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.

Potential Links between ANRIL and MiRNAs in Various Cancers.

Non-coding RNAs are mainly divided into two categories, one is small non-coding RNA represented by miRNA, and the other is long non-coding RNA longer than 200 bp. Further studies on non-coding RNAs have revealed that long non-coding RNAs not only have carcinogenic effects, but also have potential links with miRNAs. Antisense non-coding RNA in the INK4 locus (ANRIL/CDKN2B-AS1), one of the five subtypes of long non-coding RNA, has been proved to play a role of oncogene in many cancers, such as gastric cancer, cervical cancer, prostate cancer and non-small cell lung cancer. Knockdown ANRIL can significantly inhibit the proliferation and migration of cancer cells, while also negatively regulating the expression of related miRNAs. This suggests that ANRIL may serve as a potential target for the development of drugs that provide new strategies to improve the effectiveness of cancer treatment. In our review, we summarize the current association between ANRIL and miRNAs in various cancers.

Source tracing and contagion measurement of carbon emission trading price fluctuation in China from the perspective of major emergencies.

Based on monthly economic data spanning from January 2015 to December 2022, we have established an analytical framework to examine the "Russia-Ukraine conflict-financial market pressure and energy market-China carbon emission trading prices." To achieve this objective, we developed indices for financial system pressure, the energy market, and investor sentiment, applying a mediation effects model to validate their transmission mechanisms. Subsequently, the TVP-SV-VAR model was employed to scrutinize the nonlinear impact of the Russia-Ukraine conflict on the valuation of China's carbon emission trading rights. This model integrates time-varying parameters (TVP) and stochastic volatility (SV), utilizing Markov Chain Monte Carlo (MCMC) technology for parameter estimation. Finally, various wavelet analysis techniques, including continuous wavelet transform, cross-wavelet transform, and wavelet coherence spectrum, were applied to decompose time series data into distinct time-frequency scales, facilitating an analysis of the lead-lag relationships within each time series. The research outcomes provide crucial insights for safeguarding the interests of trading organizations, refining the structure of the carbon market, and mitigating systemic risks on a global scale.

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.

pH regulators and their inhibitors in tumor microenvironment.

As an important characteristic of tumor, acidic tumor microenvironment (TME) is closely related to immune escape, invasion, migration and drug resistance of tumor. The acidity of the TME mainly comes from the acidic products produced by the high level of tumor metabolism, such as lactic acid and carbon dioxide. pH regulators such as monocarboxylate transporters (MCTs), carbonic anhydrase IX (CA IX), and Na+/H+ exchange 1 (NHE1) expel protons directly or indirectly from the tumor to maintain the pH balance of tumor cells and create an acidic TME. We review the functions of several pH regulators involved in the construction of acidic TME, the structure and structure-activity relationship of pH regulator inhibitors, and provide strategies for the development of small-molecule antitumor inhibitors based on these targets.

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.

CuS@TA-Fe Nanoparticle-Doped Multifunctional Hydrogel with Peroxide-Like Properties and Photothermal Properties for Synergistic Antimicrobial Repair of Infected Wounds.

Bacterial infection is a critical factor in wound healing. Due to the abuse of antibiotics, some pathogenic bacteria have developed resistance. Thus, there is an urgent need to develop a non-antibiotic-dependent multifunctional wound dressing for the treatment of bacteria-infected wounds. In this work, a multifunctional AOCuT hydrogel embedded with CuS@TA-Fe nanoparticles (NPs) through Schiff base reaction between gelatin quaternary ammonium salt - gallic acid (O-Gel-Ga) and sodium dialdehyde alginate (ADA) along with electrostatic interactions with CuS@TA-Fe NPs is prepared. These composite hydrogels possess favorable injectability, rapid shape adaptation, electrical conductivity, photothermal antimicrobial activity, and biocompatibility. Additionally, the doped NPs not only impart fast self-healing properties and excellent adhesion performance to the hydrogels, but also provide excellent peroxide-like properties, enabling them to scavenge free radicals and exhibit anti-inflammatory and antioxidant capabilities via photothermal (PTT) and photodynamic (PDT) effects. In an S. aureus infected wound model, the composite hydrogel effectively reduces the expression level of wound inflammatory factors and accelerates collagen deposition, epithelial tissue, and vascular regeneration, thereby promoting wound healing. This safe and synergistic therapeutic system holds great promise for clinical applications in the treatment of infectious wounds.

