Salinity-Induced Variations in Bacterial Composition and Co-occurrence Patterns within Salicornia-Based Constructed Wetlands in Mariculture.

Constructed wetlands use vegetation and microorganisms to remove contaminants like nitrogen and phosphorus from water. For mariculture, the impact of salinity on the efficiency of wastewater treatment of wetlands is unneglectable. However, little is known about their impact on the microbiome in constructed wetlands. Here, we set four salinity levels (15, 22, 29, and 36) in Salicornia constructed wetlands, and the experiment was conducted for a period of 72 days. The 15 group exhibited the highest removal rates of nitrogen compounds and phosphate, compared to the other salinity groups, the nosZ gene exhibited significantly higher expression in the 22 group (p < 0.05), indicated that microorganisms in 22 salinity have higher denitrification abilities. The three dominant phyla identified within the microbiomes were Proteobacteria, known for their diverse metabolic capabilities; Cyanobacteria, important for photosynthesis and nitrogen fixation; and Firmicutes, which include many fermenters. The ecological network analysis revealed a 'small world' model, characterized by high interconnectivity and short path lengths between microbial species, and had higher co-occurrence (45.13%) observed in this study comparing to the Erdös-Réyni random one (32.35%). The genus Microbulbifer emerged as the sole connector taxon, pivotal for integrating different microbial communities involved in nitrogen removal. A negative correlation was observed between salinity levels and network complexity, as assessed by the number of connections and diversity of interactions within the microbial community. Collectively, these findings underscore the critical role of microbial community interactions in optimizing nitrogen removal in constructed wetlands, with potential applications in the design and management of such systems for improved wastewater treatment in mariculture.

Design of multi-epitope vaccine against porcine rotavirus using computational biology and molecular dynamics simulation approaches.

Porcine Rotavirus (PoRV) is a significant pathogen affecting swine-rearing regions globally, presenting a substantial threat to the economic development of the livestock sector. At present, no specific pharmaceuticals are available for this disease, and treatment options remain exceedingly limited. This study seeks to design a multi-epitope peptide vaccine for PoRV employing bioinformatics approaches to robustly activate T-cell and B-cell immune responses. Two antigenic proteins, VP7 and VP8*, were selected from PoRV, and potential immunogenic T-cell and B-cell epitopes were predicted using immunoinformatic tools. These epitopes were further screened according to non-toxicity, antigenicity, non-allergenicity, and immunogenicity criteria. The selected epitopes were linked with linkers to form a novel multi-epitope vaccine construct, with the PADRE sequence (AKFVAAWTLKAAA) and RS09 peptide attached at the N-terminus of the designed peptide chain to enhance the vaccine's antigenicity. Protein-protein docking of the vaccine constructs with toll-like receptors (TLR3 and TLR4) was conducted using computational methods, with the lowest energy docking results selected as the optimal predictive model. Subsequently, molecular dynamics (MD) simulation methods were employed to assess the stability of the protein vaccine constructs and TLR3 and TLR4 receptors. The results indicated that the vaccine-TLR3 and vaccine-TLR4 docking models remained stable throughout the simulation period. Additionally, the C-IMMSIM tool was utilized to determine the immunogenic triggering capability of the vaccine protein, demonstrating that the constructed vaccine protein could induce both cell-mediated and humoral immune responses, thereby playing a role in eliciting host immune responses. In conclusion, this study successfully constructed a multi-epitope vaccine against PoRV and validated the stability and efficacy of the vaccine through computational analysis. However, as the study is purely computational, experimental evaluation is required to validate the safety and immunogenicity of the newly constructed vaccine protein.

Additive manufacturing of degradable metallic scaffolds for material-structure-driven diabetic maxillofacial bone regeneration.

The regeneration of maxillofacial bone defects associated with diabetes mellitus remains challenging due to the occlusal loading and hyperglycemia microenvironment. Herein, we propose a material-structure-driven strategy through the additive manufacturing of degradable Zn-Mg-Cu gradient scaffolds. The in situ alloying of Mg and Cu endows Zn alloy with admirable compressive strength for mechanical support and uniform degradation mode for preventing localized rupture. The scaffolds manifest favorable antibacterial, angiogenic, and osteogenic modulation capacity in mimicked hyperglycemic microenvironment, and Mg and Cu promote osteogenic differentiation in the early and late stages, respectively. In addition, the scaffolds expedite diabetic maxillofacial bone ingrowth and regeneration by combining the metabolic regulation effect of divalent metal cations and the hyperboloid and suitable permeability of the gradient structure. RNA sequencing further reveals that RAC1 might be involved in bone formation by regulating the transport and uptake of glucose related to GLUT1 in osteoblasts, contributing to cell function recovery. Inspired by bone healing and structural cues, this study offers an essential understanding of the designation and underlying mechanisms of the material-structure-driven strategy for diabetic maxillofacial bone regeneration.

