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Wide phthalate exposure has been associated with both declines in renal function and an elevated risk of mortality. Whether phthalate-associated risk of premature mortality differs by renal function status remains unclear. This study included 9605 adults from the U.S. National Health and Nutrition Examination Survey. Urinary concentrations of 11 phthalate metabolites were assessed using high-performance liquid chromatography-electrospray ionization tandem mass spectrometry. According to estimated glomerular filtration rate (eGFR), participants were grouped as having normal or modestly declined renal functions, or chronic kidney disease (CKD). Multivariable Cox regression models estimated all-cause mortality associated with phthalate exposure, overall and by renal function status. Overall, Mono-n-butyl phthalate (MnBP), Mono-benzyl phthalate (MBzP), Mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and Mono-(2-ethyl-5-carbox-ypentyl) phthalate (MECPP) were associated with an elevated risk of mortality (P -trend across tertile <0.05). Moreover, significant interactions were observed between eGFR and MEHHP, MEOHP, MECPP, DEHP in the whole population (P for interactions <0.05). After stratification by renal function, total Di (2-ethylhexyl) phthalate (DEHP) was additionally found to be associated with mortality risk in the CKD group (HR = 1.12; 95% CI: 1.01, 1.25). Co-exposure to the 11 phthalate metabolites was associated with a higher risk of all-cause mortality in the CKD (HR = 1.47; 95% CI: 1.18, 1.84) and modestly declined renal function group (HR = 1.25; 95% CI: 1.09, 1.44). The associations between phthalate exposure and risk of all-cause mortality were primarily observed in CKD patients, reinforcing the need for monitoring phthalate exposure in this patient population. • Higher phthalate metabolites were associated with a higher risk of mortality. • The associations between DEHP and mortality were stronger among those with CKD. • Co-exposure to phthalates was associated with increased mortality among those in CKD. [ABSTRACT FROM AUTHOR]

In indirect co-culture system, chondrocytes can induce differentiation of bone marrow mesenchymal stem cells (BMSCs) to chondrocytes without additional inducer. The participation of microRNAs (miRNAs) may take part in the chondrogenic differentiation. Present study aimed to investigate the effect and mechanism of chondrocytes-derived exosomal miRNA in BMSCs chondrogenic differentiation. Our data showed that miR-8485 was the exosomal miRNA derived from chondrocytes and transmitted to BMSCs. Functionally, miR-8485 silence in chondrocytes impaired exosome-induced chondrogenic differentiation of BMSCs. Mechanistically, exosomal miR-8485 targeted GSK3B to repress GSK-3β expression and targeted DACT1 to induce p-GSK-3β (Ser9), activating Wnt/β-catenin pathways. Our study firstly showed that chondrocytes-derived exosomal miR-8485 regulated the Wnt/β-catenin pathways to promote chondrogenic differentiation of BMSCs, providing innovative thoughts for cartilage reconstruction. • miR-8485, an exosomal miRNA, could be transmit from chondrocytes to BMSCs. • miR-8485 played a role in exosome-induced chondrogenic differentiation of BMSCs. • miR-8485 targeted GSK3B by repressing GSK-3β expression and inducing GSK-3β phosphorylation to active Wnt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

We study the limiting behavior of singular values of a lag- τ sample auto-correlation matrix R τ ϵ of large dimensional vector white noise process, the error term ϵ in the high-dimensional factor model. We establish the limiting spectral distribution (LSD) that characterizes the global spectrum of R τ ϵ , and derive the limit of its largest singular value. All the asymptotic results are derived under the high-dimensional asymptotic regime where the data dimension and sample size go to infinity proportionally. Under mild assumptions, we show that the LSD of R τ ϵ is the same as that of the lag- τ sample auto-covariance matrix. Based on this asymptotic equivalence, we additionally show that the largest singular value of R τ ϵ converges almost surely to the right end point of the support of its LSD. Based on these results, we further propose two estimators of total number of factors with lag- τ sample auto-correlation matrices in a factor model. Our theoretical results are fully supported by numerical experiments as well. [ABSTRACT FROM AUTHOR]

