Poly[[diaqua-(µ(8)-benzene-1,2,4,5-tetra-carboxyl-ato)calciumzinc] monohydrate].

In the title complex, {[CaZn(C(10)H(2)O(8))(H(2)O)(2)]·H(2)O}(n), the Zn(II) ion is coordinated by four O atoms from four benzene-1,2,4,5-tetra-carboxyl-ate anions in a distorted tetra-hedral geometry. The Ca(II) ion is eight-coordinated by six O atoms from four benzene-1,2,4,5-tetra-carboxyl-ate anions and by two water mol-ecules in a distorted square-anti-prismatic geometry. The Ca(II) and Zn(II) ions and the lattice water mol-ecule are located on twofold rotation axes; the centroid of the benzene-1,2,4,5-tetra-carboxyl-ate anion is located on a centre of inversion. The µ(8)-bridging mode of the anion results in the formation of a three-dimensional structure with channels extending along [100] in which lattice water mol-ecules are situated. Inter-molecular O-H⋯O hydrogen bonds involving the coordinating and lattice water mol-ecules as donors and the carboxyl-ate O atoms and lattice water mol-ecules as acceptors are present in the structure.

The role of Wnt/ß-catenin signaling pathway in the pathogenesis and treatment of multiple myeloma (review).

Multiple myeloma (MM) is a refractory hematological malignancy characterized by aberrant accumulation of plasma cells. Patients with MM are susceptible to becoming resistant to chemotherapy, eventually leading to relapse. Progression of MM is largely dependent on the bone marrow microenvironment. Stromal cells in the bone marrow microenvironment secrete Wnt ligands to activate Wnt signaling in MM, which is mediated through the transcription regulator ß-catenin. In addition, Wnt/ß-catenin pathway encourages osteoblast differentiation and bone formation, dysregulation of which is responsible for proliferation and drug resistance of MM cells. As a result, direct inhibition or silencing of ß-catenin or associated genes in the Wnt/ß-catenin pathway has been proposed to be an effective therapeutic anti-MM strategy. However, the underlying regulatory mechanism of the Wnt/ß-catenin pathway in MM remains to be fully elucidated. Herein, we summarized research advances on the specific genes and molecular biology process of Wnt/ß-catenin pathway involved in tumorigenesis of MM, as well as the interaction with bone marrow microenvironment. Additionally, comprehensive summaries of drugs or small molecule inhibitors acting on Wnt/ß-catenin pathway and targeting MM were introduced. This review intends to provide an overview of theoretical supports for novel Wnt/ß-catenin pathway based treatment strategies in MM.

[Effects of long-term oral administration of ß-blocker on septic myocardial injury and prognosis].

