Canagliflozin alleviates pulmonary hypertension by activating PPARγ and inhibiting its S225 phosphorylation.

Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), a novel medication for diabetes, has been found to have remarkable cardiovascular benefits. However, few studies have addressed the effect and pharmacological mechanism of CANA in the treatment of PH. Therefore, our study aimed to investigate the effect and pharmacological mechanism of CANA in treating PH. First, CANA suppressed increased pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling in both mouse and rat PH models. Network pharmacology, transcriptomics, and biological results suggested that CANA could ameliorate PH by suppressing excessive oxidative stress and pulmonary artery smooth muscle cell proliferation partially through the activation of PPARγ. Further studies demonstrated that CANA inhibited phosphorylation of PPARγ at Ser225 (a novel serine phosphorylation site in PPARγ), thereby promoting the nuclear translocation of PPARγ and increasing its ability to resist oxidative stress and proliferation. Taken together, our study not only highlighted the potential pharmacological effect of CANA on PH but also revealed that CANA-induced inhibition of PPARγ Ser225 phosphorylation increases its capacity to counteract oxidative stress and inhibits proliferation. These findings may stimulate further research and encourage future clinical trials exploring the therapeutic potential of CANA in PH treatment.

Optimized lipid nanoparticles (LNPs) for organ-selective nucleic acids delivery in vivo.

Nucleic acid therapeutics offer tremendous promise for addressing a wide range of common public health conditions. However, the in vivo nucleic acids delivery faces significant biological challenges. Lipid nanoparticles (LNPs) possess several advantages, such as simple preparation, high stability, efficient cellular uptake, endosome escape capabilities, etc., making them suitable for delivery vectors. However, the extensive hepatic accumulation of LNPs poses a challenge for successful development of LNPs-based nucleic acid therapeutics for extrahepatic diseases. To overcome this hurdle, researchers have been focusing on modifying the surface properties of LNPs to achieve precise delivery. The review aims to provide current insights into strategies for LNPs-based organ-selective nucleic acid delivery. In addition, it delves into the general design principles, targeting mechanisms, and clinical development of organ-selective LNPs. In conclusion, this review provides a comprehensive overview to provide guidance and valuable insights for further research and development of organ-selective nucleic acid delivery systems.

Oral Administration Properties Evaluation of Three Milk-derived Extracellular Vesicles Based on Ultracentrifugation Extraction Methods.

Milk-derived extracellular vesicles (M-EVs) are low-cost, can be prepared in large quantities, and can cross the gastrointestinal barrier for oral administration. However, the composition of milk is complex, and M-EVs obtained by different extraction methods may affect their oral delivery. Based on this, we propose a new method for extracting M-EVs based on cryogenic freezing treatment (Cryo-M-EVs) and compare this method with the previously reported acetic acid treatment (Acid-M-EVs) method and the conventional ultracentrifugation method (Ulltr-M-EVs). The new method simplifies the pretreatment step and achieves 25-fold and 2-fold higher yields than Acid-M-EVs and Ulltr-M-EVs. And it was interesting to note that Cryo-M-EVs and Acid-M-EVs had higher cellular uptake efficiency, and Cryo-M-EVs presented the best transepithelial transport effect. After oral administration of the three M-EVs extracted by three methods in mice, Cryo-M-EVs effectively successfully crossed the gastrointestinal barrier and achieved hepatic accumulation, whereas Acid-M-EVs and Ultr-M-EVs mostly resided in the intestine. The M-EVs obtained by the three extraction methods showed a favorable safety profile at the cellular as well as animal level. Therefore, when M-EVs obtained by different extraction methods are used for oral drug delivery, we can utilize their accumulation properties at different sites to better deal with different diseases. This article is protected by copyright. All rights reserved.

Antimicrobial resistance and population genomics of emerging multidrug-resistant Salmonella 4,[5],12:i:- in Guangdong, China.

