Hyaluronic acid dissolving microneedle patch loaded with tranexamic acid for melasma treatment.

Melasma is an acquired hypermelanotic condition characterized by the presence of irregular light-to-dark brown macules that primarily manifest on the sun-exposed areas of the skin, particularly the face. The management of melasma poses significant challenges, as it is often recalcitrant to treatment and tends to recur despite successful treatment. In this study, we explored a safe, easy, and effective melasma treatment strategy. A hyaluronic acid (HA)-based microneedle (MN) patch loaded with tranexamic acid (TXA) was designed to deliver the necessary medication for melasma treatment. The MN patch features uniform needles with adequate mechanical strength and effective penetration and solubility in the skin without cytotoxicity. Remarkably, these MNs substantially reduce the thickness of the epidermis of melasma mice, curtail melanin production, and diminish dopachrome tautomerase (DCT) expression.

Novel Carrier-Free Nanodrug Enhances Photodynamic Effects by Blocking the Autophagy Pathway and Synergistically Triggers Immunogenic Cell Death for the Efficient Treatment of Breast Cancer.

Photosensitizers have been widely used to cause intratumoral generation of reactive oxygen species (ROS) for cancer therapy, but they are easily disturbed by the autophagy pathway, a self-protective mechanism by mitigating oxidative damage. Hereby, we reported a simple and effective strategy to construct a carrier-free nanodrug, Ce6@CQ namely, based on the self-assembly of the photosensitizer chlorin e6 (Ce6) and the autophagy inhibitor chloroquine (CQ). Specifically, Ce6@CQ avoided the unexpected toxicity caused by the regular nanocarrier and also ameliorated its stability in different conditions. Light-activated Ce6 generated cytotoxic ROS and elicited part of the immunogenic cell death (ICD). Moreover, CQ induced autophagy dysfunction, which hindered self-healing in tumor cells and enhanced photodynamic therapy (PDT) to exert a more potent killing effect and more efficient ICD. Also, Ce6@CQ could effectively accumulate in the xenograft breast tumor site in a mouse model through the enhanced permeability and retention (EPR) effect, and the growth of breast tumors was effectively inhibited by Ce6@CQ with light. Such a carrier-free nanodrug provided a new strategy to improve the efficacy of PDT via the suppression of autophagy to digest ROS-induced toxic substances.

Self-powered freestanding multifunctional microneedle-based extended gate device for personalized health monitoring.

Online monitoring of prognostic biomarkers is critically important when diagnosing disorders and assessing individuals' health, especially for chronic and infectious diseases. Despite this, current diagnosis techniques are time-consuming, labor-intensive, and performed offline. In this context, developing wearable devices for continuous measurements of multiple biomarkers from body fluids has considerable advantages including availability, rapidity, convenience, and minimal invasiveness over the conventional painful and time-consuming tools. However, there is still a significant challenge in powering these devices over an extended period, especially for applications that require continuous and long-term health monitoring. Herein, a new freestanding, wearable, multifunctional microneedle-based extended gate field effect transistor biosensor is fabricated for online detection of multiple biomarkers from the interstitial fluid including sodium, calcium, potassium, and pH along with excellent electrical response, reversibility, and precision. In addition, a hybrid powering system of triboelectric nanogenerator and solar cell was developed for creating a freestanding, closed-loop platform for continuous charging of the device's battery and integrated with an Internet of Things technology to broadcast the measurements online, suggesting a stand-alone, stable multifunctional tool which paves the way for advanced practical personalized health monitoring and diagnosis.

Adipose Tissue Targeting Ultra-Small Hybrid Nanoparticles for Synergistic Photodynamic Therapy and Browning Induction in Obesity Treatment.