Biomimetic Trypsin-Responsive Structure-Bridged Mesoporous Organosilica Nanomedicine for Precise Treatment of Acute Pancreatitis.

Developing strategies to target injured pancreatic acinar cells (PACs) in conjunction with primary pathophysiology-specific pharmacological therapy presents a challenge in the management of acute pancreatitis (AP). We designed and synthesized a trypsin-cleavable organosilica precursor bridged by arginine-based amide bonds, leveraging trypsin's ability to selectively identify guanidino groups on arginine via Asp189 at the active S1 pocket and cleave the carboxy-terminal (C-terminal) amide bond via catalytic triads. The precursors were incorporated into the framework of mesoporous silica nanoparticles (MSNs) for encapsulating the membrane-permeable Ca2+ chelator BAPTA-AM with a high loading content (∼43.9%). Mesenchymal stem cell membrane coating and surface modification with PAC-targeting ligands endow MSNs with inflammation recruitment and precise PAC-targeting abilities, resulting in the highest distribution at 3 h in the pancreas with 4.7-fold more accumulation than that of naked MSNs. The outcomes transpired as follows: After bioinspired MSNs' skeleton biodegradation by prematurely and massively activated trypsin, BAPTA-AM was on-demand released in injured PACs, thereby effectively eliminating intracellular calcium overload (reduced Ca2+ level by 81.3%), restoring cellular redox status, blocking inflammatory cascades, and inhibiting cell necrosis by impeding the IκBα/NF-κB/TNF-α/IL-6 and CaMK-II/p-RIP3/p-MLKL/caspase-8,9 signaling pathways. In AP mice, a single dose of the formulation significantly restored pancreatic function (lipase and amylase reduced more by 60%) and improved the survival rate from 50 to 91.6%. The formulation offers a potentially effective strategy for clinical translation in AP treatment.

Overexpression of LAG-3: a potential indicator of low immune function in tuberculosis.

Background: Tuberculosis (TB) persists as a global health challenge, with its treatment hampered by the side effects of long-term combination drug therapies and the growing issue of drug resistance. Therefore, the development of novel therapeutic strategies is critical. This study focuses on the role of immune checkpoint molecules (ICs) and functions of CD8+ T cells in the search for new potential targets against TB. Methods: We conducted differential expression genes analysis and CD8+ T cell functional gene analysis on 92 TB samples and 61 healthy individual (HI) samples from TB database GSE83456, which contains data on 34,603 genes. The GSE54992 dataset was used to validated the findings. Additionally, a cluster analysis on single-cell data from primates infected with mycobacterium tuberculosis and those vaccinated with BCG was performed. Results: The overexpression of LAG-3 gene was found as a potentially important characteristic of both pulmonary TB (PTB) and extrapulmonary TB (EPTB). Further correlation analysis showed that LAG-3 gene was correlated with GZMB, perforin, IL-2 and IL-12. A significant temporal and spatial variation in LAG-3 expression was observed in T cells and macrophages during TB infection and after BCG vaccination. Conclusion: LAG-3 was overexpressed in TB samples. Targeting LAG-3 may represent a potential therapeutic target for tuberculosis.

Self-Sulfhydrated, Nitro-Fixed Albumin Nanoparticles as a Potent Therapeutic Agent for the Treatment of Acute Liver Injury.