Salmonella 4,[5],12:i:-, a monophasic variant of Salmonella Typhimurium, has emerged as a global cause of multidrug-resistant salmonellosis and has become endemic in many developing and developed countries, especially in China. Here, we have sequenced 352 clinical isolates in Guangdong, China, during 2009-2019 and performed a large-scale collection of Salmonella 4,[5],12:i:- with whole genome sequencing (WGS) data across the globe, to better understand the population structure, antimicrobial resistance (AMR) genomic characterization, and transmission routes of Salmonella 4,[5],12:i:- across Guangdong. Salmonella 4,[5],12:i:- strains showed broad genetic diversity; Guangdong isolates were found to be widely distributed among the global lineages. Of note, we identified the formation of a novel Guangdong clade (Bayesian analysis of population structure lineage 1 [BAPS1]) genetically diversified from the global isolates and likely emerged around 1990s. BAPS1 exhibits unique genomic features, including large pan-genome, decreased ciprofloxacin susceptibility due to mutation in gyrA and carriage of plasmid-mediated quinolone resistance (PMQR) genes, and the multidrug-resistant IncHI2 plasmid. Furthermore, high genetic similarity was found between strains collected from Guangdong, Europe, and North America, indicating the association with multiple introductions from overseas. These results suggested that global dissemination and local clonal expansion simultaneously occurred in Guangdong, China, and horizontally acquired resistance to first-line and last-line antimicrobials at local level, underlying emergences of extensive drug and pan-drug resistance. Our findings have increased the knowledge of global and local epidemics of Salmonella 4,[5],12:i:- in Guangdong, China, and provided a comprehensive baseline data set essential for future molecular surveillance.IMPORTANCESalmonella 4,[5],12:i:- has been regarded as the predominant pandemic serotype causing diarrheal diseases globally, while multidrug resistance (MDR) constitutes great public health concerns. This study provided a detailed and comprehensive genome-scale analysis of this important Salmonella serovar in the past decade in Guangdong, China. Our results revealed the complexity of two distinct transmission modes, namely global transmission and local expansion, circulating in Guangdong over a decade. Using phylogeography models, the origin of Salmonella 4,[5],12:i:- was predicted from two aspects, year and country, that is, Salmonella 4,[5],12:i:- emerged in 1983, and was introduced from the UK, and subsequently differentiated into the local endemic lineage circa 1991. Additionally, based on the pan-genome analysis, it was found that the gene accumulation rate in local endemic BAPS 1 lineage was higher than in other lineages, and the horizontal transmission of MDR IncHI2 plasmid associated with high resistance played a major role, which showed the potential threat to public health.

Taurine attenuates activation of hepatic stellate cells by inhibiting autophagy and inducing ferroptosis.

BACKGROUND: Liver fibrosis is a compensatory response during the tissue repair process in chronic liver injury, and finally leads to liver cirrhosis or even hepatocellular carcinoma. The pathogenesis of hepatic fibrosis is associated with the progressive accumulation of activated hepatic stellate cells (HSCs), which can transdifferentiate into myofibroblasts to produce an excess of the extracellular matrix (ECM). Myofibroblasts are the main source of the excessive ECM responsible for hepatic fibrosis. Therefore, activated hepatic stellate cells (aHSCs), the principal ECM producing cells in the injured liver, are a promising therapeutic target for the treatment of hepatic fibrosis. AIM: To explore the effect of taurine on aHSC proliferation and the mechanisms involved. METHODS: Human HSCs (LX-2) were randomly divided into five groups: Normal control group, platelet-derived growth factor-BB (PDGF-BB) (20 ng/mL) treated group, and low, medium, and high dosage of taurine (10 mmol/L, 50 mmol/L, and 100 mmol/L, respectively) with PDGF-BB (20 ng/mL) treated group. Cell Counting Kit-8 method was performed to evaluate the effect of taurine on the viability of aHSCs. Enzyme-linked immunosorbent assay was used to estimate the effect of taurine on the levels of reactive oxygen species (ROS), malondialdehyde, glutathione, and iron concentration. Transmission electron microscopy was applied to observe the effect of taurine on the autophagosomes and ferroptosis features in aHSCs. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to detect the effect of taurine on the expression of α-SMA, Collagen I, Fibronectin 1, LC3B, ATG5, Beclin 1, PTGS2, SLC7A11, and p62. RESULTS: Taurine promoted the death of aHSCs and reduced the deposition of the ECM. Treatment with taurine could alleviate autophagy in HSCs to inhibit their activation, by decreasing autophagosome formation, downregulating LC3B and Beclin 1 protein expression, and upregulating p62 protein expression. Meanwhile, treatment with taurine triggered ferroptosis and ferritinophagy to eliminate aHSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation. Furthermore, bioinformatics analysis demonstrated that taurine had a direct targeting effect on nuclear receptor coactivator 4, exhibiting the best average binding affinity of -20.99 kcal/mol. CONCLUSION: Taurine exerts therapeutic effects on liver fibrosis via mechanisms that involve inhibition of autophagy and trigger of ferroptosis and ferritinophagy in HSCs to eliminate aHSCs.