Let ( ε j ) j ≥ 0 be a sequence of independent p -dimensional random vectors and τ ≥ 1 a given integer. From a sample ε 1 , … , ε T + τ of the sequence, the so-called lag- τ auto-covariance matrix is C τ = T − 1 ∑ j = 1 T ε τ + j ε j t . When the dimension p is large compared to the sample size T , this paper establishes the limit of the singular value distribution of C τ assuming that p and T grow to infinity proportionally and the sequence has uniformly bounded ( 4 + δ ) th order moments. Compared to existing asymptotic results on sample covariance matrices developed in random matrix theory, the case of an auto-covariance matrix is much more involved due to the fact that the summands are dependent and the matrix C τ is not symmetric. Several new techniques are introduced for the derivation of the main theorem. [ABSTRACT FROM AUTHOR]

Abstract: Insecticide resistance in parasitoids is a trait of value for a better integration of biological and chemical controls in certain situations. However, practical use of this trait has been rare and may have been partly hindered by the very low rate of success in artificial selection of insecticide resistance in parasitoids. In this study, we explored the feasibility of promoting selection of resistance to spinosad in the parasitoid Cotesia plutellae by integrating resistance of hosts to the insecticide into the selection process. Five colonies of C. plutellae were established from the same field populations and reared in strains of its host, the diamondback moth, either susceptible or highly resistant to the insecticide. These colonies were exposed to selection by spinosad in larval, pupal or adult stage. Two colonies, which were reared in either susceptible or resistant hosts and exposed to selection at adult stage, developed only marginal levels of resistance after 22 and 28 selection cycles, respectively. A colony that was reared on resistant hosts and exposed to selection at the pupal stage failed to develop resistance after 12 selection cycles. In contrast, a colony that was reared on resistant hosts and exposed to selection at the larval stage inside the host larva developed 21.7-fold resistance after 22 selection cycles, a level of resistance that may enable the parasitoid to survive field application rate. These results demonstrate that exposure of parasitoids to selection pressure at the larval stage harbored by resistant hosts can effectively promote the response to selection by the parasitoids and help produce potentially useful resistant strains of parasitoids for field application. [Copyright &y& Elsevier]

Nonalcoholic fatty liver disease (NAFLD) represents a global health problem. Impaired autophagy has been implicated in the pathogenesis of NAFLD, and CD147 is recognized to regulate lipid metabolism in a variety of cell types. This study was initiated with the aim to identify molecular makers expressed in hepatocytes that are significantly altered during the pathogenesis of NAFLD and closely associated with hepatic steatosis and autophagy. In this study, CD147 was found to be significantly associated with steatosis and autophagy in both clinical patients with NAFLD and NAFLD mouse models. In high-fat-diet-induced NAFLD mice, hepatic-specific CD147 knockout markedly reduced body weight, liver weight, serum aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT), and liver steatosis. In addition, hepatic CD147 gene knockout noticeably promoted autophagy in NAFLD mice (LC3 expression was increased with decreased P62 expression; molecular markers of autophagy). Moreover, we found that CD147 expression was significantly associated with AKT/mTOR signaling pathway; thus, suggesting that CD147 is involved in the regulation of autophagy and steatosis in NAFLD. In conclusion, this study has provided in vivo evidence for the putative role of CD147 in the pathogenesis of NAFLD and a valuable experimental basis for considering CD147 as a therapeutic target to prevent hepatic steatosis in patients with NAFLD. • CD147 is a potential target of treatment in the early stage of nonalcoholic fatty liver disease. • The increased expression of hepatic CD147 is accompanied by increased steatosis and decreased autophagy in NAFLD patients. • Hepatic CD147 gene knockout attenuates liver steatosis and alleviates liver autophagy in high-fat-diet-induced NAFLD mice. • CD147 reduces liver autophagy and alters the AKT/mTOR signaling pathway in high-fat-diet-induced NAFLD mice. [ABSTRACT FROM AUTHOR]