Research and development of N,N'-diarylureas as anti-tumor agents.

Tumor neovascularization provides abundant nutrients for the occurrence and development of tumors, and is also an important factor in tumor invasion and metastasis, which has attracted extensive attention in anti-tumor therapy. Sorafenib is a clinically approved multi-targeted anti-tumor drug that targets vascular endothelial growth factor receptor (VEGFR) and inhibits the formation of tumor angiogenesis, thereby achieving the purpose of suppressing tumor growth. Since the approval of sorafenib, N,N'-diarylureas have received extensive attention as the key pharmacophore in its chemical structure. And a series of N,N'-diarylureas were designed and synthesized to screen a new generation of anti-tumor drug candidates through chemical modification and structural optimization. Moreover, the rational design of targeted drugs is beneficial to reduce toxic side effects and drug resistance and improve the curative effect. Here, this article reviews the research progress in the design, classification, structure-activity relationship (SAR) and biological activity of N,N'-diarylureas, in order to provide some prospective routes for the development of clinically effective anti-tumor drugs.

Synthesis and anti-hepatocellular carcinoma evaluation of salicylic acid-modified indole trimethoxy flavonoid derivatives.

Simultaneous inhibition of tumor vasculature and the glycolysis pathway may be a targeted anti-tumor strategy to inhibit tumor nutrient supply. Flavonoids are natural products with strong biological activity, which inhibit hypoxia induction factor 1α (HIF-1α) regulating glycolysis and tumor angiogenesis, while salicylic acid can reduce the glycolysis level of tumor cells by inhibiting related rate-limiting enzymes. A series of salicylic acid-modified indole trimethoxy-flavone derivatives were designed and synthesized by introducing benzotrimethoxy-structure commonly used in blood vessel blockers, and their anti-tumor activities were evaluated. Among them, compound 8f exhibited significant anti-proliferative activity against two hepatoma cells, HepG-2 and SMMC-7721, with IC50 values of 4.63 ± 1.13 µM and 3.11 ± 0.35 µM, respectively. Colony formation experiments also further verified its excellent in vitro anti-tumor activity. In addition, compound 8f showed the ability to induce apoptosis in SMMC-7721 cells in a concentration-dependent manner. After treatment with compound 8f, the expressions of the rate-limiting enzymes PKM2, PFKM, HK2 and tumor angiogenesis-related vascular endothelial growth factor of the glycolytic pathway were all down-regulated, and the lactate level in the hepatoma cell SMMC-7721 was significantly reduced. The morphology of the nucleus and tubulin was also observed to disperse gradually with the increase of compound 8f concentration. And compound 8f showed strong binding ability to tubulin. Our results suggest that the strategy of synthesizing the salicylic acid-modified indole flavone derivative 8f is a way to obtain active anti-tumor candidate compounds that may be further developed as targeted agents to inhibit tumor vasculature and glycolytic pathways.

Murine Models and Research Progress on Dysmenorrhea.

Dysmenorrhea is a prevalent gynecological disease among women at reproductive age. It is classified as the primary dysmenorrhea and the secondary dysmenorrhea according to the etiology. The primary dysmenorrhea is caused by uterine hypercontraction without any identifiable pelvic lesions, while the secondary dysmenorrhea is incurred by gynecological disorder with pelvic organic lesions. However, the underlying mechanism of dysmenorrhea is not completely clear. Animal models of dysmenorrhea, especially mouse and rat model, are helpful to explore the pathophysiological mechanism of dysmenorrhea, clarify the therapeutic effect of compounds, and guide clinical treatment. The murine model of primary dysmenorrhea is commonly induced by oxytocin or prostaglandin F2α, while the secondary dysmenorrhea murine model was further created by injecting oxytocin on the basis of the established primary disease model. This review summarizes the current progress of dysmenorrhea models in rodent, including experimental methods, corresponding evaluation indexes, and the advantages and disadvantages of various murine dysmenorrhea models, in order to provide a reference for the selection of murine dysmenorrhea models and the further study of the pathophysiological mechanism of dysmenorrhea.

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.

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.

Microrna-96 In Human Cancers.