A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models.

Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease with a high mortality rate. Putative drug targets in IPF have failed to translate into effective therapies at the clinical level. We identify TRAF2- and NCK-interacting kinase (TNIK) as an anti-fibrotic target using a predictive artificial intelligence (AI) approach. Using AI-driven methodology, we generated INS018_055, a small-molecule TNIK inhibitor, which exhibits desirable drug-like properties and anti-fibrotic activity across different organs in vivo through oral, inhaled or topical administration. INS018_055 possesses anti-inflammatory effects in addition to its anti-fibrotic profile, validated in multiple in vivo studies. Its safety and tolerability as well as pharmacokinetics were validated in a randomized, double-blinded, placebo-controlled phase I clinical trial (NCT05154240) involving 78 healthy participants. A separate phase I trial in China, CTR20221542, also demonstrated comparable safety and pharmacokinetic profiles. This work was completed in roughly 18 months from target discovery to preclinical candidate nomination and demonstrates the capabilities of our generative AI-driven drug-discovery pipeline.

Blood-Brain Barrier-Penetrating and Lesion-Targeting Nanoplatforms Inspired by the Pathophysiological Features for Synergistic Ischemic Stroke Therapy.

Ischemic stroke is a dreadful vascular disorder that poses enormous threats to the public health. Due to its complicated pathophysiological features, current treatment options after ischemic stroke attack remains unsatisfactory. Insufficient drug delivery to ischemic lesions impeded by the blood-brain barrier (BBB) largely limits the therapeutic efficacy of most anti-stroke agents. Herein, inspired by the rapid BBB penetrability of 4T1 tumor cells upon their brain metastasis and natural roles of platelet in targeting injured vasculatures, a bio-derived nanojacket is developed by fusing 4T1 tumor cell membrane with platelet membrane, which further clothes on the surface of paeonol and polymetformin-loaded liposome to obtain biomimetic nanoplatforms (PP@PCL) for ischemic stroke treatment. The designed PP@PCL could remarkably alleviate ischemia-reperfusion injury by efficiently targeting ischemic lesion, preventing neuroinflammation, scavenging excess reactive oxygen species (ROS), reprogramming microglia phenotypes, and promoting angiogenesis due to the synergistic therapeutic mechanisms that anchor the pathophysiological characteristics of ischemic stroke. As a result, PP@PCL exerts desirable therapeutic efficacy in injured PC12 neuronal cells and rat model of ischemic stroke, which significantly attenuates neuronal apoptosis, reduces infarct volume, and recovers neurological functions, bringing new insights into exploiting promising treatment strategies for cerebral ischemic stroke management.

Analysis and identification of oxidative stress-ferroptosis related biomarkers in ischemic stroke.