Exogenous polysulfhydryls (R-SH) supplementation and nitric oxide (NO) gas molecules delivery provide essential antioxidant buffering pool components and anti-inflammatory species in cellular defense against injury, respectively. Herein, the intermolecular disulfide bonds in bovine serum albumin (BSA) molecules were reductively cleaved under native and mild conditions to expose multiple sulfhydryl groups (BSA-SH), then sulfhydryl-nitrosylated (R-SNO), and nanoprecipitated to form injectable self-sulfhydrated, nitro-fixed albumin nanoparticles (BSA-SNO NPs), allowing albumin to act as a NO donor reservoir and multiple sulfhydryl group transporter while also preventing unfavorable oxidation and self-cross-linking of polysulfhydryl groups. In two mouse models of ischemia/reperfusion-induced and endotoxin-induced acute liver injury (ALI), a single low dosage of BSA-SNO NPs (S-nitrosothiols: 4 µmol·kg-1) effectively attenuated oxidative stress and systemic inflammation cascades in the upstream pathophysiology of disease progression, thus rescuing dying hepatocytes, regulating host defense, repairing microcirculation, and restoring liver function. By mechanistically upregulating the antioxidative signaling pathway (Nrf-2/HO-1/NOQ1) and inhibiting the inflammatory cytokine storm (NF-κB/p-IκBα/TNF-α/IL-ß), BSA-SNO NPs blocked the initiation of the mitochondrial apoptotic signaling pathway (Cyto C/Bcl-2 family/caspase-3) and downregulated the cell pyroptosis pathway (NLRP3/ASC/IL-1ß), resulting in an increased survival rate from 26.7 to 73.3%. This self-sulfhydrated, nitro-fixed functionalized BSA nanoformulation proposes a potential drug-free treatment strategy for ALI.

Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions.

The heterogeneity of protein-rich inclusions and its significance in neurodegeneration is poorly understood. Standard patient-derived iPSC models develop inclusions neither reproducibly nor in a reasonable time frame. Here, we developed screenable iPSC "inclusionopathy" models utilizing piggyBac or targeted transgenes to rapidly induce CNS cells that express aggregation-prone proteins at brain-like levels. Inclusions and their effects on cell survival were trackable at single-inclusion resolution. Exemplar cortical neuron α-synuclein inclusionopathy models were engineered through transgenic expression of α-synuclein mutant forms or exogenous seeding with fibrils. We identified multiple inclusion classes, including neuroprotective p62-positive inclusions versus dynamic and neurotoxic lipid-rich inclusions, both identified in patient brains. Fusion events between these inclusion subtypes altered neuronal survival. Proteome-scale α-synuclein genetic- and physical-interaction screens pinpointed candidate RNA-processing and actin-cytoskeleton-modulator proteins like RhoA whose sequestration into inclusions could enhance toxicity. These tractable CNS models should prove useful in functional genomic analysis and drug development for proteinopathies.

Emodin improves renal fibrosis in chronic kidney disease by regulating mitochondrial homeostasis through the mediation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α).

Chronic kidney disease (CKD) is a leading public health issue associated with high morbidity worldwide. However, there are only a few effective therapeutic strategies for CKD. Emodin, an anthraquinone compound from rhubarb, can inhibit fibrosis in tissues and cells. Our study aims to investigate the antifibrotic effect of emodin and the underlying molecular mechanism. A unilateral ureteral obstruction (UUO)-induced rat model was established to evaluate the effect of emodin on renal fibrosis development. Hematoxylin and eosin staining, Masson's trichrome staining, and immunohistochemistry staining were performed to analyze histopathological changes and fibrotic features after emodin treatment. Subsequently, a transforming growth factor-beta 1 (TGF-ß1)-induced cell model was used to assess the inhibition of emodin on cell fibrosis in vitro. Furthermore, Western blot analysis and real-time quantitative reverse transcription-polymerase chain reaction were performed to validate the regulatory mechanism of emodin on renal fibrosis progression. As a result, emodin significantly improved histopathological abnormalities in rats with UUO. The expression of fibrosis biomarkers and mitochondrial biogenesis-related proteins also decreased after emodin treatment. Moreover, emodin blocked TGF-ß1-induced fibrotic phenotype, lipid accumulation, and mitochondrial homeostasis in NRK-52E cells. Conversely, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) silencing significantly reversed these features in emodin-treated cells. Collectively, emodin plays an important role in regulating PGC-1α-mediated mitochondria function and energy homeostasis. This indicates that emodin exhibits great inhibition against renal fibrosis and acts as a promising inhibitor of CKD.

Nkx1.2 deletion decreases fat production in zebrafish.

