synthesized, which comprises a classical trivacant Keggin [SbW9O33]9- ({SbW9}) fragment and an unclassical lacunary Dawson-like [SbWVIW15O57]15- ({SbWVIW15}) subunit. Notably, the Dawson-like {SbWVIW15} subunit is the first example of a [SbO3]3- and [WVIO6]6- mixed-heteroatom-directing POM segment. Hexacoordinated [WVIO6]6- can not only serve as the heteroatom function but its additional oxygen sites can also link to lanthanide, main-group metal, and transition-metal centers to form the innovative structure. {SbWVIW15} and {SbW9} subunits are joined by the heterometallic [Er2(H2O)2Sb2O17]22- cluster to give rise to an asymmetric sandwich-type architecture. To further realize its potential application in electrochemical sensing, a conductive 1@rGO composite was obtained by the electrochemical deposition of 1 with graphene oxide (GO). Using a 1@rGO-modified glassy carbon electrode as the working electrode, an electrochemical biosensor for detecting the antidepressant drug paroxetine (PRX) was successfully constructed. This work can provide a viable strategy for synthesizing mixed-heteroatom-directing POMs and demonstrates the application of POM-based materials for the electrochemical detection of drug molecules.

Structure-activity relationships of natural and synthetic lathyrane-based diterpenoids for suppression of NLRP3-driven inflammation and gouty arthritis.

Lathyrane-based diterpenoid is one of the critical bioactive elements of Euphorbia lathyris L., a widely used traditional Chinese medicine for the treatment of inflammation and infection. In this study, we introduced and evaluated seven synthetic or natural lathyrane-based diterpenoids with the same core structure but notable structural variations at specific positions, for their anti-inflammatory and gout-alleviating properties. There was no significant cytotoxicity below 10 µM among the initial test of the cell counting kit 8 of the seven candidate derivatives (compounds 13 to 19) in this work. Furthermore, maintaining the acyloxy group at 15-C position and the strongly hydrophobic aryl structure at 3-C and 5-C positions, compounds 15 (Euphorbia factor L3, EFL3) and 17 strikingly inhibited the production of IL-1ß related to the actuation of the inflammasome in our study. The ELISA assay indicated that the anti-inflammatory effects of EFL3 were better associated with MSU stimulation than other second-line pathways triggered by inflammasome. Further examinations on the acute paw gout model in C57BL/6 mice showed that EFL3 had a significantly inflammatory retarding effect by intraperitoneal injection. It decreased swelling volume as well as the cleavage and activation of local IL-1ß and casepas-1 in the paw. To conclude, our findings reveal several potential key structure-activity relationships that govern the anti-inflammatory effects of lathyrane-type diterpenoids, the dispensable acyl group at the 15-C position, the importance of maintaining the spatial structure of the B-ring, and the potential importance of hydrophobic substituents at the 3-C position. These insights may provide guidance for the structural design of lathyrane-type agents in the future; furthermore, we found that the lathyrane-based diterpenoid EFL3 is a potential agent for gout that is expected to provide a novel therapeutic strategy for inflammation intervention.

Role of soluble epoxide hydrolase in the abnormal activation of fibroblast-like synoviocytes from patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by enigmatic pathogenesis. Polyunsaturated fatty acids (PUFAs) are implicated in RA's development and progression, yet their exact mechanisms of influence are not fully understood. Soluble epoxide hydrolase (sEH) is an enzyme that metabolizes anti-inflammatory epoxy fatty acids (EpFAs), derivatives of PUFAs. In this study, we report elevated sEH expression in the joints of CIA (collagen-induced arthritis) rats, concomitant with diminished levels of two significant EpFAs. Additionally, increased sEH expression was detected in both the synovium of CIA rats and in the synovium and fibroblast-like synoviocytes (FLS) of RA patients. The sEH inhibitor TPPU attenuated the migration and invasion capabilities of FLS derived from RA patients and to reduce the secretion of inflammatory factors by these cells. Our findings indicate a pivotal role for sEH in RA pathogenesis and suggest that sEH inhibitors offer a promising new therapeutic strategy for managing RA.