Studies have shown that a series of molecular events caused by oxidative stress is associated with ferroptosis and oxidation after ischemic stroke (IS). Differential analysis was performed to identify differentially expressed mRNA (DEmRNAs) between IS and control groups. Critical module genes were identified using weighted gene co-expression network analysis (WGCNA). DEmRNAs, critical module genes, oxidative stress-related genes (ORGs), and ferroptosis-related genes (FRGs) were crossed to screen for intersection mRNAs. Candidate mRNAs were screened based on the protein-protein interaction (PPI) network and the MCODE plug-in. Biomarkers were identified based on two types of machine learning algorithms, and the intersection was obtained. Functional items and related pathways of the biomarkers were identified using gene set enrichment analysis (GSEA). Finally, single-sample GSEA (ssGSEA) and Wilcoxon tests were used to identify differential immune cells. An miRNA-mRNA-TF network was created. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the expression levels of biomarkers in the IS and control groups. There were 8287 DE mRNAs between the IS and control groups. The genes in the turquoise module were selected as critical module genes for IS. Thirty intersecting mRNAs were screened for overlaps. Seventeen candidate mRNAs were also identified. Four biomarkers (CDKN1A, GPX4, PRDX1, and PRDX6) were identified using two types of machine-learning algorithms. GSEA results indicated that the biomarkers were associated with steroid biosynthesis. Nine types of immune cells (activated B cells and neutrophils) were markedly different between the IS and control groups. We identified 3747 miRNA-mRNA-TF regulatory pairs in the miRNA-mRNA-TF regulatory network, including hsa-miR-4469-CDKN1A-BACH2 and hsa-miR-188-3p-GPX4-ATF2. CDKN1A, PRDX1, and PRDX6 were upregulated in IS samples compared with control samples. This study suggests that four biomarkers (CDKN1A, GPX4, PRDX1, and PRDX6) are significantly associated with IS. This study provides a new reference for the diagnosis and treatment of IS.

pH-Responsive polymer boosts cytosolic siRNA release for retinal neovascularization therapy.

Small interfering RNA (siRNA) has a promising future in the treatment of ocular diseases due to its high efficiency, specificity, and low toxicity in inhibiting the expression of target genes and proteins. However, due to the unique anatomical structure of the eye and various barriers, delivering nucleic acids to the retina remains a significant challenge. In this study, we rationally design PACD, an A-B-C type non-viral vector copolymer composed of a hydrophilic PEG block (A), a siRNA binding block (B) and a pH-responsive block (C). PACDs can self-assemble into nanosized polymeric micelles that compact siRNAs into polyplexes through simple mixing. By evaluating its pH-responsive activity, gene silencing efficiency in retinal cells, intraocular distribution, and anti-angiogenesis therapy in a mouse model of hypoxia-induced angiogenesis, we demonstrate the efficiency and safety of PACD in delivering siRNA in the retina. We are surprised to discover that, the PACD/siRNA polyplexes exhibit remarkable intracellular endosomal escape efficiency, excellent gene silencing, and inhibit retinal angiogenesis. Our study provides design guidance for developing efficient nonviral ocular nucleic acid delivery systems.

Stretchable and negative-Poisson-ratio porous metamaterials.

Highly stretchable porous materials are promising for flexible electronics but their fabrication is a great challenge. Herein, several kinds of highly stretchable conductive porous elastomers with low or negative Poisson's ratios are achieved by uniaxial, biaxial, and triaxial hot-pressing strategies. The reduced graphene oxide/polymer nanocomposite elastomers with folded porous structures obtained by uniaxial hot pressing exhibit high stretchability up to 1200% strain. Furthermore, the meta-elastomers with reentrant porous structures combining high biaxial (or triaxial) stretchability and negative Poisson's ratios are achieved by biaxial (or triaxial) hot pressing. The resulting elastomer-based wearable strain sensors exhibit an ultrawide response range (0-1200%). The materials can be applied for smart thermal management and electromagnetic interference shielding, which are achieved by regulating the porous microstructures via stretching. This work provides a versatile strategy to highly stretchable and negative-Poisson-ratio porous materials with promising features for various applications such as flexible electronics, thermal management, electromagnetic shielding, and energy storage.

A literature review and meta-analysis of the optimal factors study of repetitive transcranial magnetic stimulation in post-infarction aphasia.