OBJECTIVE: This study aimed to investigate the role of Nkx1-2, a transcription factor with the NK homeobox domain, in the regulation of fat production. METHODS: Gene expression was analyzed using quantitative real-time polymerase chain reaction or transcriptome sequencing. CRISPR/Cas9 technology was employed to generate nkx1.2 knockout zebrafish and nkx1.2-deleted 3T3-L1 cells. Lipid droplet production in zebrafish larvae was visually quantified using Nile red staining, whereas lipid droplets in 3T3-L1 cells were stained with Oil red O. The binding of Nkx1-2 to the promoter was verified through an electrophoretic mobility shift assay experiment. RESULTS: Nkx1-2 plays crucial roles in the regulation of fat production in zebrafish. Knockout of nkx1.2 in zebrafish leads to weight loss, accompanied by significantly reduced lipid droplet production and decreased visceral and liver fat content. Furthermore, genes related to lipid biosynthesis are significantly downregulated. In 3T3-L1 preadipocytes, Nkx1-2 induces differentiation into mature adipocytes by binding to the cebpa promoter, thereby activating its transcription. Additionally, the expression of nkx1.2 is regulated by the p38 MAPK, JNK, or Smad2/3 signaling pathways in 3T3-L1 cells. CONCLUSIONS: Our findings suggest that Nkx1-2 functions as a positive regulator of fat production, playing a critical role in adipocyte differentiation and lipid biosynthesis.

Unlocking the NIR-II AIEgen for High Brightness through Intramolecular Electrostatic Locking.

Fluorescent imaging and biosensing in the near-infrared-II (NIR-II) window holds great promise for non-invasive, radiation-free, and rapid-response clinical diagnosis. However, it's still challenging to develop bright NIR-II fluorophores. In this study, we report a new strategy to enhance the brightness of NIR-II aggregation-induced emission (AIE) fluorophores through intramolecular electrostatic locking. By introducing sulfur atoms into the side chains of the thiophene bridge in TSEH molecule, the molecular motion of the conjugated backbone can be locked through intramolecular interactions between the sulfur and nitrogen atoms. This leads to enhanced NIR-II fluorescent emission of TSEH in both solution and aggregation states. Notably, the encapsulated nanoparticles (NPs) of TSEH show enhanced brightness, which is 2.6-fold higher than TEH NPs with alkyl side chains. The in vivo experiments reveal the feasibility of TSEH NPs in vascular and tumor imaging with a high signal-to-background ratio and precise resection for tiny tumors. In addition, polystyrene nanospheres encapsulated with TSEH are utilized for antigen detection in lateral flow assays, showing a signal-to-noise ratio 1.9-fold higher than the TEH counterpart in detecting low-concentration antigens. This work highlights the potential for developing bright NIR-II fluorophores through intramolecular electrostatic locking and their potential applications in clinical diagnosis and biomedical research.

Habitat selection drives diatom community assembly and network complexity in sediment-laden riverine environments.

Microbial communities assemble stochastically and deterministically, but how different assembly processes shape diatom community structure across riverine habitats is unclear, especially in sediment-laden environments. In this study, we deciphered the mechanisms of riverine diatom community assembly in the water column and riverbed substrate with varying sediment concentrations. Water and sediment samples were collected from 44 sampling sites along the Yellow River mainstream during two seasons. Diatom communities were characterized based on high-throughput sequencing of the 18S ribosomal RNA genes coupled with multivariate statistical analyses. A total of 198 diatom species were taxonomically assigned, including 182 free-living and particle-attached species and 184 surface-sediment species. Planktonic communities were structurally different from benthic communities, with Cyclotella being dominant mainly in the middle and lower reaches of the river with higher sediment concentrations. Both stochastic and deterministic processes affected diatom community assembly in different habitats. Species dispersal was more important in the water than in the substrate, and this process was strengthened by increased sediment concentration across habitats. Diatom communities exhibited lower network complexity and enhanced antagonistic or competitive interactions between species in response to higher sediment concentrations compared with lower sediment concentrations mainly in the source region of the river. Differences in the species composition and community diversity of planktonic diatoms were closely correlated with the proportion of bare land area, nitrogen nutrients, precipitation, and sediment concentration. In particular, particle-attached diatoms responded sensitively to environmental factors. These findings provide strong evidence for sediment-mediated assembly and interactions of riverine diatom communities.

Exploring the interplay between triple-negative breast cancer stem cells and tumor microenvironment for effective therapeutic strategies.

Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic malignancy with poor treatment outcomes. The interaction between the tumor microenvironment (TME) and breast cancer stem cells (BCSCs) plays an important role in the development of TNBC. Owing to their ability of self-renewal and multidirectional differentiation, BCSCs maintain tumor growth, drive metastatic colonization, and facilitate the development of drug resistance. TME is the main factor regulating the phenotype and metastasis of BCSCs. Immune cells, cancer-related fibroblasts (CAFs), cytokines, mesenchymal cells, endothelial cells, and extracellular matrix within the TME form a complex communication network, exert highly selective pressure on the tumor, and provide a conducive environment for the formation of BCSC niches. Tumor growth and metastasis can be controlled by targeting the TME to eliminate BCSC niches or targeting BCSCs to modify the TME. These approaches may improve the treatment outcomes and possess great application potential in clinical settings. In this review, we summarized the relationship between BCSCs and the progression and drug resistance of TNBC, especially focusing on the interaction between BCSCs and TME. In addition, we discussed therapeutic strategies that target the TME to inhibit or eliminate BCSCs, providing valuable insights into the clinical treatment of TNBC.

Integrating bulk and single-cell sequencing data to construct a Scissor+ dendritic cells prognostic model for predicting prognosis and immune responses in ESCC.

Esophageal squamous cell carcinoma (ESCC) is characterized by molecular heterogeneity with various immune cell infiltration patterns, which have been associated with therapeutic sensitivity and resistance. In particular, dendritic cells (DCs) are recently discovered to be associated with prognosis and survival in cancer. However, how DCs differ among ESCC patients has not been fully comprehended. Recently, the advance of single-cell RNA sequencing (scRNA-seq) enables us to profile the cell types, states, and lineages in the heterogeneous ESCC tissues. Here, we dissect the ESCC tumor microenvironment at high resolution by integrating 192,078 single cells from 60 patients, including 4379 DCs. We then used Scissor, a method that identifies cell subpopulations from single-cell data that are associated bulk samples with genomic and clinical information, to stratify DCs into Scissorhi and Scissorlow subtypes. We applied the Scissorhi gene signature to stratify ESCC scRNAseq patient, and we found that PD-L1, TIGIT, PVR and IL6 ligand-receptor-mediated cell interactions existed mainly in Scissorhi patients. Finally, based on the Scissor results, we successfully developed a validated prognostic risk model for ESCC and further validated the reliability of the risk prediction model by recruiting 40 ESCC clinical patients. This information highlights the importance of these genes in assessing patient prognosis and may help in the development of targeted or personalized therapies for ESCC.

Donor-Acceptor Modulating of Ionic AIE Photosensitizers for Enhanced ROS Generation and NIR-II Emission.

Photosensitizers (PSs) with aggregation-induced emission (AIE) characteristics are competitive candidates for bioimaging and therapeutic applications. However, their short emission wavelength and nonspecific organelle targeting hinder their therapeutic effectiveness. Herein, a donor-acceptor modulation approach is reported to construct a series of ionic AIE photosensitizers with enhanced photodynamic therapy (PDT) outcomes and fluorescent emission in the second near-infrared (NIR-II) window. By employing dithieno[3,2-b:2',3'-d]pyrrole (DTP) and indolium (In) as the strong donor and acceptor, respectively, the compound DTP-In exhibits a substantial redshift in absorption and fluorescent emission reach to NIR-II region. The reduced energy gap between singlet and triplet states in DTP-In also increases the reactive oxygen species (ROS) generation rate. Further, DTP-In can self-assemble in aqueous solutions, forming positively charged nanoaggregates, which are superior to conventional encapsulated nanoparticles in cellular uptake and mitochondrial targeting. Consequently, DTP-In aggregates show efficient photodynamic ablation of 4T1 cancer cells and outstanding tumor theranostic in vivo under 660 nm laser irradiation. This work highlights the potential of molecular engineering of donor-acceptor AIE PSs with multiple functionalities, thereby facilitating the development of more effective strategies for cancer therapy.

The MdMYB44-MdTPR1 repressive complex inhibits MdCCD4 and MdCYP97A3 expression through histone deacetylation to regulate carotenoid biosynthesis in apple.

