Advancing teeth whitening efficacy via dual-phototherapeutic strategy incorporating molybdenum disulfide embedded in carrageenan hydrogel for dental healthcare.

Teeth discoloration poses a widespread challenge in dental health across various regions. Conventional teeth whitening methods often result in enamel deterioration and soft tissue harm due to the utilization of incompatible whitening agents and continuous intense light exposure. Here, we propose an effective phototherapy technique for teeth whitening, employing pathways of energy transition through intersystem crossing. The integration of MoS2 nanosheets into carrageenan gel (MoS2 NSs@Carr) facilitates both photothermal-hyperthermia and the generation of reactive oxygen species (ROS) through photocatalytic processes. The efficacy of ROS generation by the phototherapeutic MoS2 NSs@Carr on teeth whitening in all scenarios. This approach ensures comprehensive teeth whitening by eliminating deep-seated stains on the teeth while preserving structural integrity and avoiding any tissue toxicity. This research highlights the efficacy of the phototherapeutic MoS2 NSs@Carr for dental whitening and underscores the potential of exploring nanostructures based on MoS2 NSs for treating oral ailments.

Facile fabrication of recyclable robust noncovalent porous crystals from low-symmetry helicene derivative.

Porous frameworks constructed via noncovalent interactions show wide potential in molecular separation and gas adsorption. However, it remains a major challenge to prepare these materials from low-symmetry molecular building blocks. Herein, we report a facile strategy to fabricate noncovalent porous crystals through modular self-assembly of a low-symmetry helicene racemate. The P and M enantiomers in the racemate first stack into right- and left-handed triangular prisms, respectively, and subsequently the two types of prisms alternatively stack together into a hexagonal network with one-dimensional channels with a diameter of 14.5 Å. Remarkably, the framework reveals high stability upon heating to 275 °C, majorly due to the abundant π-interactions between the complementarily engaged helicene building blocks. Such porous framework can be readily prepared by fast rotary evaporation, and is easy to recycle and repeatedly reform. The refined porous structure and enriched π-conjugation also favor the selective adsorption of a series of small molecules.

Enzymes encapsulated in organic-inorganic hybrid nanoflower with spatial localization for sensitive and colorimetric detection of formate.

Formate is an important environmental pollutant, and meanwhile its concentration change is associated with a variety of diseases. Thus, rapid and sensitive detection of formate is critical for the biochemical analysis of complex samples and clinical diagnosis of multiple diseases. Herein, a colorimetric biosensor was constructed based on the cascade catalysis of formate oxidase (FOx) and horseradish peroxidase (HRP). These two enzymes were co-immobilized in Cu3(PO4)2-based hybrid nanoflower with spatial localization, in which FOx and HRP were located in the shell and core of nanoflower, respectively (FOx@HRP). In this system, FOx could catalyze the oxidation of formate to generate H2O2, which was then utilized by HRP to oxidize 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid to yield blue product. Ideal linear correlation could be obtained between the absorbance at 420 nm and formate concentration. Meanwhile, FOx@HRP exhibited excellent detection performance with low limit of detection (6 µM), wide linear detection range (10-900 µM), and favorable specificity, stability and reusability. Moreover, it could be applied in the detection of formate in environmental, food and biological samples with high accuracy. Collectively, FOx@HRP provides a useful strategy for the simple and sensitive detection of formate and is potentially to be used in biochemical analysis and clinical diagnosis.

Polyphenols as Potential Antioxidants for the Treatment of Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IDD) is a common musculoskeletal system disease, which is one of the most important causes of low back pain. Despite the high prevalence of IDD, current treatments are limited to relieving symptoms, and there are no effective therapeutic agents that can block or reverse the progression of IDD. Oxidative stress, the result of an imbalance between the production of reactive oxygen species (ROS) and clearance by the antioxidant defense system, plays an important role in the progression of IDD. Polyphenols are antioxidant compounds that can inhibit ROS production, which can scavenge free radicals, reduce hydrogen peroxide production, and inhibit lipid oxidation in nucleus pulposus (NP) cells and IDD animal models. In this review, we discussed the antioxidant effects of polyphenols and their regulatory role in different molecular pathways associated with the pathogenesis of IDD, as well as the limitations and future prospects of polyphenols as a potential treatment of IDD.

Spatiotemporal release of non-nucleotide STING agonist and AKT inhibitor from implantable 3D-printed scaffold for amplified cancer immunotherapy.

