Sodium thiosulfate: A donor or carrier signaling molecule for hydrogen sulfide?

Sodium thiosulfate has been used for decades in the treatment of calciphylaxis and cyanide detoxification, and has recently shown initial therapeutic promise in critical diseases such as neuronal ischemia, diabetes mellitus, heart failure and acute lung injury. However, the precise mechanism of sodium thiosulfate remains incompletely defined and sometimes contradictory. Although sodium thiosulfate has been widely accepted as a donor of hydrogen sulfide (H2S), emerging findings suggest that it is the executive signaling molecule for H2S and that its effects may not be dependent on H2S. This article presents an overview of the current understanding of sodium thiosulfate, including its synthesis, biological characteristics, and clinical applications of sodium thiosulfate, as well as the underlying mechanisms in vivo. We also discussed the interplay of sodium thiosulfate and H2S. Our review highlights sodium thiosulfate as a key player in sulfide signaling with the broad clinical potential for the future.

Recent advances in pyruvate dehydrogenase kinase inhibitors: Structures, inhibitory mechanisms and biological activities.

Metabolism is reprogrammed in a variety of cancer cells to ensure their rapid proliferation. Cancer cells prefer to utilize glycolysis to produce energy as well as to provide large amounts of precursors for their division. In this process, cancer cells inhibit the activity of pyruvate dehydrogenase complex (PDC) by upregulating the expression of pyruvate dehydrogenase kinases (PDKs). Inhibiting the activity of PDKs in cancer cells can effectively block this metabolic transition in cancer cells, while also activating mitochondrial oxidative metabolism and promoting apoptosis of cancer cells. To this day, the study of PDKs inhibitors has become one of the research hotspots in the field of medicinal chemistry. Novel structures targeting PDKs are constantly being discovered, and some inhibitors have entered the clinical research stage. Here, we reviewed the research progress of PDKs inhibitors in recent years and classified them according to the PDKs binding sites they acted on, aiming to summarize the structural characteristics of inhibitors acting on different binding sites and explore their clinical application value. Finally, the shortcomings of some PDKs inhibitors and the further development direction of PDKs inhibitors are discussed.

Small-molecule modulators of tumor immune microenvironment.

In recent years, tumor immunotherapy, aimed at increasing the activity of immune cells and reducing immunosuppressive effects, has attracted wide attention. Among them, immune checkpoint blocking (ICB) is the most commonly explored therapeutic approach. All approved immune checkpoint inhibitors (ICIs) are clinically effective monoclonal antibodies (mAbs). Compared with biological agents, small-molecule drugs have many unique advantages in tumor immunotherapy. Therefore, they also play an important role. Immunosuppressive signals such as PD-L1, IDO1, and TGF-ß, etc. overexpressed in tumor cells form the tumor immunosuppressive microenvironment. In addition, the efficacy of multi-pathway combined immunotherapy has also been reported and verified. Here, we mainly reviewed the mechanism of tumor immunotherapy, analyzed the research status of small-molecule modulators, and discussed drug candidates' structure-activity relationship (SAR). It provides more opportunities for further research to design more immune small-molecule modulators with novel structures.

Surface Acidity Dictates Proton Transport in WO3/ZrO2: Proton-Conductive Behavior and Mechanistic Insight.

Development of inorganic proton conductors that are applicable in a wide temperature range is crucial for applications such as fuel cells. Most of the reported proton conductors suffer from limited proton conductivity, especially at low temperature. In addition, the mechanism of proton conduction in the conductors is not fully understood, which limits the rational design of advanced proton conductors. In this work, we report the use of metal oxide solid acid as a promising proton conductor. WO3/ZrO2 (WZ) with different surface acidities is synthesized by controlling the content of WO3 on the surface of ZrO2. It is demonstrated that proton conductivity of WZ samples is closely related with their acidity. WZ with the strongest acidity exhibits the highest proton conduction performance at low temperatures, with a proton conductivity of 3.27 × 10-5 S cm-1 at 14 °C. The excellent performance of the WZ-type proton conductor is clarified with theoretical calculations. The results show that the enhanced water adsorption and the lowered activation barrier for breakage of the O-H bond in surface-adsorbed water are the key to the excellent proton-conductive performance of WZ. The experimental results and mechanistic insights gained in this work suggest that WZ is a promising proton conductor, and tailoring the surface acidity of metal oxides is an effective approach to regulate their proton-conductive performance.