Photodynamic therapy (PDT), as a means of locally and rapidly inducing adipocyte death via light illumination, in combination with adipose browning induction, a more gradual and widespread effect that could transform white adipose tissue into thermogenic adipose tissue, manifests a promising approach to combat obesity. Herein, adipose-targeting ultra-small hybrid nanoparticles (Pep-PPIX-Baic NPs) composed of an adipose-targeting peptide, Fe3+, a photosensitizer (protoporphyrin IX), and a browning agent (baicalin) are introduced. Pep-PPIX-Baic NPs have been designed to simultaneously enhance the photodynamic effect and induce browning. After intravenous injection in obese mice, the hybrid nanoparticles can specifically accumulate in white adipose tissues, especially those rich in blood supply, and drive adipose reduction owing to the synergy of the PDT effect and baicalin browning induction. Overall, Pep-PPIX-Baic NPs exhibited superior anti-obesity potential through PDT synergistic with adipose browning induction. The designed multifunctional adipose-targeting hybrid nanoparticles present a prospective nanoplatform for obesity treatment.

Association of iron status with all-cause and cause-specific mortality in individuals with diabetes.

AIMS: Current evidence regarding iron status and mortality risk among patients with diabetes is limited. This study aimed to evaluate association of iron indices with all-cause and cause-specific mortality risk among patients with diabetes. METHODS: The current study included 2080 (with ferritin data), 1974 (with transferrin saturation (Tsat) data), and 1106 (with soluble transferrin receptor (sTfR) data) adults with diabetes from NHANES 1999-2018. Death outcomes were obtained from National Death Index through December 31, 2019. Cox proportional hazards models were employed to calculate hazard ratios and 95% confidence intervals for mortality. RESULTS: Association with all-cause mortality was demonstrated to be J-shaped for serum ferritin (Pnonlinearity < 0.01), U-shaped for Tsat (Pnonlinearity < 0.01) and linear for sTfR (Plinearity < 0.01). Ferritin 300-500 ng/mL possessed lower all-cause mortality risk than ferritin ≤ 100 ng/mL, 100-300 ng/mL, and > 500 ng/mL. Tsat 25-32 % showed a protective effect on all-cause mortality risk compared with Tsat ≤ 20 %, 20-25 %, and > 32 %. Individuals with sTfR < 4 mg/L were associated with a lower risk of all-cause mortality than those with higher sTfR. CONCLUSIONS: Moderate levels of serum ferritin (300-500 ng/mL), Tsat (25 %-32 %) and a lower concentration of sTfR (< 4 mg/L) identified adults with diabetes with lower all-cause mortality risk, adding novel modifiers to diabetes management.

Gut microbiota regulates postprandial GLP-1 response via ileal bile acid-TGR5 signaling.

The gut microbiota interacts with intestinal epithelial cells through microbial metabolites to regulate the release of gut hormones. We investigated whether the gut microbiota affects the postprandial glucagon-like peptide-1 (GLP-1) response using antibiotic-treated mice and germ-free mice. Gut microbiome depletion completely abolished postprandial GLP-1 response in the circulation and ileum in a lipid tolerance test. Microbiome depletion did not influence the GLP-1 secretory function of primary ileal cells in response to stimulators in vitro, but dramatically changed the postprandial dynamics of endogenous bile acids, particularly ω-muricholic acid (ωMCA) and hyocholic acid (HCA). The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) but not farnesoid X receptor (FXR), participated in the regulation of postprandial GLP-1 response in the circulation and ileum, and ωMCA or HCA stimulated GLP-1 secretion via TGR5. Finally, fecal microbiota transplantation or ωMCA and HCA supplementation restored postprandial GLP-1 response. In conclusion, gut microbiota is indispensable for maintaining the postprandial GLP-1 response specifically in the ileum, and bile acid (ωMCA and HCA)-TGR5 signaling is involved in this process. This study helps to understand the essential interplay between the gut microbiota and host in regulating postprandial GLP-1 response and opens the foundation for new therapeutic targets.

Fecal short chain fatty acids modify therapeutic effects of sleeve gastrectomy.