Immunotherapy through the activation of the stimulator of interferon genes (STING) signaling pathway is increasingly recognized for its robust anti-tumor efficacy. However, the effectiveness of STING activation is often compromised by inadequate anti-tumor immunity and a scarcity of primed immune cells in the tumor microenvironment. Herein, we design and fabricate a co-axial 3D-printed scaffold integrating a non-nucleotide STING agonist, SR-717, and an AKT inhibitor, MK-2206, in its respective shell and core layers, to synergistically enhance STING activation, thereby suppressing tumor recurrence and growth. SR-717 initiates the STING activation to enhance the phosphorylation of the factors along the STING pathway, while MK-2206 concurrently inhibits the AKT phosphorylation to facilitate the TBK1 phosphorylation of the STING pathway. The sequential and sustained release of SR-717 and MK-2206 from the scaffold results in a synergistic STING activation, demonstrating substantial anti-tumor efficacy across multiple tumor models. Furthermore, the scaffold promotes the recruitment and enrichment of activated dendritic cells and M1 macrophages, subsequently stimulating anti-tumor T cell activity, thereby amplifying the immunotherapeutic effect. This precise and synergistic activation of STING by the scaffold offers promising potential in tumor immunotherapy.

Bacterial c-di-GMP triggers metamorphosis of mussel larvae through a STING receptor.

Bacteria induced metamorphosis observed in nearly all marine invertebrates. However, the mechanism of bacteria regulating the larvae-juvenile metamorphosis remains unknown. Here, we test the hypothesis that c-di-GMP, a ubiquitous bacterial second-messenger molecule, directly triggers the mollusc Mytilus coruscus larval metamorphosis via the stimulator of interferon genes (STING) receptor. We determined that the deletion of c-di-GMP synthesis genes resulted in reduced c-di-GMP levels and biofilm-inducing activity on larval metamorphosis, accompanied by alterations in extracellular polymeric substances. Additionally, c-di-GMP extracted from tested varying marine bacteria all exhibited inducing activity on larval metamorphosis. Simultaneously, through pharmacological and molecular experiments, we demonstrated that M. coruscus STING (McSTING) participates in larval metamorphosis by binding with c-di-GMP. Our findings reveal that new role of bacterial c-di-GMP that triggers mussel larval metamorphosis transition, and extend knowledge in the interaction of bacteria and host development in marine ecosystems.

Non-voltage gated Ca2+ channel signaling in glomerular cells in kidney health and disease.

Positioned at the head of the nephron, the renal corpuscle generates a plasma ultrafiltrate to initiate urine formation. Three major cell types within the renal corpuscle, the glomerular mesangial cells, podocytes, and glomerular capillary endothelial cells communicate via endocrine and paracrine signaling mechanisms to maintain structure and function of the glomerular capillary network and filtration barrier. Ca2+ signaling mediated by several distinct plasma membrane Ca2+ channels modulates the functions of all three cell types. The last two decades have witnessed pivotal advances in understanding of Ca2+ channel function and regulation in glomerular cells, particularly non-voltage gated Ca2+ channels, in health and renal disease. This review summarizes the current knowledge of the physiological and pathological impact of non-voltage gated Ca2+ channel signaling in glomerular capillary endothelium, mesangial cells and podocytes. The main focus is on transient receptor potential and store-operated Ca2+ channels, but ionotropic N-methyl-D-aspartate receptors and purinergic 2X receptors also are discussed. This update of Ca2+ channel functions in the renal corpuscle and their cellular signaling cascades is intended to inform development of therapeutic strategies targeting these channels to treat kidney diseases, particularly diabetic nephropathy.

Smart Microneedle Arrays Integrating Cell-Free Therapy and Nanocatalysis to Treat Liver Fibrosis.

Liver fibrosis is a chronic pathological condition lacking specific clinical treatments. Stem cells, with notable potential in regenerative medicine, offer promise in treating liver fibrosis. However, stem cell therapy is hindered by potential immunological rejection, carcinogenesis risk, efficacy variation, and high cost. Stem cell secretome-based cell-free therapy offers potential solutions to address these challenges, but it is limited by low delivery efficiency and rapid clearance. Herein, an innovative approach for in situ implantation of smart microneedle (MN) arrays enabling precisely controlled delivery of multiple therapeutic agents directly into fibrotic liver tissues is developed. By integrating cell-free and platinum-based nanocatalytic combination therapy, the MN arrays can deactivate hepatic stellate cells. Moreover, they promote excessive extracellular matrix degradation by more than 75%, approaching normal levels. Additionally, the smart MN arrays can provide hepatocyte protection while reducing inflammation levels by ≈70-90%. They can also exhibit remarkable capability in scavenging almost 100% of reactive oxygen species and alleviating hypoxia. Ultimately, this treatment strategy can effectively restrain fibrosis progression. The comprehensive in vitro and in vivo experiments, supplemented by proteome and transcriptome analyses, substantiate the effectiveness of the approach in treating liver fibrosis, holding immense promise for clinical applications.