MicroRNAs (miRNAs) are small non-coding RNAs 19-25 nucleotides in size involved in gene regulation and diverse processes in tumor cells. Abnormal expression of miRNAs is closely related to carcinogenesis. MiR-96 is a salient cancer-related miRNA in a variety of tumors. Recent evidence indicates that miR-96 has been observed to be wrapped in exosome and associated with drug resistance or radio-chemosensitivity in cancers. miR-96 is also inextricably linked with the competing endogenous RNAs (ceRNAs) in cancers. Notably, miR-96 plays both a tumor suppressor role and plays a carcinogenic role in the same cancers. This review summarizes the critical role of cancer-related miR-96 in drug resistance or radio-chemosensitivity and ceRNA mechanisms of miR-96 in cancer. And we innovatively propose that miR-96 has a yin-yang effect in cancers. Based on these several major roles of miR-96 in cancer as described above, we speculate that the abnormal expression of miR-96 is likely to be novel potential therapeutic targets in cancers. It is expected to solve the treatment problems such as low chemoradiotherapy sensitivity, poor prognosis quality of life and easy recurrence in cancer patients.

Long stress-induced non-coding transcript 5: A promising therapeutic target for cancer treatment.

Long non-coding RNAs are RNA molecules with a transcript length of more than 200 nucleotides and without protein-coding ability. They regulate gene expression by interacting with protein, RNA and DNA. Their function is closely related to their subcellular localization, with regulation of gene expression at the epigenetic and transcriptional levels occurring in the nucleus, and at the post-transcriptional and translational levels in the cytoplasm. Long stress-induced non-coding transcript 5 (LSINCT5), which is localized in the nucleus, is overexpressed in many types of cancers such as breast cancer, gastric cancer, ovarian cancer, thyroid cancer, and gastrointestinal cancer. Substantial evidence indicates that there is an obvious connection between cancers and LSINCT5, as it inhibits apoptosis and promotes proliferation, invasion and migration of cancer cells, as well as participates in the pathogenesis and progression of cancer by interacting with DNA, protein and RNA. These findings suggest that LSINCT5 could be a novel biomarker and an emerging therapeutic target in human cancers. In the present study, the structure and corresponding biological function of LSINCT5 were summarized in order to clarify its molecular mechanisms in the progression of various malignant tumors.

Boosting Interfacial Ion Transfer in Potassium-Ion Batteries via Synergy Between Nanostructured Bi@NC Bulk Anode and Electrolyte.

Using high-capacity alloy-type anodes can greatly advance potassium-ion batteries (PIBs). However, the primary limits are unstable solid electrolyte interphase (SEI) and tough interfacial ion transfer associated with large-size K+ during electrochemical (de)alloy reactions. Here, we achieve excellent energy storage performance of PIBs via the synergy between a nanostructured Bi@N-doped carbon (Bi@NC) bulk anode and a KPF6-dimethoxyethane (DME) electrolyte. The Bi@NC material with a high tap density of 3.81 g cm-3 is prepared by simply pyrolyzing a commercial Bi salt yet affords a favorable nano/microstructure consisting of Bi nanograins confined in 3D ultrathin N-doped carbon shells, facilitating electron/ion transport and structural integrity. Detailed impedance spectroscopy investigation unveils that K+ transport through SEI at the Bi@NC anode, rather than the desolvation of K+, dominates the interfacial K+ transfer. More importantly, spectroscopic and microscopic characterizations provide clear evidence that the interplay between Bi@NC anode and optimized KPF6-DME electrolyte can produce a unique SEI layer containing Bi3+-solvent complex that enables the activation energy of interfacial K+ transfer as low as 25.9 kJ mol-1, thereby ultrafast charge transfer at Bi@NC. Consequently, the Bi@NC anode in half cells achieves exceptional rate capability (206 mAh g-1 or 784 mAh cm-3 at 120C) accompanied by high specific capacity (331 mAh g-1 or 1261 mAh cm-3) and long cycle life (running 1400 cycles at 15C with a tiny capacity fading rate of 0.013% per cycle). Moreover, the Bi@NC anode and KPF6-DME electrolyte are also compatible with a potassium Prussian blue cathode and assembled full PIBs achieve stable cyclability (87.3% capacity retention after 100 cycles at 2.5C) and excellent rate performance (65.1% capacity retention upon increasing rates from 1 to 20C).

Impact of MiRNAs and LncRNAs on Multidrug Resistance of Gastric Cancer.