Cerium-Encapsulated SbIII-SeIV-Templating Polyoxotungstate for Electrochemically Sensing Human Multidrug Resistance Gene Segment.

A tower-like SbIII-SeIV-templating polyoxotungstate [H2N(CH3)2]12Na7H3[Ce0.5/Na0.5(H2O)5]2[SbSe2W21O75]2·50H2O (1) was synthesized, whose skeleton is assembled from two prolonged lacunary Dawson [SbSe2W21O75]13- units and two [Ce0.5/Na0.5(H2O)5]2+ linkers. The uncommon [SbSe2W21O75]13- unit can be viewed as a combination of one [SeW6O21]2- group grafted onto a trivacant Dawson [SbSeW15O54]11- subunit. The conductive composite 1-Au@rGO containing 1, gold nanoparticles, and reduced graphene oxide (rGO) was conveniently prepared, using which the 1-Au@rGO-based electrochemical genosensor was constructed for detecting human multidrug resistance gene segment. This work enriches structural types of dual-heteroatom-inserted polyoxometalates and promotes the application of polyoxometalates in genosensors.

CASC9 potentiates gemcitabine resistance in pancreatic cancer by reciprocally activating NRF2 and the NF-κB signaling pathway.

Gemcitabine resistance is a frequently occurring and intractable obstacle in pancreatic cancer treatment. However, the underlying mechanisms require further investigation. Adaptive regulation of oxidative stress and aberrant activation of the NF-κB signaling pathway are associated with resistance to chemotherapy. Here, we found that gemcitabine upregulated the expression of CASC9 in a dose-dependent manner, partially via induction of reactive oxygen species, whereas inhibition of CASC9 expression enhanced gemcitabine-induced oxidative stress and apoptosis in pancreatic cancer cells. Furthermore, suppression of CASC9 level inhibited the expression of NRF2 and the downstream genes NQO1 and HO-1, and vice versa, indicating that CASC9 forms a positive feedback loop with NRF2 signaling and modulates the level of oxidative stress. Silencing CASC9 attenuated NF-κB pathway activation in pancreatic cancer cells and synergistically enhanced the cytotoxic effect of gemcitabine chemotherapy in vivo. In conclusion, our findings suggest that CASC9 plays a key role in driving resistance to gemcitabine through a reciprocal loop with the NRF2-antioxidant signaling pathway and by activating NF-κB signaling. Our study reveals potential targets that can effectively reverse resistance to gemcitabine chemotherapy.

Organophosphonic Acid-Regulating Assembly of PV-SbIII Polyoxotungstate and Its Potential in Building a Dual-Signal Readout Electrochemical Aptasensor for Carcinogen Detection.

Template-directed assembly of giant cluster-based nanomaterials is an everlasting theme in cluster science. In this work, ethylenediamine tetramethylphosphonic acid [H8EDTPA = (POCH2(OH)2)4C2H4N2] and [B-α-SbW9O33]9- were, respectively, used as an organic template and an inorganic template to prepare an organophosphonic acid-regulating PV-SbIII-heteroatom-inserted polyoxotungstate aggregate [H2N(CH3)2]5Na11H9[CeW4O10(HEDTPA)SbW15O50][B-α-SbW9O33]2·36H2O (1). Noteworthily, organophosphonic acid ligand not only works as an organic template leading to the assembly of a [HEDTPASbW15O50]14- building block but also further bridges the sandwich-type [CeW4O10(B-α-SbW9O33)2]11- entity. To extend its potential application in electrochemical sensing properties, we prepared a three-dimensional 1@EGO composite (EGO = reduced graphene oxide functionalized by ethylenediamine) with porous architecture and a prominent conducting ability. Furthermore, the 1@EGO composite was explored as a modification material for glassy carbon electrodes to build a dual-signal readout electrochemical aptasensor for carcinogens, which shows much better detection performance for aflatoxin B1 compared with traditional single-signal biosensors.

Resistant starch intake alleviates collagen-induced arthritis in mice by modulating gut microbiota and promoting concomitant propionate production.