Carotenoids are photosynthetic pigments and antioxidants that contribute to different plant colors. However, the involvement of TOPLESS (TPL/TPR)-mediated histone deacetylation in the modulation of carotenoid biosynthesis through ethylene-responsive element-binding factor-associated amphiphilic repression (EAR)-containing transcription factors (TFs) in apple (Malus domestica Borkh.) is poorly understood. MdMYB44 is a transcriptional repressor that contains an EAR repression motif. In the present study, we used functional analyses and molecular assays to elucidate the molecular mechanisms through which MdMYB44-MdTPR1-mediated histone deacetylation influences carotenoid biosynthesis in apples. We identified two carotenoid biosynthetic genes, MdCCD4 and MdCYP97A3, that were confirmed to be involved in MdMYB44-mediated carotenoid biosynthesis. MdMYB44 enhanced ß-branch carotenoid biosynthesis by repressing MdCCD4 expression, whereas MdMYB44 suppressed lutein level by repressing MdCYP97A3 expression. Moreover, MdMYB44 partially influences carotenoid biosynthesis by interacting with the co-repressor TPR1 through the EAR motif to inhibit MdCCD4 and MdCYP97A3 expression via histone deacetylation. Our findings indicate that the MdTPR1-MdMYB44 repressive cascade regulates carotenoid biosynthesis, providing profound insights into the molecular basis of histone deacetylation-mediated carotenoid biosynthesis in plants. These results also provide evidence that the EAR-harboring TF/TPL repressive complex plays a universal role in histone deacetylation-mediated inhibition of gene expression in various plants.

[Effects of tetramethylpyrazine on pharmacokinetics in plasma and brain dialysate and neuropathic pain in rat model of spared sciatic nerve injury].

This study aims to explore the effects of tetramethylpyrazine(TMP) on pharmacokinetics in plasma and brain dialysate and neuropathic pain in the rat model of partial sciatic nerve injury(SNI), and to investigate the correlation between the analgesic effect of TMP and its concentrations in the plasma and brain dialysate. Male SD rats were randomized into Sham, SNI, and SNI+TMP groups. Mechanical stimulation with von frey filaments and cold spray method were employed to evaluate the mechanical sensitivity and cold sensitivity of rats. Another two groups, Sham+TMP and SNI+TMP, were used to intubate the common jugular vein and implant microdialysis probes into the anterior cingulate gyrus(ACC), respectively.After intraperitoneal injection of TMP at a dose of 80 mg·kg~(-1), automatic blood collection and intracerebral microdialysis(perfusion rate of 1 µL·min~(-1)) systems were used to collect the blood and brain dialysate for 24 h. HSS T3 C_(18) reversed-phase chromatographic column(2.1 mm×50 mm, 2.5 µm) was used for liquid chromatographic separation. Gradient elution was carried out with the mobile phase of methanol-water(containing 0.005% formic acid) at a flow rate of 0.25 mL·min~(-1). Electrospray ion source was used for mass spectrometry, and the scanning mode was multi-reaction monitoring under the positive ion mode. The ion pairs for quantitative analysis were TMP m/z 137/122 and aspirin m/z 179/137, respectively. DAS 2.11 was used to calculate the pharmacokinetic parameters. The optimal time of TMP to exert the analgesia effect and inhibit cold pain sensitivity was 60 min after treatment. The TMP in the plasma and brain dialysate of SNI rats showed the T_(max) of 15 min and 30 min, the C_(max) of(2 866.43±135.39) and(1 462.14±197.38) µg·L~(-1), the AUC_(0-t) of(241 463.30±28 070.31) and(213 115.62±32 570.07) µg·min·L~(-1), the MRT_(0-t) of(353.13±47.73) and(172.16±12.72) min, and the CL_Z of 0.73 and 0.36 L·min·kg~(-1), respectively. The analgesic effect of TMP had a significant correlation with the blood drug concentration in the ACC, which indicated that this method was suitable for the detection of TMP in rat plasma and brain dialysate. The method is accurate, reliable, and sensitive and can realize the important value of the application of correlation analysis theory of "automatic blood collection-microdialysis/PK-PD" in the research on neuropathic pain.

Inflammation and Acinar Cell Dual-Targeting Nanomedicines for Synergistic Treatment of Acute Pancreatitis via Ca2+ Homeostasis Regulation and Pancreas Autodigestion Inhibition.