Aims: We aimed to investigate changes of fecal short chain fatty acids (SCFAs) and their association with metabolic benefits after sleeve gastrectomy (SG). Specifically, whether pre-surgery SCFAs modify surgical therapeutic effects was determined. Methods: 62 participants with measurements of fecal SCFAs and metabolic indices before and 1, 3, 6 months after SG were included. Changes of fecal SCFAs and their association with post-surgery metabolic benefits were calculated. Then, participants were stratified by medians of pre-surgery fecal SCFAs and modification effects of pre-surgery fecal SCFAs on surgical therapeutic effects were investigated, through calculating interaction of group by surgery. Results: Fecal SCFAs were markedly changed by SG. Changes of propionate and acetate were positively correlated with serum triglycerides and total cholesterol, respectively. Notably, high pre-surgery fecal hexanoate group showed a better effect of SG treatment on lowering body weight (P=0.01), BMI (P=0.041) and serum triglycerides (P=0.031), and low pre-surgery fecal butyrate had a better effect of SG on lowering ALT (P=0.003) and AST (P=0.019). Conclusion: Fecal SCFAs were changed and correlated with lipid profiles improvement after SG. Pre-surgery fecal hexanoate and butyrate were potential modifiers impacting metabolic benefits of SG.

A carrier-free supramolecular nano-twin-drug for overcoming irinotecan-resistance and enhancing efficacy against colorectal cancer.

Irinotecan (Ir) is commonly employed as a first-line chemotherapeutic treatment for colorectal cancer (CRC). However, tremendous impediments remain to be addressed to surmount drug resistance and ameliorate adverse events. Poly-ADP-Ribose Polymerase (PARP) participates in the maintenance of genome stability and the repair of DNA damage, thus playing a critical role in chemotherapy resistance. In this work, we introduce a novel curative strategy that utilizes nanoparticles (NPs) prepared by dynamic supramolecular co-assembly of Ir and a PARP inhibitor (PARPi) niraparib (Nir) through π-π stacking and hydrogen bond interactions. The Ir and Nir self-assembled Nano-Twin-Drug of (Nir-Ir NPs) could enhance the therapeutic effect on CRC by synergistically inhibiting the DNA damage repair pathway and activating the tumor cell apoptosis process without obvious toxicity. In addition, the Nir-Ir NPs could effectively reverse irinotecan-resistance by inhibiting the expression of multiple resistance protein-1 (MRP-1). Overall, our study underscores the distinctive advantages and potential of Nir-Ir NPs as a complementary strategy to chemotherapy by simultaneously overcoming the Ir resistance and improving the anti-tumor efficacy against CRC.

Discovery of dolutegravir-1,2,3-triazole derivatives against prostate cancer via inducing DNA damage.

Prostate cancer (PCa) is the second most frequently diagnosed cancer among men, causing a huge number of deaths each year. Traditional chemotherapy for PCa mostly focused on targeting androgen receptors. However, some of the patients would develop resistance to hormonal therapy. In these cases, it is suggested for these patients to administer treatments in combination with other chemotherapeutics. Current chemotherapeutics for metastatic castration-resistant PCa could hardly reach satisfying effects, therefore it is crucial to explore novel agents with low cytotoxicity. Herein, a common drug against the human immunodeficiency virus (HIV), the dolutegravir (DTG) was modified to become a series of dolutegravir-1,2,3-triazole derivatives. Among these compounds, the 4d and 4q derivatives were verified with high anti-tumor efficiency, suppressing the proliferation of the prostate cancer cells PC3 and DU145. These compounds function by binding to the poly (adenosine diphosphate-ribose) polymerase (PARP), inactivating the PARP and inducing DNA damage in cancer cells. It is noteworthy that the 4d and 4q derivatives showed almost no impact on normal cells and mice. Thereby, the results reveal that these dolutegravir-1,2,3-triazole compounds are potential chemotherapeutics for PCa treatment.

Genetic Basis and Expression Pattern Indicate the Biocontrol Potential and Soil Adaption of Lysobacter capsici CK09.