BACKGROUND: The existing literature indicates that repetitive transcranial magnetic stimulation (rTMS) can potentially enhance the prognosis of poststroke aphasia (PSA). Nevertheless, these investigations did not identify the most effective parameters or settings for achieving optimal treatment outcomes. This study involved a meta-analysis aimed to identify the optimal variables for rTMS in treating post-infarction aphasia to guide the use of rTMS in rehabilitating PSA. METHODS: PubMed, Embase, and Cochrane Library databases were searched from inception to May 2023, and articles were reviewed manually using subject words and free words and supplemented with references from the included literature to obtain additional relevant literature. The search terms included "poststroke aphasia" and "repetitive transcranial magnetic stimulation (rTMS)" repetitive transcranial magnetic stimulation. Additionally, a review of the reference lists of previously published systematic reviews identified through the Cochrane Database of Systematic Reviews (search terms: poststroke aphasia, rTMS; restrictions: none) and PubMed (search terms: poststroke aphasia, rTMSs; restrictions: systematic review or meta-analysis) was performed. Information from studies involving different doses of rTMS in PSA was independently screened and extracted by 2 researchers. RESULTS: This meta-analysis included 387 participants with PSA across 18 randomized controlled trials. The results showed that the total pulse had a trend toward a significant correlation with the treatment effect (P = 0.088), while all other variables did not correlate significantly. When rTMS was not grouped by stimulus parameter and location, our nonlinear results showed that when the total pulses were 40,000 (standardized mean difference (SMD):1.86, 95% credible interval (CrI) 0.50 to 3.33), the pulse/session was 1000 (SMD:1.05, 95% CrI 0.55-1.57), and an RMT of 80% (SMD:1.08, 95% CrI 0.60-1.57) had the best treatment effect. When rTMS was grouped by stimulus parameters and location, our nonlinear results showed that when the total low-frequency (LF)-rTMS-right inferior frontal gyrus (RIFG) pulse was 40,000 (SMD:1.76, 95% CrI:0.36-3.29), the pulse/session was 1000 (SMD:1.06, 95% CrI:0.54-1.59). Optimal results were obtained with an RMT of 80% (SMD:1.14, 95% CrI 0.54 - 1.76). CONCLUSIONS: The optimal treatment effects of rTMS for PSA may be obtained with a total pulse of 40,000, a pulse/session of 1000, and an RMT of 80%. Further rigorous randomized controlled studies are required to substantiate the validity of these results.

A Class of Activatable NIR-II Photoacoustic Dyes for High-Contrast Bioimaging.

Photoacoustic (PA) imaging is emerging as one of the important non-invasive imaging techniques in biomedical research. Small molecule- second near-infrared window (NIR-II) PA dyes combined with imaging data can provide comprehensive and in-depth in vivo physiological and pathological information. However, the NIR-II PA dyes usually exhibit "always-on" properties due to the lack of a readily optically tunable group, which hinders the further applications in vivo. Herein, a novel class of dyes GX have been designed and synthesized as an activatable NIR-II PA platform, in which the absorption/emission wavelength of GX-5 extends up to 1082/1360 nm. Importantly, the GX dyes have a strong tissue penetration depth and high-resolution for the mouse vasculature structures in NIR-II PA 3D imaging and high signal-to-noise ratio in NIR-II fluorescence (FL) imaging. Furthermore, to demonstrate the applicability of GX dyes, the first NIR-II PA probe GX-5-CO activated by carbon monoxide (CO) was engineered and employed to reveal the enhancement of the CO levels in the hypertensive mice by high-contrast NIR-II PA and FL imaging. We expect that many derivatives of GX dyes will be developed to afford versatile NIR-II PA platforms for designing a wide variety activatable NIR-II PA probes as biomedical tools.

Lipid Nanoparticles Optimized for Targeting and Release of Nucleic Acid.

Lipid nanoparticles (LNPs) are currently the most promising clinical nucleic acids drug delivery vehicles. LNPs prevent the degradation of cargo nucleic acids during blood circulation. Upon entry into the cell, specific components of the lipid nanoparticles can promote the endosomal escape of nucleic acids. These are the basic properties of lipid nanoparticles as nucleic acid carriers. As LNPs exhibit hepatic aggregation characteristics, enhancing targeting out of the liver is a crucial way to improve LNPs administrated in vivo. Meanwhile, endosomal escape of nucleic acids loaded in LNPs is often considered inadequate, and therefore, much effort is devoted to enhancing the intracellular release efficiency of nucleic acids. Here, different strategies to efficiently deliver nucleic acid delivery from LNPs are concluded and their mechanisms are investigated. In addition, based on the information on LNPs that are in clinical trials or have completed clinical trials, the issues that are necessary to be approached in the clinical translation of LNPs are discussed, which it is hoped will shed light on the development of LNP nucleic acid drugs.

Traditional Chinese Medicine Formulae QY305 Reducing Cutaneous Adverse Reaction and Diarrhea by its Nanostructure.