Advances in antitumor research of HIF-1α inhibitor YC-1 and its derivatives.

Generally, hypoxia-inducible factor-1α (HIF-1α) is highly expressed in solid tumors, it plays a key role in the occurrence and development of tumors, hindering cancer treatment in various ways. The antitumor activity and pharmacological mechanism of YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1­benzyl indazole], an HIF-1α inhibitor, and the design and synthesis of its derivatives have attracted tremendous attention in the field of antitumor research. YC-1 is a potential drug candidate and a lead compound for tumor therapy. Hence, the multifaceted mechanism of action of YC-1 and the structure activity relationship (SAR) of its derivatives are important factors to be considered for the development of HIF-1α inhibitors. Therefore, this review aimed to provide a comprehensive overview of the various antitumor mechanisms of YC-1 in antitumor research and an in-depth summary of the SAR for the development of its derivatives. A full understanding and discussion of these aspects are expected to provide potential ideas for developing novel HIF-1α inhibitors and antitumor drugs belonging to the YC-1 class. The review also highlighted the application prospects of the YC-1 class of potential antitumor candidates, and provided some unique insights about these antitumor agents.

Design, synthesis, and antitumor evaluation of trimethoxyflavonoid with arylurea structure against hepatocellular carcinoma.

Simultaneous targeting of tumor vasculature and inhibitors of tumor cell glycolysis may be a promising antitumor strategy. Here, we reported the total synthesis and biological evaluation of A-ring arylurea flavonoid derivatives with B-ring trimethoxy group, which exhibited potent antitumor activity against a variety of tumor cells in vitro. Most of the derivatives showed in vitro antitumor activity on HepG-2, HGC-27, MDA-MB-231, and A549 cells. Among them, compounds 8e, 8f, 8g, 8h, 8j, and 8l also exhibited significant anti-proliferation effects on liver tumor cell subtypes BEL-7402 and SMMC-7721. Compound 8l had the lowest IC50 value (5.61 ± 0.39 µM) on HepG-2 cells, and showed the effects of inhibiting colony formation, arresting the cell cycle in G0 /G1 phase, and inducing apoptosis in a concentration-dependent manner. In addition, the toxicity of compound 8l on human normal cells LO2 and GES-1 was lower than that of sorafenib. The inhibitory effects of compound 8l on the expression of glycolytic rate-limiting enzymes HKII, PFK-1, PKM2 and vascular endothelial growth factor were further evaluated. Corresponding reduction in intracellular lactate was also detected after compound 8 treatment. Our results support an antitumor strategy targeting tumor vasculature and glycolysis to discover and develop a new generation of antitumor drugs.

Tuning the Intrinsic Activity and Electrochemical Surface Area of MoS2 via Tiny Zn Doping: Toward an Efficient Hydrogen Evolution Reaction (HER) Catalyst.

Molybdenum sulfide (MoS2 ) is considered as an alternative material for commercial platinum catalysts for electrocatalytic hydrogen evolution reaction (HER). Improving the apparent HER activity of MoS2 to a level comparable to that of Pt is an essential premise for the commercial use of MoS2 . In this work, a Zn-doping strategy is proposed to enhance the HER performance of MoS2 . It is shown that tiny Zn doping into MoS2 leads to the enhancement of the electrochemical surface area, increases in proportion of HER active 1T phase in the material and formation of catalytic sites of higher intrinsic activity. These benefits result in a high-performance HER electrocatalyst with a low overpotential of 190 mV(@10 mA cm-2 ) and a low Tafel slope of 58 mV dec-1 . The origin for the excellent electrochemical performance of the doped MoS2 is rationalized with both experimental and theoretical investigations.

A sandwich-type photoelectrochemical aptasensor using Au/BiVO4 and CdS quantum dots for carcinoembryonic antigen assay.