OBJECTIVE: To investigate the effect of long-term oral administration of ß-blocker on septic myocardial injury and prognosis. METHODS: A retrospective study was conducted. Patients who were admitted to the emergency intensive care unit (EICU) and intensive care unit (ICU) of Tongde Hospital of Zhejiang Province from January 2015 to June 2020 were enrolled. A total of 289 patients who met the criteria of myocardial injury induced by sepsis were included in the analysis. Among them, 187 patients who had never taken ß-blocker within 3 months before diagnosis were divided in the non-ß-blocker group, and 102 patients who took ß-blocker daily for more than 3 months before diagnosis were in the ß-blocker group. The physiological and biochemical characteristics were compared between the two groups, including heart rate, mean arterial pressure (MAP) at the time of diagnosis, cardiac troponin I (cTnI), brain natriuretic peptide (BNP), MB isoenzyme of creatine kinase (CK-MB), blood lactic acid (Lac), central venous oxygen saturation (ScvO2), sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation II (APACHE II) score within 24 hours of diagnosis, left ventricular ejection fraction (LVEF), early and late mitral orifice diastolic peak flow velocity ratio (E/A), utilization rate of vasoactive drugs during hospitalization and 28-day mortality. RESULTS: The heart rate in the ß-blocker group at the time of diagnosis was significantly lower than that in the non-ß-blocker group (bpm: 107±8 vs. 110±7, P < 0.01), and the levels of cTnI and BNP within 24 hours of diagnosis were significantly lower than those in the non-ß-blocker group [cTnI (µg/L): 0.191 (0.220) vs. 0.291 (0.300), BNP (ng/L): 627 (133) vs. 690 (201), both P < 0.05]. However, there were no significant differences in MAP, CK-MB, Lac, ScvO2, SOFA score, APACHE II score, LVEF, E/A, vasoactive drug utilization rate, and 28-day mortality between the ß-blocker and non-ß-blocker groups [MAP (mmHg, 1 mmHg = 0.133 kPa): 70.6±3.9 vs. 69.9±3.8, CK-MB (µg/L): 4.24 (3.33) vs. 4.32 (3.13), Lac (mmol/L): 3.50 (1.80) vs. 3.50 (1.90), ScvO2: 0.729±0.032 vs. 0.735±0.041, SOFA score: 7.74±2.34 vs. 7.25±2.23, APACHE II score: 17.19±5.13 vs. 18.27±6.12, LVEF: 0.567±0.058 vs. 0.557±0.051, E/A: 0.71 (0.20) vs. 0.69 (0.20), vasoactive drug utilization rate: 60.8% (62/102) vs. 56.7% (106/187), 28-day mortality: 23.5% (24/102) vs. 25.7% (48/187), all P > 0.05]. CONCLUSIONS: Long-term oral administration of ß-blocker reduce myocardial injury in septic patients, and has no effect on disease severity and prognosis.

BUB1B and circBUB1B_544aa aggravate multiple myeloma malignancy through evoking chromosomal instability.

Multiple myeloma (MM) is an incurable plasma cell malignancy in the bone marrow characterized by chromosome instability (CIN), which contributes to the acquisition of heterogeneity, along with MM progression, drug resistance, and relapse. In this study, we elucidated that the expression of BUB1B increased strikingly in MM patients and was closely correlated with poor outcomes. Overexpression of BUB1B facilitated cellular proliferation and induced drug resistance in vitro and in vivo, while genetic targeting BUB1B abrogated this effect. Mechanistic studies unveiled that enforced expression of BUB1B evoked CIN resulting in MM poor outcomes mainly through phosphorylating CEP170. Interestingly, we discovered the existence of circBUB1B_544aa containing the kinase catalytic center of BUB1B, which was translated by a circular RNA of BUB1B. The circBUB1B_544aa elevated in MM peripheral blood samples was closely associated with MM poor outcomes and played a synergistic effect with BUB1B on evoking CIN. In addition, MM cells could secrete circBUB1B_544aa and interfere the MM microenvironmental cells in the same manner as BUB1B full-length protein. Intriguingly, BUB1B siRNA, targeting the kinase catalytic center of both BUB1B and circBUB1B_544aa, significantly inhibited MM malignancy in vitro and in vivo. Collectively, BUB1B and circBUB1B_544aa are promising prognostic and therapeutic targets of MM.

Suppression of steroid 5α-reductase type I promotes cellular apoptosis and autophagy via PI3K/Akt/mTOR pathway in multiple myeloma.

Steroid 5α-reductase type I (SRD5A1) is a validated oncogene in many sex hormone-related cancers, but its role in multiple myeloma (MM) remains unknown. Based on gene expression profiling (GEP) of sequential MM samples during the disease course, we found that the aberrant expression of SRD5A1 was correlated with progression and poor prognosis in MM patients. In this study, the oncogenic roles of SRD5A1 were validated in human MM cell lines (ARP1 and H929) and the xenograft MM model as well as the 5TMM mouse model. MTT and flow cytometry were used to assess MM cell proliferation, cell cycle, and apoptosis post inducible knockdown SRD5A1 by lentivirus-mediated short-hairpin RNA (shRNA). Transcriptomic sequencing, immunofluorescence, and western blot were used to investigate the effects of SRD5A1 suppression on cell apoptosis and autophagy. Mechanistically, SRD5A1 downregulation simultaneously regulated both the Bcl-2 family protein-mediated apoptosis and the autophagic process via PI3K/Akt/mTOR signaling pathway in MM cells. Meanwhile, the autophagy inhibitor (3-methyladenine) and SRD5A1 inhibitor (Dutasteride) were utilized to evaluate their anti-myeloma effect. Thus, our results demonstrated that SRD5A1 downregulation simultaneously regulated both the apoptosis and the autophagic process in MM cells. The dual autophagy-apoptosis regulatory SRD5A1 may serve as a biomarker and potential target for MM progression and prognosis.