[Display omitted] • Two series of novel tryptanthrin derivatives were designed, synthesized and biological evaluation. • n1 showed reversible selective inhibitory activity for AChE. • n1 significantly inhibited the aggregation of Aβ. • n1 presented good neuroprotective effect and anti-neuroinflammatory activity. • n1 displayed proper blood–brain barrier permeability. • n1 improved cognitive impairment in scopolamine-induced mouse models. Two novel series of tryptanthrin (TRYP) derivatives were designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD). Inhibition assay against cholinesterase (ChE) indicated that these derivatives can act as acetylcholinesterase (AChE) inhibitors with selectivity over butyrylcholinesterase (BuChE). Among them, n1 exhibited the most excellent ChE inhibitory potency (AChE, IC 50 = 12.17 ± 1.50 nM; BuChE, IC 50 = 6.29 ± 0.48 μΜ; selectivity index = 517). Molecular docking studies indicated that compound n1 can interact with amino acid residues in the catalytic active site and peripheral anionic site of AChE and the molecular dynamics (MD) simulation studies demonstrated that the AChE– n1 complex had good stability. N1 also exhibited anti-amyloid-β (Aβ) aggregation (63.48 % ± 1.02 %, 100 μΜ) and anti-neuroinflammation activity (NO, IL-1β, TNF-α; IC 50 = 2.13 ± 0.54 μΜ, 2.21 ± 0.37 μΜ, 2.47 ± 0.07 μΜ, respectively), and n1 had neuroprotective and metal-chelating properties. Further studies indicated n1 had proper blood–brain barrier permeability in the Parallel artificial membrane permeation assay. In vivo studies found that n1 effectively improved learning and memory impairment in scopolamine-induced AD mouse models. Nissl staining of mice hippocampal tissue sections revealed that n1 restored neuronal cells in the hippocampus CA3 and CA1 regions. These findings suggested that n1 can be a promising compound for further development of multifunctional agents for AD treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • TLR4/MD2 inhibitors were obtained through receptor structure-based virtual screening. • Hit 94 showed good anti-inflammatory activity. • Hit 94 inhibits activation of the NF-κB/MAPK signaling pathway. • Hit 94 has therapeutic effect in adjuvant-arthritis (AIA) rats. In this study, a receptor structure-based virtual screening strategy was constructed using a computer-aided drug design. First, the compounds were filtered based on the Lipinski pentad and adsorption, distribution, metabolism, excretion, and toxicity profiles. Then, receptor structure-based pharmacophore models were constructed and screened. Finally, the in vitro toxicity and anti-inflammatory activities of hit compounds were initially evaluated to investigate their in vitro anti-inflammatory effects and mechanisms of action. The results revealed that hit 94 had the best anti-inflammatory activity and low toxicity while inhibiting the activation of Toll-like receptor (TLR) 4/myeloid differentiation factor 2 (MD2)-associated signaling pathways of nuclear factor-κB and mitogen-activated protein kinase. In vivo adjuvant arthritis results also revealed that hit 94 ameliorated foot swelling to a greater extent in rats compared with the positive control drug indomethacin. These results suggest that hit 94 can be used as a potential TLR/MD2 inhibitor for inflammatory diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] • Design and synthesis of two new fluorinated CPT derivatives, 9-fluorocamptothecin ( A1 ) and 7-ethyl-9-fluorocamptothecin ( A2 ). • Compounds A1 and A2 have effective activities against six human cancer cell lines in vitro , with IC 50 values ranging from 0.12 μM to 0.77 μM and 0.006 μM to 0.25 μM. • Compounds A1 and A2 exhibit enhanced anti-tumor activity in both primary and xenograft HCC mouse models compared to topotecan. • Compounds A1 and A1 not only inhibit enzymatic activity of topoisomerase I, but also promote its degradation, thus playing an anti-tumor role. Primary liver cancer is one of the most common malignant cancers of the digestive system that lacks effective chemotherapeutic drugs in clinical settings. Camptothecin (CPT) and its derivatives have been approved for cancer treatment; however, their application is limited by their systemic toxicity. For lead optimization in new drug discovery stages, fluorination is an effective and robust approach to increase the bioavailability and optimize the pharmacokinetics of candidate compounds, thereby improving their efficacy. To obtain new and highly active CPT derivatives, we designed, synthesized, and evaluated two new fluorinated CPT derivatives, 9-fluorocamptothecin ( A1 ) and 7-ethyl-9-fluorocamptothecin ( A2 ), in this study. In vitro , A1 and A2 exhibited more robust anti-tumor activity than topotecan (TPT) in various cancer cells, particularly hepatocellular carcinoma (HCC) cells. In vivo , A1 and A2 exhibited greater anti-tumor activity than TPT in both AKT/Met induced primary HCC mouse models and implanted HepG2 cell xenografts. Acute toxicity tests revealed that A1 and A2 were not lethal and did not cause significant body weight loss at high doses. Moreover, A1 and A2 exhibited no significant toxicity in the mouse liver, heart, lung, spleen, kidney, and hematopoietic systems at therapeutic doses. Mechanistically, A1 and A2 blocked HCC cell proliferation by inhibiting the enzymatic activity of Topo I, subsequently inducing DNA damage, cell cycle arrest, and apoptosis. In summary, our results indicate that fluorination improves the anti-tumor activity of CPT while decreasing its toxicity and highlight the application potential of fluorination products A1 and A2 in clinical settings. [ABSTRACT FROM AUTHOR]