Neurotransmitters: Impressive regulators of tumor progression.

In contemporary times, tumors have emerged as the primary cause of mortality in the global population. Ongoing research has shed light on the significance of neurotransmitters in the regulation of tumors. It has been established that neurotransmitters play a pivotal role in tumor cell angiogenesis by triggering the transformation of stromal cells into tumor cells, modulating receptors on tumor stem cells, and even inducing immunosuppression. These actions ultimately foster the proliferation and metastasis of tumor cells. Several major neurotransmitters have been found to exert modulatory effects on tumor cells, including the ability to restrict emergency hematopoiesis and bind to receptors on the postsynaptic membrane, thereby inhibiting malignant progression. The abnormal secretion of neurotransmitters is closely associated with tumor progression, suggesting that focusing on neurotransmitters may yield unexpected breakthroughs in tumor therapy. This article presents an analysis and outlook on the potential of targeting neurotransmitters in tumor therapy.

The spectrum of Ih ice using terahertz time-domain spectroscopy.

Here, we report the frequency-dependent spectrum of ice Ih in the range of 0.2-2 THz. We confirm the presence of a feature that blue-shifts from around 1.55-1.65 THz with a decreasing temperature from 260 to 160 K. There is also a change in the trend of the refractive index of ice corresponding to a dispersion, which is also around 1.6 THz. The features are reproduced in data acquired with three commercial terahertz time-domain spectrometers. Computer-simulated spectra assign the feature to lattice translations perpendicular to the 110 and 1̄10 planes of the ice Ih crystal. The feature's existence should be recognized in the terahertz measurements of frozen aqueous solution samples to avoid false interpretations.

Exploring new frontiers: a rare case of catheter ablation for persistent atrial fibrillation in a patient with cor triatriatum sinister guided by intracardiac echocardiography.

BACKGROUND: Cor triatriatum sinister (CTS) is an uncommon congenital cardiac anomaly. Atrial fibrillation (AF) is commonly the initial symptom in patients with CTS, occurring in approximately 32% of the cases. The complexity of performing AF catheter ablation, particularly in cases with persistent AF, increases in patients with CTS due to its unique structural challenges. CASE PRESENTATION: We report the treatment course of a 60-year-old male patient diagnosed with CTS, who underwent catheter ablation of drug-refractory, persistent AF. The complex anatomical structure of the condition made catheter ablation of AF challenging. To navigate these challenges, we performed comprehensive assessments using transthoracic echocardiography and transesophageal echocardiography, along with cardiac computed tomography angiography, prior to treatment initiation. The intricate anatomy of CTS was further clarified during the procedure via intracardiac echocardiography (ICE). Additionally, the complexity of catheter manipulation was further reduced with the aid of the VIZIGO sheath and the vein of Marshall ethanol infusion to achieve effective mitral isthmus blockage, thereby circumventing the impact of the CTS membrane. CONCLUSIONS: This case underscores the complexity and potential of advanced ablation techniques in managing cardiac arrhythmias associated with unusual cardiac anatomies. During the procedure, ICE facilitated detailed modeling of the left atrium, including the membranous structure and its openings, thus providing a clearer understanding of CTS. It is noteworthy that the membrane within the CTS may serve as a potential substrate for arrhythmias, which warrants further validation through larger sample studies.

Lipid nanoparticle encapsulated oleic acid induced lipotoxicity to hepatocytes via ROS overload and the DDIT3/BCL2/BAX/Caspases signaling in vitro and in vivo.

BACKGROUND: To date, Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver disease associated with clinical complications. Dietary fatty acids have been suggested to be involved in preventing or reversing the accumulation of hepatic fat. However, contradicting roles of monounsaturated fatty acids to the liver have been implicated in various human and murine models, mainly due to the insolubility nature of fatty acids. METHODS: High pressure homogenization methods were used to fabricate oleic acid embedded lipid nanoparticles (OALNs). The in vitro and in vivo models were used to validate the physiological effect of this OALNs via various cellular and molecular approaches including cell viability essay, fluorescent staining, electron microscope, RNAseq, qPCR, Western blots, and IHC staining. RESULTS: We successfully fabricated OALNs with enhanced stability and solubility. More importantly, lipid accumulation was successfully induced in hepatocytes via the application of OALNs in a dose-dependent manner. Overload of OALNs resulted in ROS accumulation and apoptosis of hepatocytes dose-dependently. With the help of transcriptome sequencing and traditional experimental approaches, we demonstrated that the lipotoxic effect induced by OALNs was exerted via the DDIT3/BCL2/BAX/Caspases signaling. Moreover, we also verified that OALNs induced steatosis and subsequent apoptosis in the liver of mice via the activation of DDIT3 in vivo. CONCLUSIONS: In all, our results established a potential pathogenic model of NAFLD for further studies and indicated the possible involvement of DDIT3 signaling in abnormal steatosis process of the liver.