Severe acute pancreatitis (AP) is a life-threatening pancreatic inflammatory disease with a high mortality rate (∼40%). Existing pharmaceutical therapies in development or in clinical trials showed insufficient treatment efficacy due to their single molecular therapeutic target, poor water solubility, short half-life, limited pancreas-targeting specificity, etc. Herein, acid-responsive hollow mesoporous Prussian blue nanoparticles wrapped with neutrophil membranes and surface modified with the N,N-dimethyl-1,3-propanediamine moiety were developed for codelivering membrane-permeable calcium chelator BAPTA-AM (BA) and trypsin activity inhibitor gabexate mesylate (Ga). In the AP mouse model, the formulation exhibited efficient recruitment at the inflammatory endothelium, trans-endothelial migration, and precise acinar cell targeting, resulting in rapid pancreatic localization and higher accumulation. A single low dose of the formulation (BA: 200 µg kg-1, Ga: 0.75 mg kg-1) significantly reduced pancreas function indicators to close to normal levels at 24 h, effectively restored the cell redox status, reduced apoptotic cell proportion, and blocked the systemic inflammatory amplified cascade, resulting in a dramatic increase in the survival rate from 58.3 to even 100%. Mechanistically, the formulation inhibited endoplasmic reticulum stress (IRE1/XBP1 and ATF4/CHOP axis) and restored impaired autophagy (Beclin-1/p62/LC3 axis), thereby preserving dying acinar cells and restoring the cellular "health status". This formulation provides an upstream therapeutic strategy with clinical translation prospects for AP management through synergistic ion homeostasis regulation and pancreatic autodigestion inhibition.

Curcumol Attenuates Portal Hypertension and Collateral Shunting Via Inhibition of Extrahepatic Angiogenesis in Cirrhotic Rats.

Liver cirrhosis can cause disturbances in blood circulation in the liver, resulting in impaired portal blood flow and ultimately increasing portal venous pressure. Portal hypertension induces portal-systemic collateral formation and fatal complications. Extrahepatic angiogenesis plays a crucial role in the development of portal hypertension. Curcumol is a sesquiterpenoid derived from the rhizome of Curcumae Rhizoma and has been confirmed to alleviate liver fibrosis by inhibiting angiogenesis. Therefore, our study was designed to explore the effects of curcumol on extrahepatic angiogenesis and portal hypertension. To induce cirrhosis, Sprague Dawley rats underwent bile duct ligation (BDL) surgery. Rats received oral administration with curcumol (30 mg/kg/d) or vehicle (distilled water) starting on day 15 following surgery, when BDL-induced liver fibrosis had developed. The effect of curcumol was assessed on day 28, which is the typical time of BDL-induced cirrhosis. The results showed that curcumol markedly reduced portal pressure in cirrhotic rats. Curcumol inhibited abnormal splanchnic inflow, mitigated liver injury, improved liver fibrosis, and attenuated portal-systemic collateral shunting in cirrhotic rats. These protective effects were partially attributed to the inhibition on mesenteric angiogenesis by curcumol. Mechanically, curcumol partially reversed the BDL-induced activation of the JAK2/STAT3 signaling pathway in cirrhotic rats. Collectively, curcumol attenuates portal hypertension in liver cirrhosis by suppressing extrahepatic angiogenesis through inhibiting the JAK2/STAT3 signaling pathway.

Association between obstructive sleep apnea and low bone mass in adults: a systematic review and meta-analysis.

Introduction: This study aimed to synthesize existing evidence on the potential association between obstructive sleep apnea (OSA) and low bone mass in adults. Methods: Electronic searches of four main databases were performed. The inclusion criteria consisted of observational studies investigating the relationship between OSA and bone mass, osteoporosis, fractures, or bone metabolism markers in adult population. Bone mineral density (BMD) and T score of lumbar and femur neck, incidence of osteoporosis and fractures, bone metabolism marker levels were extracted as primary outcomes. Results: Among the 693 relevant publications, 10 studies consisting of 158,427 participants met with the inclusion and exclusion criteria. Meta-analysis showed a significant lower BMD of lumbar (mean difference (MD) = - 0.03; 95% CI - 0.05, - 0.01; I2 = 46%), femur neck (MD = - 0.06; 95% CI - 0.12, 0.00; I2 = 71%), and a significant lower T score of lumbar (MD = - 0.42; 95% CI - 0.79, - 0.05; I2 = 63%) in the OSA group. The results suggested that both male (odds ratio (OR) = 2.03; 95% CI 1.23, 3.35; I2 = 38%) and female (OR = 2.56; 95% CI 1.96, 3.34; I2 = 0%) had higher risk of osteoporosis in the OSA group. Besides, meta-analysis also showed that bone-specific alkaline phosphatase was significantly lower in OSA patients (MD = - 1.90; 95% CI - 3.48, - 0.32; I2 = 48%). Conclusions: A potential association between OSA and lower bone mass in adults is preliminarily proved. It also seems plausible that both male and female with OSA have a higher risk of osteoporosis. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-023-00481-1.

Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion.

Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.