Abstract Background HA modified by bisphosphonate (BP) (HA-BP) was synthesized by chemical reaction and possessed promising properties such as self-healing, injection ability, and strong adhesion. The main aim of this study was to confirm its role in promoting osteogenic differentiation in vitro and bone regeneration in vivo. Methods The cell biocompatibility of this material was determined using the CCK-8 assay. Alkaline phosphatase (ALP), osteocalcin (OT), vascular endothelial growth factor (VEGF), and collagen I were assessed by quantitative real-time polymerase chain reaction (Q-PCR) in the treated group. The number and density of calcium nodules and ALP were evaluated by Alizarin Red staining and ALP staining. We have successfully developed an animal model simulating osteonecrosis of the femoral head (ONFH). Utilizing this animal model, the impact of HA-BP/CaP on bone formation was assessed. The amount of bone regeneration at 1 and 2 months after HA-BP/CaP injection was estimated by micro-computed tomography (micro-CT) analysis and H&E, collagen I, and periostin staining. Results The number of cells gradually increased in the experimental group over time and was close to that of the blank control group. ALP, collagen I, and VEGF expression was significantly higher in the experimental group than in the blank group (VEGF, ALP, both ** p < 0.01; collagen I, *** p <0.001). In addition, the number and density of calcium nodules and ALP was clearly greater in the material group than in the control group. The quantification analysis showed that the mineral contents of regenerated bone at 1 and 2 months after HA-BP/CaP injection were significantly greater than those in the control group, according to micro-CT evaluation (** p <0.01). The amount of organic components in the HA-BP/CaP group was greater than that in the control group after decalcification and H&E staining. In addition, collagen I and periostin staining further confirmed the results of H&E staining. Conclusion This material can boost proliferation and osteogenic differentiation of MC3T3-E1 cells in vitro. It can intensely accelerate bone regeneration in vivo , which is a promising strategy for tissue engineering. Highlights • We have successfully established a model of ONFH (osteonecrosis of the femoral head) • A non-covalent crosslinked hybrid hydrogel could boost proliferation and osteogenic differentiation of MC3T3-E1 cells in vitro. • This biomaterial with injectable and shear-thinning abilities could intensely accelerate bone regeneration in vivo. • Other bioactive molecules may be loaded onto the biomaterial, such as VEGF and bone morphogenetic protein-2. [ABSTRACT FROM AUTHOR]