Adaptive Neural Control of a Kinematically Redundant Exoskeleton Robot Using Brain-Machine Interfaces.

In this paper, a closed-loop control has been developed for the exoskeleton robot system based on brain-machine interface (BMI). Adaptive controllers in joint space, a redundancy resolution method at the velocity level, and commands that generated from BMI in task space have been integrated effectively to make the robot perform manipulation tasks controlled by human operator's electroencephalogram. By extracting the features from neural activity, the proposed intention decoding algorithm can generate the commands to control the exoskeleton robot. To achieve optimal motion, a redundancy resolution at the velocity level has been implemented through neural dynamics optimization. Considering human-robot interaction force as well as coupled dynamics during the exoskeleton operation, an adaptive controller with redundancy resolution has been designed to drive the exoskeleton tracking the planned trajectory in human brain and to offer a convenient method of dynamics compensation with minimal knowledge of the dynamics parameters of the exoskeleton robot. Extensive experiments which employed a few subjects have been carried out. In the experiments, subjects successfully fulfilled the given manipulation tasks with convergence of tracking errors, which verified that the proposed brain-controlled exoskeleton robot system is effective.

Targeting MK2 Is a Novel Approach to Interfere in Multiple Myeloma.

MAPKAPK2 (MK2), the direct substrate of p38 MAPK, has been well-acknowledged as an attractive drug target for cancer therapy. However, few studies have assessed the functions of it in multiple myeloma (MM). In the present study, MK2 expression of MM patients was analyzed by gene expression profiling (GEP) and array-based comparative genomic hybridization (aCGH). Several experiments in vitro including MTT assay, Western blot and flow cytometry analysis were performed to identify the function of MK2 in MM. In addition, we conducted mouse survival experiments to explain the effects of MK2 on MM in vivo. mRNA level of MK2 and chromosomal gain of MK2 locus in MM cells significantly increased compared to normal samples. Furthermore, MM patients with high expression of MK2 were associated with a poor outcome. Follow-up studies showed that MK2 exerted a remarkably positive effect on MM cell proliferation and drug-resistance. Further exploration focusing on MK2 inhibitor IV revealed its inhibitory action on MM growth and drug-resistance, as well as improving survival in mouse models. In addition, a combination of MK2 inhibitor IV and the key MM therapeutic agents including bortezomib, doxorubicin, or dexamethasone facilitated curative effects on inhibiting MM cell proliferation. Taken together, our study reveals the clinical relevance of MK2 inhibition in MM and demonstrates that targeting MK2 may afford a new therapeutic approach to MM.

Increasing the anticancer performance of bufalin (BUF) by introducing an endosome-escaping polymer and tumor-targeting peptide in the design of a polymeric prodrug.