A novel sandwich-type photoelectrochemical (PEC) aptasensor for the carcinoembryonic antigen (CEA) assay was fabricated using the CEA aptamer, Au/BiVO4 and CdS quantum dots (CdS QDs). In virtue of the localized surface plasmon resonance effect of Au nanoparticles, Au/BiVO4 showed an effective utilization of visible light and excellent photoactivity, and was employed as the photoanode. After CdS QDs were conjugated to Au/BiVO4 through the sandwich structure based on the hybridization of the CEA aptamer with two partially complementary single-stranded DNA molecules, the photocurrents were further enhanced by a resonance energy transfer between CdS QDs and Au nanoparticles. Meanwhile, the consumption of the photo-induced holes by ascorbic acid could also retard the combination of the electron-hole pairs and cause an increase of the photocurrents. However, the specific recognition of CEA by the CEA aptamer could destroy the sandwich structure and remarkably weaken the photocurrent response. Thus, the quantitative detection of CEA was connected with the decrease of the photocurrent. Benefitting from the above methods for signal enhancement, the PEC aptasensor showed a wide sensing range of 0.0001-10 ng mL-1 and a low detection limit of 0.047 pg mL-1 for CEA detection. The specificity, stability and recoveries of the PEC aptasensor were also excellent. Therefore, the construction of the present PEC aptasensor provides a universal and practical method for sensing other substances.

Anti-chronic myeloid leukemia activity and quantitative structure-activity relationship of novel thiazole aminobenzamide derivatives.

The anti-chronic myeloid leukemia activity of thiazole aminobenzamide derivatives in vitro was tested by a methanethiosulfonate (MTS)-based viability assay method, and the result showed that some compounds exhibited good inhibitory activities against human chronic myeloid leukemia cell line K562, imatinib-resistant strain K562/R and T135I mutant cell line BaF3-ABL-BCR-T315I. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods were used to analyze the relationship between the structure of thiazole aminobenzamide derivatives and the inhibition of K562/R cell activity. In CoMFA, Q2 was 0.899 and R2 was 0.963; in CoMSIA, Q2 and R2 were 0.840 and 0.903, respectively. These data indicated that the selected test set showed suitable external predictive ability. Combined with the contour map results, we further analyzed the three-dimensional quantitative structure (3D-QSAR) model. The results demonstrated that in the backbone of the thiazole aminobenzamide derivative, the substitution of a small group at R1 position, or the introduction of a hydrophilic group at R2 position, or the introduction of a large-volume amino acid at R3 position may be beneficial to improve the anti-CML activity of the compound.

Discovery and development of tumor glycolysis rate-limiting enzyme inhibitors.

Tumor cells mainly provide necessary energy and substances for rapid cell growth through aerobic perglycolysis rather than oxidative phosphorylation. This phenomenon is called the "Warburg effect". The mechanism of glycolysis in tumor cells is more complicated, which is caused by the comprehensive regulation of multiple factors. Abnormal enzyme metabolism is one of the main influencing factors and inhibiting the three main rate-limiting enzymes in glycolysis is thought to be important strategy for cancer treatment. Therefore, numerous inhibitors of glycolysis rate-limiting enzyme have been developed in recent years, such as the latest HKII inhibitor and PKM2 inhibitor Pachymic acid (PA) and N-(4-(3-(3-(methylamino)-3-oxopropyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1-yl)phenyl)propiolamide. The review focuses on source, structure-activity relationship, bioecological activity and mechanism of the three main rate-limiting enzymes inhibitors, and hopes to guide the future research on the design and synthesis of rate-limiting enzyme inhibitors.

Design, synthesis, and biological evaluation of 3',4',5'-trimethoxy evodiamine derivatives as potential antitumor agents.