Lysobacter species have attracted increasing attention in recent years due to their capacities to produce diverse secondary metabolites against phytopathogens. In this research, we analyzed the genomic and transcriptomic patterns of Lysobacter capsici CK09. Our data showed that L. capsici CK09 harbored various contact-independent biocontrol traits, such as fungal cell wall lytic enzymes and HSAF/WAP-8294A2 biosynthesis, as well as several contact-dependent machineries, including type 2/4/6 secretion systems. Additionally, a variety of hydrolytic enzymes, particularly extracellular enzymes, were found in the L. capsici CK09 genome and predicted to improve its adaption in soil. Furthermore, several systems, including type 4 pili, type 3 secretion system and polysaccharide biosynthesis, can provide a selective advantage to L. capsici CK09, enabling the species to live on the surface in soil. The expression of these genes was then confirmed via transcriptomic analysis, indicating the activities of these genes. Collectively, our research provides a comprehensive understanding of the biocontrol potential and soil adaption of L. capsici CK09 and implies the potential of this strain for application in the future.

An ultrasmall PVP-Fe-Cu-Ni-S nano-agent for synergistic cancer therapy through triggering ferroptosis and autophagy.

Photothermal therapy (PTT) is an emerging field where photothermal agents could convert visible or near-infrared (NIR) radiation into heat to kill tumor cells. However, the low photothermal conversion efficiency of photothermal agents and their limited antitumor activities hinder the development of these agents into monotherapies for cancer. Herein, we have fabricated an ultrasmall polyvinylpyrrolidone (PVP)-Fe-Cu-Ni-S (PVP-NP) nano-agent via a simple hot injection method with excellent photothermal conversion efficiency (∼96%). Photothermal therapy with this nano-agent effectively inhibits tumor growth without apparent toxic side-effects. Mechanistically, our results demonstrated that, after NIR irradiation, PVP-NPs can induce ROS/singlet oxygen generation, decrease the mitochondrial membrane potential, release extracellular Fe2+, and consume glutathione, triggering autophagy and ferroptosis of cancer cells. Moreover, PVP-NPs exhibit excellent contrast enhancement according to magnetic resonance imaging (MRI) analysis. In summary, PVP-NPs have a high photothermal conversion efficiency and can be applied for MRI-guided synergistic photothermal/photodynamic/chemodynamic cancer therapy, resolving the bottleneck of existing phototherapeutic agents.

Toxicity Analysis of Mesoporous Polydopamine on Intestinal Tissue and Microflora.

As a promising therapy, photothermal therapy (PTT) converts near-infrared (NIR) light into heat through efficient photothermal agents (PTAs), causing a rapid increase in local temperature. Considering the importance of PTAs in the clinical application of PTT, the safety of PTAs should be carefully evaluated before their widespread use. As a promising PTA, mesoporous polydopamine (MPDA) was studied for its clinical applications for tumor photothermal therapy and drug delivery. Given the important role that intestinal microflora plays in health, the impacts of MPDA on the intestine and on intestinal microflora were systematically evaluated in this study. Through biological and animal experiments, it was found that MPDA exhibited excellent biocompatibility, in vitro and in vivo. Moreover, 16S rRNA analysis demonstrated that there was no obvious difference in the composition and classification of intestinal microflora between different drug delivery groups and the control group. The results provided new evidence that MPDA was safe to use in large doses via different drug delivery means, and this lays the foundation for further clinical applications.

Volatolomics in healthcare and its advanced detection technology.

Various diseases increasingly challenge the health status and life quality of human beings. Volatolome emitted from patients has been considered as a potential family of markers, volatolomics, for diagnosis/screening. There are two fundamental issues of volatolomics in healthcare. On one hand, the solid relationship between the volatolome and specific diseases needs to be clarified and verified. On the other hand, effective methods should be explored for the precise detection of volatolome. Several comprehensive review articles had been published in this field. However, a timely and systematical summary and elaboration is still desired. In this review article, the research methodology of volatolomics in healthcare is critically considered and given out, at first. Then, the sets of volatolome according to specific diseases through different body sources and the analytical instruments for their identifications are systematically summarized. Thirdly, the advanced electronic nose and photonic nose technologies for volatile organic compounds (VOCs) detection are well introduced. The existed obstacles and future perspectives are deeply thought and discussed. This article could give a good guidance to researchers in this interdisciplinary field, not only understanding the cutting-edge detection technologies for doctors (medicinal background), but also making reference to clarify the choice of aimed VOCs during the sensor research for chemists, materials scientists, electronics engineers, etc.