Gut dysbiosis precedes clinic symptoms in rheumatoid arthritis (RA) and has been implicated in the initiation and persistence of RA. The early treatment of RA is critical to better clinical outcome especially for joint destruction. Although dietary interventions have been reported to be beneficial for RA patients, it is unclear to whether diet-induced gut microbiome changes can be a preventive strategy to RA development. Here, we investigated the effect of a high fiber diet (HFD) rich with resistant starch (RS) on collagen-induced arthritis (CIA) and gut microbial composition in mice. RS-HFD significantly reduced arthritis severity and bone erosion in CIA mice. The therapeutic effects of RS-HFD were correlated with splenic regulatory T cell (Treg) expansion and serum interleukin-10 (IL-10) increase. The increased abundance of Lactobacillus and Lachnoclostridium genera concomitant with CIA were eliminated in CIA mice fed the RS-HFD diet. Notably, RS-HFD also led to a predominance of Bacteroidetes, and increased abundances of Lachnospiraceae_NK4A136_group and Bacteroidales_S24-7_group genera in CIA mice. Accompanied with the gut microbiome changes, serum levels of the short-chain fatty acid (SCFA) acetate, propionate and isobutyrate detected by GC-TOFMS were also increased in CIA mice fed RS-HFD. While, addition of ß-acids from hops extract to the drinking water of mice fed RS-HFD significantly decreased serum propionate and completely eliminated RS-HFD-induced disease improvement, Treg cell increase and IL-10 production in CIA mice. Moreover, exogenous propionate added to drinking water replicated the protective role of RS-HFD in CIA including reduced bone damage. The direct effect of propionate on T cells in vitro was further explored as at least one mechanistic explanation for the dietary effects of microbial metabolites on immune regulation in experimental RA. Taken together, RS-HFD significantly reduced CIA and bone damage and altered gut microbial composition with concomitant increase in circulating propionate, indicating that RS-rich diet might be a promising therapy especially in the early stage of RA.

Three Lanthanide-Functionalized Antimonotungstate Clusters with a {Sb4O4Ln3(H2O)8} Core: Syntheses, Structures, and Properties.

Three lanthanide (Ln)-functionalized antimonotungstate (AT) clusters with a {Sb4O4Ln3(H2O)8} core [H2N(CH3)2]14Na8H16[Sb4O4Ln3(H2O)8W2O4(H2O)2(B-α-SbW9O33)4]2·87H2O [Ln = Dy3+ (1), Ho3+ (2), Y3+ (3)] were synthesized in an acidic aqueous solution. Their molecular structural unit comprises two {Sb4O4Ln3(H2O)8}-core-incorporated tetrameric [Sb4O4Ln3(H2O)8W2O4(H2O)2 (B-α-SbW9O33)4]19- polyanionic units, each of which is assembled from an unprecedented [Sb4O4Ln3(H2O)8W2O4(H2O)2]17+ heteroatom cluster surrounded by four trivacant [B-α-SbW9O33]9- subunits. What is noteworthy is that a tetrahedral {Sb4O4} cluster is located at the center of the polyanionic unit, as far as we know, which is very infrequent in multi-Ln-functionalized polyoxometalate chemistry. Solid-state luminescent properties and energy migration of AT ligands to Dy3+ and Ho3+ cations in 1 and 2 have been intensively probed at ambient temperature. By varying the exciting wavelength from 250 to 450 nm, the emitting color could vary from blue to yellow for 1 and blue to green-yellow for 2, separately. In addition, high catalytic activities and good reusability of 2 as a heterogeneous catalyst for oxygenation reaction of sulfides have been systematically performed.

Tricarboxylic-Ligand-Decorated Lanthanoid-Inserted Heteropolyoxometalates Built by Mixed-Heteroatom-Directing Polyoxotungstate Units: Syntheses, Structures, and Electrochemical Sensing for 17ß-Estradiol.