A well-defined multifunctional brush-type polymeric prodrug covalently linked with an anticancer drug (bufalin, BUF), a tumor-targeting peptide (RGD), and an endosome-escaping polymer, poly(N,N-diethylaminoethyl methacrylate-co-butyl methacrylate (P(DEA-co-BMA)), was developed. Its anticancer performance against colon cancer was investigated in vitro and in vivo. Reversible addition-fragmentation transfer (RAFT) polymerization of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA), 2-((3-(tert-butoxy)-3-oxopropyl)thio)ethyl methacrylate (BSTMA), and 2-(2-bromoisobutyryloxy)ethylmethacrylate (BIEM) afforded the multifunctional random copolymer, P(OEGMA-co-BSTMA-co-BIEM), in which hydrophilic POEGMA can stabilize nanoparticles in water, PBSTMA can be converted into carboxyl groups, and PBIEM can be employed as a macromolecular atom radical transfer polymerization (ATRP) initiator. The ATRP of DEA and BMA using P(OEGMA-co-BSTMA-co-BIEM) as a macromolecular ATRP initiator led to the formation of the pH-responsive brush-type copolymer, P(OEGMA-co-BSTMA)-g-P(DEA-co- BMA). After hydrolysis by trifluoroacetic acid and post-functionalization the final polymeric prodrug, P(OEGMA-co-BUF-co-RGD)-g-P(DEA-co-BMA), was obtained with a drug content of ∼7.8 wt%. P(OEGMA-co-BUF-co-RGD)-g-P(DEA-co-BMA) can be assembled into nanoparticles (BUF- NP-RGD) in aqueous solution with a diameter of 148.4 ±â€¯0.7 nm and a zeta potential of -7.6 ±â€¯0.4 mV. BUF-NP-RGD exhibited controlled drug release in the presence of esterase. Additionally, P(OEGMA-co- BSMA)-g-P(DEA-co-BMA) showed a significant hemolysis effect at a pH comparable to that of endosomes/lysosomes. Cell viability and a tumor-bearing nude mouse model were employed to evaluate the anticancer efficacy of BUF-NP-RGD. It was revealed that BUF-NP-RGD showed improved anticancer performance compared with that of free BUF both in vitro and in vivo. Histological and immunochemical analysis further demonstrated that BUF-NP-RGD exhibited improved cell apoptosis, angiogenesis inhibition, and an anti-proliferation effect.

Zuo Jin Wan Reverses DDP Resistance in Gastric Cancer through ROCK/PTEN/PI3K Signaling Pathway.

Gastric cancer (GC) is the third leading cause of cancer-related death. Chemotherapy resistance remains the major reason for GC treatment failure and poor overall survival of patients. Our previous studies have proved that Zuo Jin Wan (ZJW), a traditional Chinese medicine (TCM) formula, could significantly enhance the sensitivity of cisplatin (DDP)-resistant gastric cancer cells to DDP by inducing apoptosis via mitochondrial translocation of cofilin-1. However, the underlying mechanism remains poorly understood. This study aimed to evaluate the effects of ROCK/PTEN/PI3K on ZJW-induced apoptosis in vitro and in vivo. We found that ZJW could significantly activate the ROCK/PTEN pathway, inhibit PI3K/Akt, and promote the apoptosis of SGC-7901/DDP cells. Inhibition of ROCK obviously attenuated ZJW-induced apoptosis as well as cofilin-1 mitochondrial translocation, while inhibition of PI3K had the opposite effects. In vivo, combination treatment of DDP and ZJW (2000 mg/kg) significantly reduced tumor growth compared with DDP alone. Moreover, the combined administration of ZJW and DDP increased the expression of cleaved ROCK and p-PTEN while it decreased p-PI3K and p-cofilin-1, which was consistent with our in vitro results. These findings indicated that ZJW could effectively inhibit DDP resistance in GC by regulating ROCK/PTEN/PI3K signaling and provide a promising treatment strategy for gastric cancer.

Bufalin-loaded vitamin E succinate-grafted-chitosan oligosaccharide/RGD conjugated TPGS mixed micelles demonstrated improved antitumor activity against drug-resistant colon cancer.