A series of compounds bearing 3',4',5'-trimethoxy module into the core structure of evodiamine were designed and synthesized. The synthesized compounds were screened in vitro for their antitumor potential. MTT results showed that compounds 14a-14c and 14i-14j had significant effects, with compound 14h being the most prominent, with an IC50 value of 3.3 ± 1.5 µM, which was lower than evodiamine and 5-Fu. Subsequent experiments further confirmed that compound 14h could inhibit cell proliferation and migration, and induce G2/M phase arrest to inhibit the proliferation of HGC-27 cells, which is consistent with the results of the cytotoxicity experiment. Besides, 14h could inhibit microtubule assembly and might kill tumor cells by inhibiting VEGF and glycolysis. All experimental results indicate that compound 14h might be a potential drug candidate for the treatment of gastric cancer and was worthy of further study.

A novel salvianolic acid A analog with resveratrol structure and its antioxidant activities in vitro and in vivo.

E-DRS is a novel salvianolic acid A (SAA) analog, which was synthesized from resveratrol (RES) and methyldopate. Its structure is similar to that of SAA, but the 3',4'-dihydroxy-trans-stilbene group and the ester structure in SAA were replaced by the RES structure and an amine group, respectively. E-DRS scavenged free oxygen radicals effectively, including superoxide anion (ascorbic acid > E-DRS > SAA ≥ rutin > RES) and DPPH radical (rutin > E-DRS ≥ ascorbic acid > SAA > RES), and exhibited powerful total antioxidant capacity (ascorbic acid > E-DRS > SAA ≥ rutin > RES) in vitro. Furthermore, oral administration of E-DRS dose-dependently and significantly decreased CCl4 -induced oxidative stress in mice as indicated by the decreased content of hepatic malondialdehyde (MDA). In addition, oral administration of E-DRS also increased the content of nonenzymatic antioxidant glutathione (GSH) and the activity of antioxidant enzymes such as catalase (CAT) and superoxide dismutase (SOD) in the liver of mice. All these results demonstrated that E-DRS had good antioxidant activities both in vitro and in vivo, and could be a potential antioxidant agent after further optimization and evaluation.

Multifunctional Polypropylene Separator via Cooperative Modification and Its Application in the Lithium-Sulfur Battery.

The continuous shuttling of dissolved polysulfides between the electrodes is the primary cause for the rapid decay of lithium-sulfur batteries. Modulation of the separator-electrolyte interface through separator modification is a promising strategy to inhibit polysulfide shuttling. In this work, we develop a graphene oxide and ferrocene comodified polypropylene separator with multifunctionality at the separator-electrolyte interface. The graphene oxide on the functionalized separator could physically adsorb the polysulfide while the ferrocene component could effectively facilitate the conversion of the adsorbed polysulfide. Due to the combination of these beneficial functionalities, the separator exhibits an excellent battery performance, with a high reversible capacity of 409 mAh g-1 after 500 cycles at 0.2 C. We anticipate that the combinatorial separator functionalization proposed herein is an effective approach for improving the performance of lithium-sulfur batteries.

Synthesis and biological evaluation of novel 5,6,7-trimethoxy flavonoid salicylate derivatives as potential anti-tumor agents.

5,6,7-Trimethoxy flavonoid salicylate derivatives were designed by the joining of three important pharmacophores (TMP, flavonoid, and SA) according to the combination principle. A series of novel trimethoxy flavonoid salicylate derivatives were synthesized and their in vitro anti-tumor activities were evaluated. Among these derivatives, compound 7f exhibited excellent antiproliferative activity against HGC-27 cells and MGC-803 cells with IC50 values of 10.26 ± 6.94 µM and 17.17 ± 3.03 µM, respectively. Subsequently, the effects on cell colony formation (clonogenic survival assay), cell migration (wound healing assay), cell cycle distribution (PI staining assay), cell apoptosis (Hoechst 33258 staining assay and annexin V-FITC/PI dual staining assay), lactate level (lactate measurement), microtubules disarrangement (immunofluorescence staining analysis) and docking posture (molecular docking simulation) were determined. Further western blot analysis confirmed that compound 7f could effectively down-regulate the expression of glycolysis-related proteins HIF-1α, PFKM and PKM2 and tumor angiogenesis-related proteins VEGF. Overall, these studies suggested that compound 7f, as the representative compound of those, might be a promising candidate for the treatment of gastric cancer and deserved the further studies.