[Display omitted] • HDAC6is capped by flavonoid or flavonoid-analogous moieties were discovered. • Azaflavone-capped compound 20 exerted single-digit nanomolar HDAC6 inhibitory activity and favorable specificity. • It exhibited submicromolar anti-proliferative efficacies against all the tested tumor cell lines. • It remarkably alleviated immune escape-related STAT3 signaling and attenuated PD-L1 expression. • It displayed acceptable half-life and exposure following intravenous administration in SD rats. Specific HDAC6 inhibitors (HDAC6is) simultaneously harboring anti-proliferative and immunomodulatory properties may prohibit tumor progression via intrinsic and immune driven effects. Herein, built upon the structurally novel lead TFH-7, structure–activity relationship study culminated in the identification of azaflavone-capped compound 20 , which exhibited comparable HDAC6 inhibitory activity (IC 50 = 8.5 nM) to that of Tubastatin A, a highly selective HDAC6i, as well as favorable subtype specificity. Importantly, concurrent with its impressive anti-proliferative efficacy against several solid tumor cell lines, 20 remarkably alleviated the transduction of immune-related STAT3 signaling and attenuated the expression of immunosuppressive checkpoint PD-L1 at submicromolar concentration, highlighting the immunomodulatory properties. Moreover, consistent with its favorable subtype selectivity, 20 displayed low cytotoxicity against normal human umbilical vein endothelial cells, revealing a promising safety profile. Following the intravenous administration, it demonstrated acceptable elimination half-life and exposure in Sprague-Dawley rats. Hence, the extensive functional investigation or structural modification of 20 is valuable. [ABSTRACT FROM AUTHOR]

5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3 H -1,2-dithiol-3-one (COH-203) is a novel synthesized analogue of combretastatin A-4 that can be classified as a microtubule inhibitor. In this study, we evaluated the anti-hepatoma effect of COH-203 in vitro and in vivo and explored the underlying molecular mechanisms. COH-203 was shown to be more effective in inhibiting the proliferation of liver cancer cells compared with normal liver cells. COH-203 also displayed potent anti-tumor activity in a hepatocellular carcinoma xenograft model without significant toxicity. Mechanistic studies demonstrated that treatment with COH-203 induced mitotic arrest by inhibiting tubulin polymerization in BEL-7402 liver cancer cells. Long-term COH-203 treatment in BEL-7402 cells led to mitotic slippage followed by senescence via the p14 Arf –p53–p21 and p16 INK4α –Rb pathways. Furthermore, suppression of p53 via pifithrin-α (p53 inhibitor) and p53-siRNA attenuated COH-203-induced senescence in BEL-7402 cells, suggesting that COH-203 induced senescence p53-dependently. In conclusion, we report for the first time that COH-203, one compound in the combretastatin family, promotes anti-proliferative activity through the induction of p-53 dependent senescence. Our findings will provide a molecular rationale for the development of COH-203 as a promising anti-tumor agent. [ABSTRACT FROM AUTHOR]