BACKGROUND: Multidrug resistance (MDR) is the major reason for the failure of chemotherapy in colon cancer. Bufalin (BU) is one of the most effective antitumor active constituents in Chansu. Our previous study found that BU can effectively reverse P-glycoprotein (P-gp)-mediated MDR in colon cancer. However, the clinical application of BU is limited due to its low solubility in water and high toxicity. In the present study, a multifunctional delivery system based on vitamin-E- succinate grafted chitosan oligosaccharide (VES-CSO) and cyclic (arginine-glycine-aspartic acid peptide) (RGD)-modified d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared by emulsion solvent evaporation method for targeted delivery of BU to improve the efficacy of drug-resistant colon cancer therapy. METHODS: The cytotoxicity of BU-loaded micelles against drug-resistant colon cancer LoVo/ADR and HCT116/LOHP cells was measured by CCK-8 assay. The cellular uptake, Rho123 accumulation, and cell apoptosis were determined by flow cytometry. The expression of apoptosis-related protein and P-gp was measured by Western blot assay. The antitumor activity of BU-loaded micelles was evaluated in LoVo/ADR-bearing nude mice. RESULTS: BU-loaded VES-CSO/TPGS-RGD mixed micelles (BU@VeC/T-RGD MM) were 140.3 nm in diameter with zeta potential of 8.66 mV. The BU@VeC/T-RGD MM exhibited good stability, sustained-release pattern, higher intracellular uptake, and greater cytotoxicity in LoVo/ADR cells. Furthermore, the mechanisms of the BU@VeC/T-RGD MM to overcome MDR might be due to enhanced apoptosis rate and P-gp efflux inhibition. Subsequently, in vivo studies confirmed an enhanced therapeutic efficiency and reduced side effects associated with BU@VeC/T-RGD MM compared with free BU, owing to the enhanced permeation and retention effect, improved pharmacokinetic behavior, and tumor targeting, which lead to MDR-inhibiting effect in LoVo/ADR-bearing nude mice. CONCLUSION: Our results demonstrated that VeC/T-RGD MM could be developed as a potential delivery system for BU to improve its antitumor activity against drug-resistant colon cancer.

Bufalin reverses ABCB1-mediated drug resistance in colorectal cancer.

Multidrug resistance (MDR), mainly mediated by ABCB1 transporter, is a major cause for chemotherapy failure. Bufalin (BU), an active component of the traditional Chinese medicine chan'su, has been reported to have antitumor effects on various types of cancer cells. The purpose of this present study was to investigate the reversal effect of BU on ABCB1-mediated multidrug resistance in colorectal cancer. BU at safe concentration (5, 10, 20 nM) could reverse chemosensitivity of ABCB1-overexpression HCT8/ADR, LoVo/ADR and HCT8/ABCB1 nearly back to their parental cells level. In addition, results from the drug accumulation studies revealed that BU was able to enhance intracellular accumulation of doxorubicin (DOX) and Rhodamine 123 (Rho-123) in a dose-dependent manner. Furthermore, Western blot assays showed that BU significantly inhibited the expression level of ABCB1 protein. Meanwhile, BU stimulated the ATPase activity of ABCB1, which suggested that BU might be a substrate of ABCB1. More interestingly, docking analysis predicted that BU could be docked into the large hydrophobic drug-binding cavity of human ABCB1. Importantly, BU remarkable increased the effect of DOX against the ABCB1 resistant HCT8/ADR colorectal cell xenografts in nude mice, without inducing any obvious toxicity. Overall, we concluded that BU efficiently reversed ABCB1-mediated MDR through not only inhibited the efflux function of ABCB1, but also down-regulate its protein expression, which might represent a potential and superior ABCB1 modulator in colorectal cancer.

Reversal of P-gp-mediated multidrug resistance in colon cancer by cinobufagin.

Cinobufagin (CBF) is isolated from the skin and posterior auricular glands of the Asiatic toad (Bufo gargarizans). This study investigated the reversal effect of CBF on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in colon cancer. The effect of CBF on the cytotoxicity of anticancer drugs in P-gp overexpressing LoVo/ADR, HCT116/L, Cao-2/ADR cells and their parental cells was determined using CCK-8 assay. Apoptosis of anti-cancer drugs and accumulation of doxorubicin (DOX) and Rhodamine 123 (Rho123) in P-gp overexpressing cells were evaluated by flow cytometry. Results indicated that CBF significantly enhanced the sensitivity of P-gp substrate drugs on P-gp overexpressing cells, but had no effect on their parental cells. CBF enhanced the effect of DOX against P-gp-overexpressing LoVo/ADR cell xenografts in nude mice. Moreover, CBF also increased cell apoptosis of chemotherapy agents and intracellular accumulation of DOX and Rho123 in the MDR cells. Further research on the mechanisms revealed non-competitive inhibition of P-gp ATPase activity, but without altering the expression of P-gp. These findings demonstrated that CBF could be further developed into a safe and potent P-gp modulator for combination use with anticancer drugs in cancer chemotherapy.