Organic-inorganic hybrid metal-oxide clusters have been pursued for many years, benefiting from their abundant structures and prominent performances. Upon our exploration, a family of unusual mixed-heteroatom (SbIII, PIII)-directing lanthanoid (Ln)-inserted heteropolyoxotungstates (Ln-HPOTs), [(CH3)2NH2]2Na7H3[Ln4(HPIII)W8(H2O)12(H2ptca)2O28][SbIIIW9O33]2·27H2O [Ln = Ce3+ (1), La3+ (2), Pr3+ (3)], functionalized by 1,2,3-propanetricarboxylic acid (H3ptca) was achieved. The intriguing trimeric [Ln4(HPIII)W8(H2O)12(H2ptca)2O28][SbIIIW9O33]212- polyanion was established by two trivacant [B-α-SbIIIW9O33]9- segments mounted on both sides and one rare [HPIIIW4O18]8- segment at the bottom, which are bridged via an organic-inorganic hybrid [W4Ln4(H2O)12O10(H2ptca)2]14+ central moiety. Such Ln-HPOTs involving dual-heteroatom-directing mixed building blocks, and even simultaneously modified by tricarboxylic ligands, are rather unseen in polyoxometalate chemistry. Moreover, the detection of 17ß-estradiol through a 1-based electrochemical biosensor has been explored, demonstrating a low detection limit (7.08 × 10-14 M) and considerable stability.

Efficacy of extended versus standard lymphadenectomy in pancreatoduodenectomy for pancreatic head adenocarcinoma. An update meta-analysis.

BACKGROUND: Surgical resection is the only possible cure for pancreatic cancer, it remains controversial whether extend lymphadenectomy in pancreatoduodenectomy (EPD) is better than standard lymphadenectomy in pancreatoduodenectomy (SPD). The aim of this study was to compare the efficacy of EPD with SPD for pancreatic head adenocarcinoma. METHODS: A specific search of online databases including PubMed, Web of Science, Embase, and Cochrane library was conducted from January 1990 to October 2018. Relative perioperative outcomes were synthesized. Single-arm meta-analysis was also performed. RESULTS: A total of eight studies involving 687 (342 vs 345) patients were included for analysis in our study. The number of lymph nodes harvested [24.54 vs 13.29; weighted mean difference (WMD) -10.69, P = 0.000], operative time (469.84 min vs 354.85 min; WMD -99.09, P = 0.000), and diarrhea (postoperative three months) [45.1% vs 18.2%; odds radio (OR) 0.20, P = 0.014] were significantly higher in patients who underwent EPD than SPD. The perioperative complications (35% vs 28.8%; OR 0.79, P = 0.186), tumor size (3.27 cm vs 3.248 cm; WMD -0.11, P = 0.256), lymph node metastasis (66% vs 55.9%; OR 0.71, P = 0.105), and positive margin (10.4% vs 11.3%; OR 1.28, P = 0.392) were no significant differences between EPD group and SPD group. Extended lymphadenectomy in pancreatoduodenectomy dose not contribute to the overall survival of patients with adenocarcinoma of the pancreatic head [hazard ratio (HR) 0.95; 95% CI 0.78-1.15; P = 0.61]. CONCLUSION: The update meta-analysis shows that EPD failed to improve the overall survival, may even lead to increased morbidity.

Paenibacillus assamensis in Joint Fluid of Man with Suspected Tularemia, China.

Paenibacillus assamensis is a bacterium usually found in warm springs. We detected P. assamensis in a man with suspected tularemia. The strain isolated from the man's knee joint fluid was identified as P. assamensis after analysis of a homologous sequence of the 16S rRNA gene.

Overexpressed HSPA2 correlates with tumor angiogenesis and unfavorable prognosis in pancreatic carcinoma.

