A new evaluation system for drug-microbiota interactions.

The drug response phenotype is determined by a combination of genetic and environmental factors. The high clinical conversion failure rate of gene-targeted drugs might be attributed to the lack of emphasis on environmental factors and the inherent individual variability in drug response (IVDR). Current evidence suggests that environmental variables, rather than the disease itself, are the primary determinants of both gut microbiota composition and drug metabolism. Additionally, individual differences in gut microbiota create a unique metabolic environment that influences the in vivo processes underlying drug absorption, distribution, metabolism, and excretion (ADME). Here, we discuss how gut microbiota, shaped by both genetic and environmental factors, affects the host's ADME microenvironment within a new evaluation system for drug-microbiota interactions. Furthermore, we propose a new top-down research approach to investigate the intricate nature of drug-microbiota interactions in vivo. This approach utilizes germ-free animal models, providing foundation for the development of a new evaluation system for drug-microbiota interactions.

Organic-Hydrochloride-Modified ZnO Electron Transport Layer for Efficient Defect Passivation and Stress Release in Rigid and Flexible all Inorganic Perovskite Solar Cells.

All inorganic CsPbI2Br perovskite (AIP) has attracted great attention due to its excellent resistance against thermal stress as well as the remarkable capability to deliver high-voltage output. However, CsPbI2Br perovskite solar cells (PeSCs) still encounter critical challenges in attaining both high efficiency and mechanical stability for commercial applications. In this work, formamidine disulfide dihydrochloride (FADD) modified ZnO electron transport layer (ETL) has been developed for fabricating inverted devices on either rigid or flexible substrate. It is found that the FADD modification leads to efficient defects passivation, thereby significantly reducing charge recombination at the AIP/ETL interface. As a result, rigid PeSCs (r-PeSCs) deliver an enhanced efficiency of 16.05% and improved long-term thermal stability. Moreover, the introduced FADD can regulate the Young's modulus (or Derjaguin-Muller-Toporov (DMT) modilus) of ZnO ETL and dissipate stress concentration at the AIP/ETL interface, effectively restraining the crack generation and improving the mechanical stability of PeSCs. The flexible PeSCs (f-PeSCs) exhibit one of the best performances so far reported with excellent stability against 6000 bending cycles at a curvature radius of 5 mm. This work thus provides an effective strategy to simultaneously improve the photovoltaic performance and mechanical stability.

Corrigendum to "Cilengitide inhibits osteoclast adhesion through blocking the αvß3-mediated FAK/Src signaling pathway" [Heliyon 9(7) (July 2023) e17841].

[This corrects the article DOI: 10.1016/j.heliyon.2023.e17841.].

Crystalline architectures of C84 with tunable morphology and linearly polarized red emission.

Fullerene-based micro/nano-architectures (FMNAs) with remarkable photoluminescence (PL) emissions have attracted considerable interest as potential building blocks for optical and biolabeling applications, by virtue of their low toxicity and environmentally friendly nature. Nevertheless, the PL polarization properties of FMNAs have rarely been explored. Herein, we demonstrate the preparation of highly crystalline architectures of C84, which exhibit polymorphism depending on the preparation conditions but possess similar hexagonal close-packed (hcp) structures. The PL data demonstrate that the as-prepared carambola-like hexagonal microprisms (c-HPs) show enhanced red emission compared to regular hexagonal microprisms (r-HPs). More importantly, the linear polarization of the PL emission is verified and estimated through single-prism spectroscopy, which changes from 0.42 (r-HP) to 0.58 (c-HP), comparable to those of traditional rod-like semiconductors. Thus, we demonstrate a significant correlation between the morphology and emission characteristics of C84-based microprisms, highlighting the possibility of controlling the photophysical properties of FMNAs by finely tailoring their external morphologies. This study expands the range of carbon materials with linearly polarized emissions and offers potential for use in polarization-based micro-scale sensors or detectors.