Recognition on pharmacodynamic ingredients of natural products.

Natural products (NPs) play an irreplaceable role in the intervention of various diseases and have been considered a critical source of drug development. Many new pharmacodynamic compounds with potential clinical applications have recently been derived from NPs. These compounds range from small molecules to polysaccharides, polypeptides, proteins, self-assembled nanoparticles, and extracellular vesicles. This review summarizes various active substances found in NPs. The investigation of active substances in NPs can potentiate new drug development and promote the in-depth comprehension of the mechanism of action of NPs that can be beneficial in the prevention and treatment of human diseases.

A functional study reveals CsNAC086 regulated the biosynthesis of flavonols in Camellia sinensis.

MAIN CONCLUSION: CsNAC086 was found to promote the expression of CsFLS, thus promoting the accumulation of flavonols in Camellia sinensis. Flavonols, the main flavonoids in tea plants, play an important role in the taste and quality of tea. In this study, a NAC TF gene CsNAC086 was isolated from tea plants and confirmed its regulatory role in the expression of flavonol synthase which is a key gene involved in the biosynthesis of flavonols in tea plant. Yeast transcription-activity assays showed that CsNAC086 has self-activation activity. The transcriptional activator domain of CsNAC086 is located in the non-conserved C-terminal region (positions 171-550), while the conserved NAC domain (positions 1-170) does not have self-activation activity. Silencing the CsNAC086 gene using antisense oligonucleotides significantly decreased the expression of CsFLS. As a result, the concentration of flavonols decreased significantly. In overexpressing CsNAC086 tobacco leaves, the expression of NtFLS was significantly increased. Compared with wild-type tobacco, the flavonols concentration increased. Yeast one-hybrid assays showed CsNAC086 did not directly regulate the gene expression of CsFLS. These findings indicate that CsNAC086 plays a role in regulating flavonols biosynthesis in tea plants, which has important implications for selecting and breeding of high-flavonols-concentration containing tea-plant cultivars.

Nonlinear associations between the ratio of family income to poverty and all-cause mortality among adults in NHANES study.

Socioeconomic status (SES) has been linked to mortality rates, with family income being a quantifiable marker of SES. However, the precise association between the family income-to-poverty ratio (PIR) and all-cause mortality in adults aged 40 and older remains unclear. A cross-sectional study was conducted using data from NHANES III, including 20,497 individuals. The PIR was used to assess financial status, and various demographic, lifestyle, and clinical factors were considered. Mortality data were collected from the NHANES III linked mortality file. The study revealed a non-linear association between PIR and all-cause mortality. The piecewise Cox proportional hazards regression model showed an inflection point at PIR 3.5. Below this threshold, the hazard ratio (HR) for all-cause mortality was 0.85 (95% CI 0.79-0.91), while above 3.5, the HR decreased to 0.66 (95% CI 0.57-0.76). Participants with lower income had a higher probability of all-cause mortality, with middle-income and high-income groups showing lower multivariate-adjusted HRs compared to the low-income group. This study provides evidence of a non-linear association between PIR and all-cause mortality in adults aged 40 and older, with an inflection point at PIR 3.5. These findings emphasize the importance of considering the non-linear relationship between family income and mortality when addressing socioeconomic health disparities.

Functionalized extracellular nanovesicles as advanced CRISPR delivery systems.

The clustered regularly interspaced short palindromic repeat (CRISPR) system, an emerging tool for genome editing, has garnered significant public interest for its potential in treating genetic diseases. Despite the rapid advancements in CRISPR technology, the progress in developing effective delivery strategies lags, impeding its clinical application. Extracellular nanovesicles (EVs), either in their endogenous forms or with engineered modifications, have emerged as a promising solution for CRISPR delivery. These EVs offer several advantages, including high biocompatibility, biological permeability, negligible immunogenicity, and straightforward production. Herein, we first summarize various types of functional EVs for CRISPR delivery, such as unmodified, modified, engineered virus-like particles (VLPs), and exosome-liposome hybrid vesicles, and examine their distinct intracellular pathways. Then, we outline the cutting-edge techniques for functionalizing extracellular vesicles, involving producer cell engineering, vesicle engineering, and virus-like particle engineering, emphasizing the diverse CRISPR delivery capabilities of these nanovesicles. Lastly, we address the current challenges and propose rational design strategies for their clinical translation, offering future perspectives on the development of functionalized EVs.