Traditional Chinese medicine (TCM) is widely used in clinical practice, including skin and gastrointestinal diseases. Here, a potential TCM QY305 (T-QY305) is reported that can modulate the recruitment of neutrophil in skin and colon tissue thus reducing cutaneous adverse reaction and diarrhea induced by epidermal growth factor receptor inhibitors (EGFRIs). On another hand, the T-QY305 formula, through regulating neutrophil recruitment features would highlight the presence of N-QY305, a subunit nanostructure contained in T-QY305, and confirm its role as potentially being the biomaterial conferring to T-QY305 its pharmacodynamic features. Here, the clinical records of two patients are analyzed expressing cutaneous adverse reaction and demonstrate positive effect of T-QY305 on the simultaneous inhibition of both cutaneous adverse reaction and diarrhea in animal models. The satisfying results obtained from T-QY305, lead to further process to the isolation of N-QY305 from T-QY305, in order to demonstrate that the potency of T-QY305 originates from the nanostructure N-QY305. Compared to T-QY305, N-QY305 exhibits higher potency upon reducing adverse reactions. The data represent a promising candidate for reducing cutaneous adverse reaction and diarrhea, meanwhile proposing a new strategy to highlight the presence of nanostructures being the "King" of Chinese medicine formula as the pharmacodynamic basis.

Modulating the Coordination Environment of Carbon-Dot-Supported Fe Single-Atom Nanozymes for Enhanced Tumor Therapy.

Herein, carbon dot (CD)-supported Fe single-atom nanozymes with high content of pyrrolic N and ultrasmall size (ph-CDs-Fe SAzyme) are fabricated by a phenanthroline-mediated ligand-assisted strategy. Compared with phenanthroline-free nanozymes (CDs-Fe SAzyme), ph-CDs-Fe SAzyme exhibit higher peroxidase (POD)-like activity due to their structure similar to that of ferriporphyrin in natural POD. Aberration-corrected high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM) and X-ray absorption fine structure spectroscopy (XAFS) analyses show that metal Fe is dispersed in ph-CDs-Fe SAzyme as single atoms. Steady-state kinetic studies show that the maximum velocity (Vmax ) and turnover number (kcat ) of H2 O2  homolytic cleavage catalyzed by ph-CDs-Fe SAzyme are 3.0 and 6.2 more than those of the reaction catalyzed by CDs-Fe SAzyme. Density functional theory (DFT) calculations show that the energy barrier of the reaction catalyzed by ph-CDs-Fe SAzyme is lower than that catalyzed by CDs-Fe SAzyme. Antitumor efficacy experiments show that ph-CDs-Fe SAzyme can efficiently inhibit the growth of tumor cells both in vitro and in vivo by synergistic chemodynamic and photothermal effects. Here a new paradigm is provided for the development of efficient antitumor therapeutic approaches based on SAzyme with POD-like activity.

Broad-Range-Response Battery-Type All-in-one Self-Powered Stretchable Pressure-Sensitive Electronic Skin.

Highly sensitive self-powered stretchable electronic skins with the capability of detecting broad-range dynamic and static pressures are urgently needed with the increasing demands for miniaturized wearable electronics, robots, artificial intelligence, etc. However, it remains a great challenge to achieve this kind of electronic skins. Here, unprecedented battery-type all-in-one self-powered stretchable electronic skins with a novel structure composed of pressure-sensitive elastic vanadium pentoxide (V2 O5 ) nanowire-based porous cathode, elastic porous polyurethane /carbon nanotube/polypyrrole anode, and polyacrylamide ionic gel electrolyte are reported. A new battery-type self-powered pressure sensing mechanism involving the output current variation caused by the resistance variation of the electrodes and electrolytes under external pressure is revealed. The battery-type self-powered electronic skins combining high sensitivity, broad response range (1.8 Pa-1.5 MPa), high fatigue resistance, and excellent stability against stretching (50% tensile strain) are achieved for the first time. This work provides a new and versatile battery-type sensing strategy for the design of next-generation all-in-one self-powered miniaturized sensors and electronic skins.

Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review

SUMMARY Primary pigmented nodular adrenocortical disease (PPNAD) is a rare adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS). Pediatric patients with PPNAD typically have unusual skin lesions and slow growth with unknown causes. We present a case of a female Chinese patient with PPNAD caused by the germline PRKACA gene copy number gain of chromosome 19. The patient initially presented with kidney stones, short stature, and obesity. After further testing, it was discovered that the patient had diabetes, mild hypertension, low bone mass, a low ACTH level, and hypercortisolemia, and neither the low-dose or high-dose dexamethasone suppression test was able to inhibit hematuric cortisol, which paradoxically increased. PPNAD was pathologically diagnosed after unilateral adrenalectomy. Chromosome microarrays and whole exon sequencing analyses of the peripheral blood, as well as testing of sectioned adrenal tissue, showed a rise in the copy number of the duplication-containing PRKACA gene on chromosome 19p13.13p13.12, a de novo but not heritable gene defect that causes disease. The clinical signs and symptoms supported the diagnosis of Carney complex (CNC). One significant mechanism of CNC pathogenesis may be the rise in germline PRKACA copy number of chromosome 19. When assessing PPNAD patients for CNC, the possibility of PRKACA gene amplification should be considered. The effect of PRKACA gene amplification on the clinical manifestations of CNC needs to be confirmed by more cases.

Biomimetic Grapefruit-Derived Extracellular Vesicles for Safe and Targeted Delivery of Sodium Thiosulfate against Vascular Calcification.

As the prevalence of vascular calcification (VC), a strong contributor to cardiovascular morbidity and mortality, continues to increase, the need for pharmacologic therapies becomes urgent. Sodium thiosulfate (STS) is a clinically approved drug for therapy against VC; however, its efficacy is hampered by poor bioavailability and severe adverse effects. Plant-derived extracellular vesicles have provided options for VC treatment since they can be used as biomimetic drug carriers with higher biosafety and targeting abilities than artificial carriers. Inspired by natural grapefruit-derived extracellular vesicles (EVs), we fabricated a biomimetic nanocarrier comprising EVs loaded with STS and further modified with hydroxyapatite crystal binding peptide (ESTP) for VC-targeted delivery of STS. In vitro, the ESTP nanodrug exhibited excellent cellular uptake capacity by calcified vascular smooth muscle cells (VSMCs) and subsequently inhibited VSMCs calcification. In the VC mice model, the ESTP nanodrug showed preferentially the highest accumulation in the calcified arteries compared to other treatment groups. Mechanistically, the ESTP nanodrug significantly prevented VC via driving M2 macrophage polarization, reducing inflammation, and suppressing bone-vascular axis as demonstrated by inhibiting osteogenic phenotype trans-differentiation of VSMCs while enhancing bone quality. In addition, the ESTP nanodrug did not induce hemolysis or cause any damage to other organs. These results suggest that the ESTP nanodrug can prove to be a promising agent against VC without the concern of systemic toxicity.

Highly hydrophilic and dispersed TiO2 nano-system with enhanced photocatalytic antibacterial activities and accelerated tissue regeneration under visible light.

Titanium dioxide (TiO2)-based photodynamic antibacterial (PDA) agents present a novel approach for addressing drug-resistant bacterial infections and the associated tissue damage. However, the suboptimal dispersibility, negative charge, and weak photocatalytic activity under visible light of TiO2 hinder its practical applications. This study aimed to address these limitations by developing a highly hydrophilic and dispersed Zn-TiO2/reduced graphene oxide (rGO) (HTGZ) nano-system with exceptional visible light catalytic activity and tissue repair ability. HTGZ produced an antibacterial ratio over 98% within a short time, likely due to the enhanced production of reactive oxygen species under visible light. After being co-cultured for 4 days, L929 cells and BMSCs maintained over 90% activity, indicating that HTGZ had no significant cytotoxicity. Furthermore, the transcriptomic and metabolic analyses revealed that the antibacterial mechanism mainly came from the destruction of cell membranes and the disruption of various metabolic processes, such as purine metabolism and fatty acid biosynthesis. Critically, results of in vivo experiments had authenticated that HTGZ significantly promoted infected tissue regeneration by slaughtering bacteria and release Zn2+. After 14 days, the wound area was only one-third that of the control group. Overall, the enhanced antibacterial efficacy and wound-healing potential position HTGZ as a promising nano-antibacterial medication for the clinical treatment of infectious bacterial diseases.