2-Deoxy-D-glucose and combined 2-Deoxy-D-glucose/albendazole exhibit therapeutic efficacy against Echinococcus granulosus protoscoleces and experimental alveolar echinococcosis.

2-Deoxy-D-glucose (2-DG) is a glucose analog used as a promising anticancer agent. It exerts its effects by inhibiting the glycolytic energy metabolism to deplete cells of energy. The larval stage of Echinococcus relies on glycolysis for energy production. Therefore, in this study, we investigated the in vitro and in vivo efficacy of 2-DG against the larval stage of Echinococcus granulosus and E. multilocularis. 2-DG exhibited significant time- and dose-dependent effects against in vitro cultured E. granulosus protoscoleces and E. multilocularis metacestodes. A daily oral administration of 500 mg/kg 2-DG in E. multilocularis-infected mice effectively reduced the weight of metacestodes. Notably, the combination treatment, either 2-DG (500 mg/kg/day) + albendazole (ABZ) (200 mg/kg/day) or 2-DG (500 mg/kg/day) + half-dose of ABZ (100 mg/kg/day), exhibited a potent therapeutic effect against E. multilocularis, significantly promoting the reduction of metacestodes weight compared with the administration of 2-DG or ABZ alone. Furthermore, the combination significantly promoted apoptosis of the cells of metacestodes and inhibited glycolysis in metacestodes, compared with the administration of 2-DG or ABZ alone. In conclusion, 2-DG exerts an effective activity against the larval stage of Echinococcus. Thus, it may be a promising anti-Echinococcus drug, and its combination with ABZ may provide a new strategy for the treatment of echinococcosis in humans.

Artificially Intelligent Olfaction for Fast and Noninvasive Diagnosis of Bladder Cancer from Urine.

Globally, bladder cancer (BLC) is one of the most common cancers and has a high recurrence and mortality rate. Current clinical diagnostic approaches are either invasive or inaccurate. Here, we report on a cost-efficient, artificially intelligent chemiresistive sensor array made of polyaniline (PANI) derivatives that can noninvasively diagnose BLC at an early stage and maintain postoperative surveillance through ″smelling″ clinical urine samples at room temperature. In clinical trials, 18 healthy controls and 76 BLC patients (60 and 16 at early and advanced stages, respectively) are assessed by the artificial olfactory system. With the assistance of a support vector machine (SVM), very high sensitivity and accuracy from healthy controls are achieved, exceeding those obtained by the current techniques in practice. In addition, the recurrences of both early and advanced stages are diagnosed well, with the effect of confounding factors on the performance of the artificial olfactory system found to have a negligible influence on the diagnostic performance. Overall, this study contributes a novel, noninvasive, easy-to-use, inexpensive, real-time, accurate method for urine disease diagnosis, which can be useful for personalized care/diagnosis and postoperative surveillance, resulting in saving more lives.

RNA-Seq Based Toxicity Analysis of Mesoporous Polydopamine Nanoparticles in Mice Following Different Exposure Routes.

Mesoporous polydopamine nanoparticles (MPDA NPs) are promising nanomaterials that have the prospect of clinical application for multi-strategy antitumor therapy, while the biosecurity of MPDA NPs remains indistinct. Here, transcriptome sequencing (RNA-Seq) was performed to systematically reveal the toxicity of MPDA NPs to five categories of organs after three different exposure routes, including intravenous injection, intramuscular injection, and intragastric administration. Our results uncovered that MPDA NPs could be deposited in various organs in small amounts after intravenous administration, not for the other two exposure routes. The number of differentially expressed genes (DEGs) identified in the heart, liver, spleen, lung, and kidney from the intragastric administration group was from 22 to 519. Similarly, the corresponding number was from 23 to 64 for the intramuscular injection group and was from 11 to 153 for the intravenous injection group. Functional enrichment analyses showed 6, 39, and 4 GO terms enriched for DEGs in intragastric administration, intramuscular injection, and intravenous injection groups, respectively. One enriched pathway was revealed in intragastric administration group, while no enriched pathway was found in other groups. Our results indicated that MPDA NPs produced only slight changes at the transcriptome level in mice, which provided new insights for further clinical application of MPDA NPs.