Chemical constituents from stems and leaves of Lonicera confusa and their anti-inflammatory activities / 中成药

AIM To study the chemical constituents and their anti-inflammatory activities of stems and leaves of Lonicera confusa DC.METHODS The 80%methanol extract from stems and leaves of L.confusa DC was isolated and purified by Diaion HP20SS,Sephadex LH-20,HSCCC and preparative HPLC,then the structures of obtained compounds were identified by physicochemical properties and spectral data.Their anti-inflammatory activities were evaluated by measuring NO production of LPS-stimulated RAW264.7 cells in vitro.RESULTS Thirteen compounds were isolated and identified as benzyl alcohol-O-β-D-glucopyranosyl-(1 →6)-β-D-glucopyranoside(1),sweroside(2),epi-vogeloside(3),vogeloside(4),secologanoside(5),secoxyloganin(6),secologanin dimethyl acetal(7),methyl chlorogenate(8),apigenin-7-O-β-D-glucopyranoside(9),luteolin-7-O-β-D-glucopyranoside(10),rhoifolin(11),luteolin-7-O-α-L-arabinopyranosyl(1→6)-β-D-glucopyranoside(12),and lonicerin(13).Compounds 2-8,11-13 inhibited the NO production of LPS-induced cells.CONCLUSION Compound 1 is first isolated from family Lonicera,compounds 3,5,7,9,11,and 12 are obtained from the stems and leaves of this plant for the first time.Compounds 2-8,11-13 exhibited anti-inflammatory activities.

Acid-sensing ion channel 1a modulation of apoptosis in acidosis-related diseases: implications for therapeutic intervention.

Acid-sensing ion channel 1a (ASIC1a), a prominent member of the acid-sensing ion channel (ASIC) superfamily activated by extracellular protons, is ubiquitously expressed throughout the human body, including the nervous system and peripheral tissues. Excessive accumulation of Ca2+ ions via ASIC1a activation may occur in the acidified microenvironment of blood or local tissues. ASIC1a-mediated Ca2+­induced apoptosis has been implicated in numerous pathologies, including neurological disorders, cancer, and rheumatoid arthritis. This review summarizes the role of ASIC1a in the modulation of apoptosis via various signaling pathways across different disease states to provide insights for future studies on the underlying mechanisms and development of therapeutic strategies.

Citric acid-modified pH-sensitive bone-targeted delivery of estrogen for the treatment of postmenopausal osteoporosis.

Bone targeted delivery of estrogen offers great promise for the clinical application of estrogen in the treatment of postmenopausal osteoporosis (PMOP). However, the current bone-targeted drug delivery system still has several issues that need to be solved, such as the side effects of bone-targeted modifier molecules and the failure of the delivery system to release rapidly in the bone tissue. It is important to aggressively search for new bone-targeted modifier molecules and bone microenvironment-responsive delivery vehicles. Inspired by the distribution of citric acid (CA) mainly in bone tissue and the acidic bone resorption microenvironment, we constructed a CA-modified diblock copolymer poly(2-ethyl-2-oxazoline)-poly(ε-caprolactone) (CA-PEOz) drug delivery system. In our study, we found that the CA modification significantly increased the bone targeting of this drug delivery system, and the delivery system was able to achieve rapid drug release under bone acidic conditions. The delivery system significantly reduced bone loss in postmenopausal osteoporotic mice with a significant reduction in estrogenic side effects on the uterus. In summary, our study shows that CA can act as an effective bone targeting modifier molecule and provides a new option for bone targeting modifications. Our study also provides a new approach for bone-targeted delivery of estrogen for the treatment of PMOP.

Cilengitide inhibits osteoclast adhesion through blocking the αvß3-mediated FAK/Src signaling pathway.

The remodeling of actin cytoskeleton of osteoclasts on the bone matrix is essential for osteoclastic resorption activity. A specific regulator of the osteoclast cytoskeleton, integrin αvß3, is known to provide a key role in the degradation of mineralized bone matrixes. Cilengitide is a potent inhibitor of integrins and is capable of affecting αvß3 receptors, and has anti-tumor and anti-angiogenic and apoptosis-inducing effects. However, its function on osteoclasts is not fully understood. Here, the cilengitide role on nuclear factor κB ligand-receptor activator (RANKL)-induced osteoclasts was explored. Cells were cultured with varying concentrations of cilengitide (0,0.002,0.2 and 20 µM) for 7 days, followed by detected via Cell Counting Kit-8, staining for tartrate resistant acid phosphatase (TRAP), F-actin ring formation, bone resorption assays, adhesion assays, immunoblotting assays, and real-time fluorescent quantitative PCR. Results demonstrated that cilengitide effectively restrained the functionality and formation of osteoclasts in a concentration-dependent manner, without causing any cytotoxic effects. Mechanistically, cilengitide inhibited osteoclast-relevant genes expression; meanwhile, cilengitide downregulated the expression of key signaling molecules associated with the osteoclast cytoskeleton, including focal adhesion kinase (FAK), integrin αvß3 and c-Src. Therefore, this results have confirmed that cilengitide regulates osteoclast activity by blocking the integrin αvß3 signal pathway resulting in diminished adhesion and bone resorption of osteoclasts.