Incorporating spin-orbit effects into surface hopping dynamics using the diagonal representation: a linear-response time-dependent density functional theory implementation with applications to 2-thiouracil.

In this study, we present a trajectory surface hopping (TSH) method that incorporates spin-orbit (SO) effects using the "diagonal representation" within the Linear-Response Time-Dependent Density Functional Theory (LR-TDDFT) framework. In this approach, the evaluation of spin-orbit coupling (SOC) matrix elements between singlet and triplet states employs the Casida's wave functions and the Breit-Pauli (BP) spin-orbit Hamiltonian with effective charge approximation. The new TSH approach is then used to investigate the excited-state relaxation of 2-thiouracil (2TU) in vacuum and water. On the basis of the simulation results, relaxation of the initially populated bright state is found to be dominated by the route S2 → S1 → T. The intersystem crossing (ISC) can occur at either the C2-puckered structure or the C2-pyramidalized S1 minimum, and is promoted by a three-state near-degeneracy (S1/T2/T1 in vacuum or S1/T3/T2 in water) as well as sizable SOCs. Our simulations achieve a good agreement with the available experimental measurements in terms of the internal conversion (IC) and ISC time scales, and complement the picture of the relaxation mechanisms of 2TU after photo-excitation to the first bright state.

Aryl fluorosulfate analogues as potent antimicrobial agents: SAR, cytotoxicity and docking studies.

A series of aryl fluorosulfate analogues (1-37) were synthesized and tested for in vitro antibacterial and antifungal studies, and validated by docking studies. The compounds 9, 12, 14, 19, 25, 26, 35, 36 and 37 exhibited superior antibacterial potency against tested bacterial strains, while compounds 2, 4, 5, 15, 35, 36 and 37 were found to have better antifungal activity against tested fungal strains, compared to standard antibiotic gentamicin and ketoconazole respectively. Among all the synthesized 37 analogs, compounds 25, 26, 35, 36 and 37 displayed excellent anti-biofilm property against Staphylococcus aureus. The structure-activity relationship (SAR) revealed that the antimicrobial activity depends upon the presence of -OSO2F group and slender effect of different substituent's on the phenyl rings. The electron donating (OCH3) groups in analogs increase the antibacterial activity, and interestingly the electron withdrawing (Cl, NO2, F and Br) groups increase the antifungal activity (except compound 35, 36 and 37). The mechanism of potent compounds showed membrane damage on bacteria confirmed by SEM. Compounds 35, 36 and 37 exhibited highest glide g-scores in molecular docking studies and validated the biocidal property.

The effects of structural properties on the lithium storage behavior of mesoporous TiO2.

Understanding the effects of structural properties on the lithium storage behavior of mesoporous TiO2 is crucial for further optimizing its performance through rational structure design. To achieve this, herein, the surface area and the grain size of the prepared mesoporous TiO2 are intentionally adjusted by controlling the calcination temperatures. It is found that the capacities of the mesoporous TiO2 contain both the lithium-ion insertion into the bulk phase (Q in) and the additional surface lithium storage (Q as). The Q in gradually increases with grain sizes to a steady level and then slightly drops. By contrast, the Q as is directly proportional to the specific surface area of the mesoporous TiO2 and is ascribed to the capacity originated from the lithium-ion insertion into the surface layer. The experimental comparison and analysis demonstrate that the fast kinetics of the Q as ensure both the better rate performance and capacity retention of mesoporous TiO2 than bulk ones. Specially, the mesoporous TiO2 calcinated at 350 °C shows the highest reversible specific capacity of 250.2 mA h g-1, the best rate capability (132.5 mA h g-1 at 2C) and good cycling stability. Our findings shed great light on the design of high-performance nanostructured TiO2 with surface lithium storage.

Internal conversion and intersystem crossing in α,ß-enones: a combination of electronic structure calculations and dynamics simulations.