The Role of Alpha-7 Nicotinic Acetylcholine Receptors in Pain: Potential Therapeutic Implications.

Chronic pain represents a prevalent and costly medical challenge globally. Nicotinic acetylcholine receptors (nAChRs), one type of ligand-gated ion channels found extensively in both the central and peripheral nervous systems, have emerged as promising therapeutic targets for chronic pain. Although there are currently no FDA-approved analgesics specifically targeting nAChRs, accumulating preclinical and clinical evidence suggest that selective ligands for alpha 7 (α7) nAChRs show potential for treating chronic pain, boasting a reduced incidence of side effects compared with other nicotinic receptor types. The recent structural resolution of human α7 nAChRs has confirmed their negative association with heightened pain, providing a valuable foundation for the development of targeted medications. This review presents a comprehensive overview, encompassing insights into the roles of α7 nAChRs derived from structural and functional studies, recent advancements in pharmacology, and investigations into their involvement in the pathophysiology of chronic pain. Moreover, the review addresses the variability in analgesic effects based on the type of receptor agonist and highlights the current research limitations. As such, this review offers potential therapeutic approaches for the development of innovative strategies for chronic pain management.

Assessment of the antimicrobial and immunomodulatory activity of QS-CATH, a promising therapeutic agent isolated from the Chinese spiny frogs (Quasipaa spinosa).

Cathelicidins are important antimicrobial peptides in various vertebrate species where they are crucial parts of the innate immune system. The current understanding of amphibian cathelicidins is limited, particularly with regard to their immunomodulatory effects. To address this knowledge gap, we produced the cDNA sequence of the cathelicidin gene from a skin transcriptome of the Chinese spiny frog Quasipaa spinosa. The amino acid sequence of the Quasipaa spinosa cathelicidin (QS-CATH) was predicted to consist of a signal peptide, a cathelin domain, and a mature peptide. Comparative analysis of the QS-CATH amino acid sequence with that of other amphibian cathelicidins revealed high variability in the functional mature peptide among amphibians, whereas the cathelin domain was conserved. The QS-CATH gene was expressed in several tissues, with the highest level of expression in the spleen. Upregulation of QS-CATH after Aeromonas hydrophila infection occurred in the kidney, gut, spleen, skin, and liver. Chemically synthesized QS-CATH exhibited pronounced antibacterial activity against Shigella flexneri, Staphylococcus warneri, Escherichia coli, Salmonella enterica, and Listeria monocytogenes. Furthermore, QS-CATH disrupted the cell membrane integrity of S. flexneri, as evidenced by a lactate dehydrogenase release assay, and it hydrolyzed the genomic DNA of S. flexneri. Additionally, QS-CATH elicited chemotaxis and modulated the expression of inflammatory cytokine genes in RAW264.7 mouse leukemic monocyte/macrophage cells. These findings confirm the antimicrobial effects of amphibian cathelicidin and its ability to influence immune cell function. This will expedite the potential utilization of amphibian antimicrobial peptides as therapeutic agents.

An antifouling membrane-fusogenic liposome for effective intracellular delivery in vivo.

The membrane-fusion-based internalization without lysosomal entrapment is advantageous for intracellular delivery over endocytosis. However, protein corona formed on the membrane-fusogenic liposome surface converts its membrane-fusion performance to lysosome-dependent endocytosis, causing poorer delivery efficiency in biological conditions. Herein, we develop an antifouling membrane-fusogenic liposome for effective intracellular delivery in vivo. Leveraging specific lipid composition at an optimized ratio, such antifouling membrane-fusogenic liposome facilitates fusion capacity even in protein-rich conditions, attributed to the copious zwitterionic phosphorylcholine groups for protein-adsorption resistance. Consequently, the antifouling membrane-fusogenic liposome demonstrates robust membrane-fusion-mediated delivery in the medium with up to 38% fetal bovine serum, outclassing two traditional membrane-fusogenic liposomes effective at 4% and 6% concentrations. When injected into mice, antifouling membrane-fusogenic liposomes can keep their membrane-fusion-transportation behaviors, thereby achieving efficient luciferase transfection and enhancing gene-editing-mediated viral inhibition. This study provides a promising tool for effective intracellular delivery under complex physiological environments, enlightening future nanomedicine design.