Effects of Surface Polarity on the Structure and Magnetic Properties of Co Implanted and Co-Sm Co-Implanted Polar ZnO Films.

We present a comprehensive experimental and theoretical study of the effects of surface polarity on the structure and ferromagnetic properties of Co implanted and Co-Sm co-implanted polar ZnO films deposited on sapphire substrates by molecular beam epitaxy. Substantial intrinsic ferromagnetism (FM) is found for all the implanted polar ZnO films. The magnetization of O-polar ZnO is observed to be higher than that of Zn-polar ZnO under the same implantation conditions, and the magnetization is enhanced for Co-Sm co-implanted ZnO in contrast with unimplanted and Co implanted films. First-principles calculations reveal that the Sm 4f and Co 3d states have strong hybridization with the O 2p state in O-polar ZnO, leading to larger magnetic moments for Co and Co-Sm substituting Zn atoms on the O-polar surface. Meanwhile, X-ray photoelectron spectroscopy results confirm that more oxygen vacancies are introduced into O-polar films by implantation and annealing. We consider that the stronger ferromagnetism in O-polar ZnO is associated with the combined influence of more oxygen vacancies and larger local moments related to Co and Sm doping. These results not only contribute to understanding the origin of FM in diluted magnetic semiconductors but also highlight the feasibility of developing polar spintronic devices for future polar thin film systems.

Sprayable hydrogel for biomedical applications.

Polymeric hydrogels have extraordinary potential to be utilized for biomedical applications. Recently, sprayable hydrogels have received increasing attention for their biocompatibility, degradability, tunable mechanical properties and rapid spray-filming abilities. In this review, hydrogel-based biomaterials, especially those based on natural polymers, such as polysaccharides and proteins, have been explained. The focus of this review lies on illuminating recent advances in sprayable hydrogel systems and highlighting the properties and applications of sprayable hydrogels, such as wound management, postoperative adhesion and cancer therapeutics. In addition, future research directions and challenges are also discussed.

Effects of Echinococcus multilocularis metacestodes infection and drug treatment on the activities of biotransformation enzymes in mouse liver.

The changes of biotransformation enzymes will substantially affect the host's ability to metabolize drugs and other xenobiotic compounds. In order to further elucidate this process and promote the development in treatment of echinococcosis, we investigated the effects of Echinococcus multilocularis infection and drug treatment on biotransformation enzymes in mouse liver. In microsomal and cytosolic fractions, from the six activities assayed, significant decrease of glutathione S-transferases (GST) activity and significant increase of 7-pentoxyresorufin (PROD) and NADPH-cytochrome P450 reductase (CPR) activity were observed in the mice infected with E. multilocularis metacestodes. In addition, after six weeks treatment of albendazole in E. multilocularis infected mice, significant decreased GST activity and significant increase of 7- ethoxyresorufin (EROD), PROD, and particularly 3-fold higher 7-methoxyresorufin (MROD) activity were observed. The 3-bromopyruvate treated mice only exhibited significantly lower GST activity. Our results demonstrate that E. multilocularis metacestodes infection can affect the activities of main hepatic biotransformation enzymes and such alterations of activity may further affect the hepatic biotransformation of xenobiotics. Moreover, albendazole and 3-bromopyruvate, the promising potential drug against Echinococcus, affected different hepatic biotransformation enzymes and may affect their metabolism. The findings will help to develop rational treatments with less side effects and promote the development of more efficient treatments against E. multilocularis.