[Display omitted] • Compound 3l showed good anti-inflammatory activity. • Compound 3l disrupts TLR4/MD-2 dimerization and homodimerization of TLR4. • Compound 3l blocks the NF-κB/MAPK signaling pathway by preventing TLR4/MD-2. • Compound 3l had a significant therapeutic effect on adjuvant-induced arthritis (AIA) in rats. In this study, a series of 8-quinolinesulfonamide derivatives was synthesized, and their anti-inflammatory activity was evaluated. Among them, compound 3l was found to be the best anti-inflammatory agent, with IC 50 values of 2.61 ± 0.39, 9.74 ± 0.85, and 12.71 ± 1.34 μM against NO, TNF-α and IL-1β production respectively. And 3l could significantly prevent lipopolysaccharide (LPS)-induced expression of inflammatory mediators (iNOS and COX-2). Molecule docking results showed that 3l could bind to the LPS binding site of toll-like receptor 4 (TLR4)/MD-2, and 3l was then identified as TLR4/MD-2 inhibitor by co-immunoprecipitation (co-IP) and cellular thermal shift assay (CTESA). Preliminary mechanism studies indicated that 3l could prevent TLR4 from being activated by disrupting TLR4/MD-2 heterodimerization and TLR4 homodimerization, thereby blocking the activation of the NF-κB/MAPK signaling pathway. Furthermore, observation of rat foot swelling, joint pathology and serum inflammatory cytokine levels proved that compound 3l had a significant therapeutic effect on adjuvant-induced arthritis (AIA) in rats in vivo. These results indicated that compound 3l is a potential anti-inflammatory agent, from which more effective anti-inflammatory drugs could be developed. [ABSTRACT FROM AUTHOR]

Abstract: Staphylococcus enterotoxin A (SEA) stimulates T cells bearing certain TCR β-chain variable regions, when bound to MHC-II molecules, and is a potent inducer of CTL activity and cytokines production. To decrease toxicity of SEA to the normal MHC-II+ cells and to localize the immune response induced by SEA to the tumor site, my colleague previously genetically fused SEA with B7.1 transmembrane region (named as SEAtm) to make SEA express on the surface of tumor cells and tumor cells modified with SEAtm could induce efficient antitumor immunity in vitro. The tumor cell vaccines modified with multiple immune activators frequently elicited stronger antitumor immune responses than single-modified vaccines. In this study, we modified the tumor cell vaccine with B7.1 and SEAtm to improve efficiency in the application of SEA. First, SEAtm gene was subcloned from recombinant plasmid pLXSNSEP by PCR and murine B7.1 gene was cloned from splenocytes derived from C57BL/6 mice by RT-PCR. Then, the eukaryotic co-expression vector of SEA and murine B7.1 gene was constructed and named as pcDNA-BIS. B16 cell lines stably expressing SEA and/or B7.1 were established by screening with G418 after transfection and inactivated for the preparation of tumor cell vaccines to treat mice bearing established B16 tumors. The results indicated that the dual-modified tumor cell vaccine B16/B7.1+SEAtm (B16-BIS) elicited significantly stronger antitumor immune responses in vivo when compared with the single-modified tumor cell vaccines B16/B7.1 (B16-B7.1) and B16/SEAtm (B16-SEAtm), and supported the feasibility and effectiveness of the dual-modified tumor cell vaccine with superantigen and co-stimulatory molecule. [Copyright &y& Elsevier]

In this study, response surface methodology (RSM) and two artificial neural networks (ANN), multi-layer perceptron (MLP) and radial basis function (RBF), were used for the first time to model and optimize the extraction conditions of phenolic compounds in kidney beans in order to compare and establish effective prediction models. A total of 40 experiments were performed to screen for variables. The highest amount of polyphenols (917.2 mg GAE/100 g DW) and the strongest antioxidant activity (56.03 μmol Trolox/g DW) were obtained under optimal extraction conditions (70 min extraction time, 53% acetone, and 37 mL/g solvent-to-solid ratio). Response values were close to the predicted values with prediction accuracy as RBF > MLP > RSM, indicating that ANN model has higher prediction accuracy than RSM. Furthermore, UPLC-QTOF-MS analysis of extracts under the optimal extraction conditions showed that there were 25 antioxidant compounds detected, 13 of which were proposed from kidney beans for the first time. • ANN and RSM were first applied to optimize kidney bean antioxidant extracts. • In terms of TPC and bioactivity, ANN had higher prediction accuracy than RSM. • Under optimal UAE conditions, TPC was up to 917.2 mg GAE/100 g DW. • Thirteen new antioxidant compounds were discovered in kidney beans by UPLC-QTOF-MS. [ABSTRACT FROM AUTHOR]