Acylated iridoid glucoside and xanthones from Canscora lucidissima: Their structures and ferroptosis inhibitory activity.

Phytochemical study on the whole plants of a Gentianaceous medicinal plant, Canscora lucidissima, gave one new acylated iridoid glucoside, canscorin A (1), and two new xanthone glycosides (2 and 3) together with 17 known compounds including five xanthones, eight xanthone glycosides, two benzophenone glucosides, caffeic acid, and loganic acid. Canscorin A (1) was assigned as a loganic acid derivative having a hydroxyterephthalic acid moiety by spectroscopic analysis together with chemical evidence, while 2 and 3 were elucidated to be a rutinosylxanthone and a glucosylxanthone, respectively. The absolute configurations of the sugar moieties of 2 and 3 were determined by HPLC analysis. The isolated compounds were evaluated for their inhibitory activities against erastin-induced ferroptosis on human hepatoma Hep3B cells and LPS-stimulated IL-1ß production from murine microglial cells.

Chemodivergent Photocatalyzed Heterocyclization of Hydrazones and Isothiocyanates for the Selectivity Synthesis of 2-Amino-1,3,4-thiadiazoles and 1,2,4-Triazole-3-thiones.

A photocatalytic chemodivergent reaction for the selectivity formation of C-S and C-N bonds in a controlled manner was proposed. The reaction medium, either neutral or acidic, is critical to dictate the formation of 2-amino-1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones from isothiocyanates and hydrazones. This is a practical protocol to achieve the chemoselectivity under mild and metal-free conditions.

Unraveling a bifunctional mechanism for methanol-to-formate electro-oxidation on nickel-based hydroxides.

For nickel-based catalysts, in-situ formed nickel oxyhydroxide has been generally believed as the origin for anodic biomass electro-oxidations. However, rationally understanding the catalytic mechanism still remains challenging. In this work, we demonstrate that NiMn hydroxide as the anodic catalyst can enable methanol-to-formate electro-oxidation reaction (MOR) with a low cell-potential of 1.33/1.41 V at 10/100 mA cm-2, a Faradaic efficiency of nearly 100% and good durability in alkaline media, remarkably outperforming NiFe hydroxide. Based on a combined experimental and computational study, we propose a cyclic pathway that consists of reversible redox transitions of NiII-(OH)2/NiIII-OOH and a concomitant MOR. More importantly, it is proved that the NiIII-OOH provides combined active sites including NiIII and nearby electrophilic oxygen species, which work in a cooperative manner to promote either spontaneous or non-spontaneous MOR process. Such a bifunctional mechanism can well account for not only the highly selective formate formation but also the transient presence of NiIII-OOH. The different catalytic activities of NiMn and NiFe hydroxides can be attributed to their different oxidation behaviors. Thus, our work provides a clear and rational understanding of the overall MOR mechanism on nickel-based hydroxides, which is beneficial for advanced catalyst design.

Systematic analysis of the cuprotosis in tumor microenvironment and prognosis of gastric cancer.

Cuprotosis is a new programmed cell death related to cancer. However, the characteristics of cuprotosis in gastric cancer (GC) remain unknown. Ten cuprotosis molecules from 1544 GC patients were used to identify three GC molecular genotypes. Cluster A was characterized by the best clinical outcome and was significantly enriched in metabolic signaling pathways. Cluster B exhibited elevated immune activation, high immune stroma scores and was significantly enriched in tumor immune signaling pathways. Cluster C was characterized by severe immunosuppression and poor response to immunotherapy. Notably, the citrate cycle, cell cycle, and p53 signaling pathways were enriched in the differentially expressed genes among the three subtypes, which were critical signaling pathways for cell death. We also developed a cuprotosis signature risk score that could accurately predict the survival, immunity, and subtype of GC. This study presents a systematic analysis of cuprotosis molecules and provides new immunotherapeutic targets for GC patients.

Lindenane-Type Sesquiterpene Dimers Mitigate Lipopolysaccharide-Induced Inflammation by Inhibiting Toll-Like Receptor Signaling.