The ab initio electronic structure calculations and CASSCF-based nonadiabatic dynamics simulations have been used to investigate the internal conversion and intersystem crossing process of both trans-acrolein and 2-cyclopentenone in the gas phase. Our calculation results show that relaxation from the Franck-Condon region to an S1 minimum is ultrafast and that the S1 state will dominantly undergo intersystem crossing to triplet states due to the existence of significant barriers to access the S1/S0 intersection points and of energetically close-lying triplet states. The S1/T2/T1 three-state intersection is observed in our dynamics simulations to play an important role in the population of the lowest triplet state, which is consistent with previous suggestions. Although the evolution into triplet states involves a similar path and gives rise to a similar triplet quantum yield for these two molecules, the intersystem crossing rate of 2-cyclopentenone is lower owing to the ring constraint that results in a smaller spin-orbital coupling in the singlet-triplet crossing region. The present theoretical study reproduces the experimental results and gives an explanation about the structural factors that govern the excited-state decay of some types of α,ß-enones.

ClC-3 deficiency prevents atherosclerotic lesion development in ApoE-/- mice.

BACKGROUND: Recent evidence suggested that ClC-3, encoding Cl(-) channel or Cl(-)/H(+) antiporter, plays a critical role in regulation of a variety of physiological functions. However, remarkably little is known about whether ClC-3 is involved in atherosclerosis. This study aims to establish the involvement and direct role of ClC-3 in atherogenesis and underlying mechanisms by using ClC-3 and ApoE double null mice. METHODS AND RESULTS: After a 16-week western-type high-fat diet, the ClC-3(+/+)ApoE(-/-) mice developed widespread atherosclerotic lesions in aorta. However, the lesion size was significantly reduced in aorta of ClC-3(-/-)ApoE(-/-) mice. Compared with the ClC-3(+/+) controls, there was significantly decreased ox-LDL binding and uptake in isolated peritoneal macrophages from ClC-3(-/-) mice. Moreover, the expression of scavenger receptor SR-A, but not CD36, was significantly decreased in both ClC-3(-/-) peritoneal macrophages and aortic lesions from ClC-3(-/-)ApoE(-/-) mice. These findings were further confirmed in ox-LDL-treated RAW264.7 macrophages, which showed that silence of ClC-3 inhibited SR-A expression, ox-LDL accumulation and foam cell formation, whereas overexpression of ClC-3 produced the opposite effects. In addition, ClC-3 siRNA significantly inhibited, whereas ClC-3 overexpression increased, the phosphorylation of JNK/p38 MAPK in ox-LDL-treated RAW264.7 foam cells. Pretreatment with JNK or p38 inhibitor abolished ClC-3-induced increase in SR-A expression and ox-LDL uptake. Finally, the increased JNK/p38 phosphorylation and SR-A expression induced by ClC-3 could be mimicked by reduction of [Cl(-)]i by low Cl(-) solution. CONCLUSIONS: Our findings demonstrated that ClC-3 deficiency inhibits atherosclerotic lesion development, possibly via suppression of JNK/p38 MAPK dependent SR-A expression and foam cell formation.

Hydrogen sulfide protects testicular germ cells against heat-induced injury.

OBJECTIVE: The present study was designed to investigate whether H2S can protect testicular germ cells against heat exposure induced injury and the underlying mechanisms. RESULTS: It was found that all three H2S generating enzymes, cystathionine ß-synthase (CBS), cystathionine γ-lysase (CSE), and 3-mercaptopyruvate sulfurtransferase (3 MST), were expressed in mouse testicular tissue. Three episodes of heat exposure (42 °C, 30 min/day, 3 days) significantly decreased endogenous H2S production and down-regulated the expression of CBS and CSE in testes. In primary cultured testicular germ cells, exogenous application of NaHS (an H2S donor) attenuated heat stress (42 °C, 30 min) induced cell death and apoptosis. This was mediated by the inhibitory effects of H2S on cytochrome C release and the ratio of the Bax/Bcl-2. NaHS also improved mitochondrial function by decreasing oxygen consumption and increasing ATP production. NaHS treatment also stimulated SOD activity and reduced ROS production. CONCLUSIONS: Our results revealed both physiological and pharmacological roles of H2S in testicular germ cells. Exogenous application of H2S may protect germ cells by preservation of mitochondrial function and stimulation of anti-oxidant activity.