Heat shock-related 70-kDa protein 2 (HSPA2) is known to correlate with tumor development and progression. This work aimed to determine the expression and prognostic roles of HSPA2 in pancreatic carcinoma. Tumor and their corresponding non-tumor tissues were obtained from 80 patients with pancreatic carcinoma. HSPA2 expression in tumor and non-tumor tissues was evaluated by immunohistochemistry. Expression of vascular endothelial growth factor (VEGF) and CD31 in tumor tissues were also evaluated by immunostaining. The relationships of HSPA2 with clinicopathological data, tumor angiogenesis and prognosis were analyzed. The results showed that HSPA2 expression was significantly elevated in tumor tissues compared with adjacent non-tumor tissues (P < 0.05). High HSPA2 expression was significantly associated with aggressive clinicopathological characteristics. HSPA2 staining was positively correlated with VEGF (r = 0.466, P < 0.001) and microvessel density (MVD) (r = 0.366, P = 0.001) in tumor tissues. Patients with high HSPA2 expression showed worse relapse-free survival (RFS) (P < 0.001) and overall survival (OS) (P < 0.001) than those with low HSPA2 expression. Multivariate analysis indicated that high HSPA2 expression was an independent predictor for poor RFS (P < 0.001) and OS (P = 0.001). Taken together, overexpressed HSPA2 is correlated with tumor angiogenesis and poor prognosis in pancreatic carcinoma. HSPA2 may play an important role in tumor progression, and serve as a potential biomarker for the prediction of adverse prognosis in pancreatic carcinoma.

Deep lymph node enlargement and renal failure caused by hypercalcemia­associated sarcoidosis: A case report.

Sarcoidosis is a rare disease that severely affects the lungs and superficial lymph nodes. In addition, this disease can also affect the skin, eyes and kidneys to varying degrees. The present report described a 32-year-old male patient who was admitted to Renmin Hospital of Wuhan University (Wuhan, China) due to joint pain in the extremities. He was diagnosed with uncorrectable hypercalcemia. A lymph node biopsy revealed the hypercalcemia to be associated with sarcoidosis, with the patient also demonstrating renal failure and lymph node enlargement. Administration of glucocorticoids provided benefits in terms of both primary and recurrent sarcoidosis, which also improved and preserved renal function. After being prescribed with oral prednisone treatment, blood calcium levels returned to normal, which indicated markedly improving renal function. However, the discontinuation of glucocorticoids for 2 months resulted in increased serum calcium and creatinine levels, both of which returned to abnormal levels. Overall, the present case report suggests that clinicians should actively perform sarcoidosis treatment in clinical practice to overcome any unexpected results associated with organ damage.

Mapping and analysis of protein and gene profiles identify the important role of TGF-ß in synovial invasion in pigmented villonodular synovitis.

BACKGROUND: Pigmented villonodular synovitis (PVNS) is a rare benign proliferative disease affecting the soft tissue lining the synovial joints and tendons. Its etiology is poorly understood, largely limiting the availability of current therapeutic options. Here, we mapped the synovial gene and protein profiles of patients with PVNS, revealed a link between synovial inflammation and invasion, and elucidated the potential molecular mechanism involved. METHODS: The expression of synovial genes from six control individuals, seven OA patients, and nineteen PVNS patients was analyzed via RNA sequencing. Protein profiles from five control individuals, ten OA patients, and thirty-two PVNS patients were analyzed using label-free proteomics. Microarray and RT-PCR analyses and immunohistochemical staining were used to evaluate inflammatory cytokine and target gene expression levels in synovial tissue, epithelial cells, and synovial fibroblasts (FLSs) derived from PVNS tissue. Various signaling pathway inhibitors, siRNAs, and western blots were used for molecular mechanism studies. Transwell migration and invasion assays were subsequently performed. RESULTS: In total, 522 differentially expressed proteins were identified in the PVNS tissues. By integrating RNA sequencing and microarray analyses, significant changes in the expression of EMT-related genes, including TGFBI, N-cadherin, E-cadherin, SNAIL, and TWIST, were confirmed in the PVNS tissue compared to the control tissue. In vitro, TGF-ß induced EMT and increased epithelial cell migration and invasion. Moreover, TGF-ß not only promoted interactions between epithelial cells and FLSs but also directly increased the migration and invasion abilities of FLSs by activating the classical Smad2/3 and nonclassical JNK/AKT signaling pathways. CONCLUSION: This study provides overall protein and gene profiles of PVNS and identifies the crucial role of TGF-ß in synovial invasion pathology. Exploring the related molecular mechanism may also reveal a new strategy or target for PVNS therapy.