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns and trigger an inflammatory response via the myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter-inducing interferon-ß (TRIF)-dependent pathways. Lindenane type sesquiterpene dimers (LSDs) are characteristic metabolites of plants belonging to the genus Sarcandra (Chloranthaceae). The aim of this study was to evaluate the potential anti-inflammatory effects of the LSDs shizukaol D (1) and sarcandrolide E (2) on lipopolysaccharides (LPS)-stimulated RAW264.7 macrophages in vitro, and explore the underlying mechanisms. Both LSDs neutralized the LPS-induced morphological changes and production of nitric oxide (NO), as determined by CCK-8 assay and Griess assay, respectively. Furthermore, shizukaol D (1) and sarcandrolide E (2) downregulated interferon ß (IFNß), tumor necrosis factor α (TNFα) and interleukin-1ß (IL-1ß) mRNA levels as measured by reverse transcription polymerase chain reaction (RT-PCR), and inhibited the phosphorylation of nuclear factor kappa B p65 (p65), nuclear factor kappa-Bα (IκBα), Jun N-terminal kinase (JNK), extracellular regulated kinase (ERK), mitogen-activated protein kinase p38 (p38), MyD88, IL-1RI-associated protein kinase 1 (IRAK1), and transforming growth factor-ß-activated kinase 1 (TAK1) proteins in the Western blotting assay. In conclusion, LSDs can alleviate the inflammatory response by inhibiting the TLR/MyD88 signalling pathway.

Hierarchical Nanospheres with Polycrystalline Ir&Cu and Amorphous Cu2 O toward Energy-Efficient Nitrate Electrolysis to Ammonia.

Electrochemical reduction reaction of nitrate (NITRR) provides a sustainable route toward the green synthesis of ammonia. Nevertheless, it remains challenging to achieve high-performance electrocatalysts for NITRR especially at low overpotentials. In this work, hierarchical nanospheres consisting of polycrystalline Iridium&copper (Ir&Cu) and amorphous Cu2 O (Cux Iry Oz NS) have been fabricated. The optimal species Cu0.86 Ir0.14 Oz delivers excellent catalytic performance with a desirable NH3 yield rate (YR) up to 0.423 mmol h-1  cm-2 (or 4.8 mg h-1  mgcat -1 ) and a high NH3 Faradaic efficiency (FE) over 90% at a low overpotential of 0.69 V (or 0 VRHE ), where hydrogen evolution reaction (HER) is almost negligible. The electrolyzer toward NITRR and hydrazine oxidation (HzOR) is constructed for the first time with an electrode pair of Cu0.86 Ir0.14 Oz //Cu0.86 Ir0.14 Oz , yielding a high energy efficiency (EE) up to 87%. Density functional theory (DFT) calculations demonstrate that the dispersed Ir atom provides active site that not only promotes the NO3 - adsorption but also modulates the H adsorption/desorption to facilitate the proton supply for the hydrogenation of *N, hence boosting the NITRR. This work thus points to the importance of both morphological/structural and compositional engineering for achieving the highly efficient catalysts toward NITRR.

Physiological functions of podosomes: From structure and function to therapy implications in osteoclast biology of bone resorption.

With increasing age, bone tissue undergoes significant alterations in composition, architecture, and metabolic functions, probably causing senile osteoporosis. Osteoporosis possess the vast majority of bone disease and associates with a reduction in bone mass and increased fracture risk. Bone loss is on account of the disorder in osteoblast-induced bone formation and osteoclast-induced bone resorption. As a unique bone resorptive cell type, mature bone-resorbing osteoclasts exhibit dynamic actin-based cytoskeletal structures called podosomes that participate in cell-matrix adhesions specialized in the degradation of mineralized bone matrix. Podosomes share many of the same molecular constitutions as focal adhesions, but they have a unique structural organization, with a central core abundant in F-actin and encircled by scaffolding proteins, kinases and integrins. Here, we conclude recent advancements in our knowledge of the architecture and the functions of podosomes. We also discuss the regulatory pathways in osteoclast podosomes, providing a reference for future research on the podosomes of osteoclasts and considering podosomes as a therapeutic target for inhibiting bone resorption.

Circadian clock genes as promising therapeutic targets for bone loss.

The circadian clock regulates many key physiological processes such as the sleep-wake cycle, hormone release, cardiovascular health, glucose metabolism and body temperature. Recent evidence has suggested a critical role of the circadian system in controlling bone metabolism. Here we review the connection between bone metabolism and the biological clock, and the roles of these mechanisms in bone loss. We also analyze the regulatory effects of clock-related genes on signaling pathways and transcription factors in osteoblasts and osteoclasts. Additionally, osteocytes and endothelial cells (ECs) regulated by the circadian clock are also discussed in our review. Furthermore, we also summarize the regulation of circadian clock genes by some novel modulators, which provides us with a new insight into a potential strategy to prevent and treat bone diseases such as osteoporosis by targeting circadian genes.