Multi-drug resistance (MDR) is characterized by the resistance of tumor cells to some antitumor drugs with different structures and mechanisms after the use of a single chemotherapy drug or even the first use of the drug. Notably, MDR has become the largest obstacle to the success of gastric cancer chemotherapies. Non-coding RNAs are defined as a class of RNAs that do not have the ability to code proteins. They are widely involved in important biological functions in life activities. Multiple lines of evidence demonstrated that ncRNAs are closely related to human cancers, including gastric cancer. However, the relationship between ncRNAs and MDR in gastric cancer has been reported, yet the mechanisms are not fully clarified. Therefore, in this review, we systematically summarized the detailed molecular mechanisms of lncRNAs (long noncoding RNAs) and miRNAs (microRNAs) associated with MDR in gastric cancer. Additionally, we speculate that the abnormal expression of ncRNAs is likely to be a novel potential therapeutic target reversing MDR for gastric cancer. Future therapeutics for gastric cancer will most likely be based on noncoding RNAs (ncRNAs) that regulate MDR-related genes.

Lactic acid, a driver of tumor-stroma interactions.

Warburg effect is one of the hallmarks of tumor favoring the suppression of normal oxidative phosphorylation (OxPhos) and the adaptation to hypoxia. In addition to providing continuous energy to meet the demands of tumors, acceleratedWarburg effect also producesa large amount of lactic acid. Lactic acid shuttles between different cell populations within the tumor microenvironment (TME) and confers tumor cells to interact with surrounding cells, which has emerged as a new phenomenon in the field of tumor biology and tumorigenesis. Lactic acid not only fulfills the energetic demands of stromal cells, but becomes a major regulator of their activity by serving as a signaling molecule. Activated stromal cells in turn support tumor development. In this review, we discuss the role of lactic acid in transformation and oncogenic function of stromal cells including fibroblasts, macrophages, adipocytes and vascular endothelial cells, and suggest the relevance of lactic acid in therapy response and essential questions in this field.

Two-dimensional colloidal crystal of soft microgel spheres: Development, preparation and applications.

Two-dimensional (2D) colloidal crystals are ordered monolayer arrays of colloidal sphere particles assembled on the substrates or at phase interfaces. Owing to their unique periodic structure and fascinating properties, 2D colloidal crystals have aroused considerable interest because of their potential applications. Among them, 2D colloidal crystals self-assembled from soft microgel spheres stand out particularly. The 2D colloidal crystals of soft microgel spheres combine the advantages of monolayer colloidal crystals and sensitive microgels, which have a good application prospect in biomedical area. In this article, we provide a systematic overview of 2D colloidal crystals of soft microgel spheres related to their development, preparation and applications. First, various preparation methods of 2D colloidal crystal of microgels are introduced, including dip-coating, drop-coating, spin-coating, interface assembly, surface reaction-assisted assembly, and so forth. Second, representative biomedical applications consisting of optical sensor, drug delivery, antibacterial coating, cell culture, and colloidal template are also exemplified to show the high performance of 2D colloidal crystals of soft microgel spheres. In addition, we also present prospects of future developments of 2D microgel colloidal crystals.

Tumor-derived or non-tumor-derived exosomal noncodingRNAs and signaling pathways in tumor microenvironment.

The tumor microenvironment (TME) involved in multiple pathological processes of tumors is highly complex. Exosomes, as organelles, can be produced by some cells in the TME and have been verified as a special carriers and a key factor for communication between tumor and TME-associated cells. Noncoding RNAs (ncRNAs) involved in tumorigenesis and development have been demonstrated to be released into the TME by exosomes. However, the detailed regulatory functions of exosomal ncRNAs through signaling pathways in the TME are still unclear. In this review, we systematically summarized the detailed molecular mechanisms by which exosomal ncRNAs mediate the modulation of both tumor cells and nontumor cells. Exosomal ncRNAs in the TME exhibited the potential ability to influence cancer development through signaling pathways, including PTEN signaling, NF-κB signaling, Wnt/ß-catenin signaling, PI3K/AKT signaling, etc. Expressly, considering that research on circRNAs has gained much momentum in recent years, we more thoroughly described the implication of exosomal circRNAs in the regulation of signaling. Our review might hopefully inspire a deeper understanding of exosomal ncRNA function in terms of signaling pathways. We speculated that exosomal ncRNAs, as useful biomarkers and therapeutic targets, play an important role in the diagnosis and prognosis of cancer.