Analysis of Changes and Diagnostic Value of Doppler Ultrasound Parameters in Patients with Acute Kidney Injury after Laparoscopic Radical Prostatectomy.

BACKGROUND: Early diagnosis of postoperative acute kidney injury (AKI) is crucial. This study investigated the changes and early diagnostic value of Doppler ultrasound parameters in patients with AKI after laparoscopic radical prostatectomy (LRP). METHODS: This study retrospectively analysed the clinical data of 198 patients with LRP undergoing Doppler ultrasound from May 2020 to May 2022. The incidence of AKI after LRP was measured based on diagnostic criteria of AKI developed by Kidney Disease: Improving Global Outcomes. The patients were divided into AKI group (n = 12) and non-AKI group (n = 186) in accordance with the presence or absence of AKI. This study compared changes in Doppler ultrasound parameters between two groups, and evaluated the clinical efficacy of single and combined diagnosis of ultrasound parameters using receiver operating characteristic (ROC) curve and area under the curve (AUC). RESULTS: Twelve patients experienced postoperative AKI, with an incidence rate of 6.06%. No significant difference was found in baseline data, serum creatinine (Scr), urinary output and blood potassium levels of both groups (p > 0.05). The urinary output 1 day after surgery was significantly lower than that before surgery (p < 0.05). The AKI group demonstrated higher pulsatility index (PI) and resistive index (RI) of the renal interlobar artery than the non-AKI group (p < 0.05), with no significant difference in peak systolic velocity (PSV) in both groups (p > 0.05). No significant difference was observed in the Doppler ultrasound parameters of renal segmental artery and main renal artery (p > 0.05). The AUCs in the PI of the renal interlobar artery, the RI of the renal interlobar artery, and the combined diagnosis were 0.720, 0.704 and 0.724, respectively. ROC curve showed that the above two Doppler ultrasound parameters had good diagnostic efficacy for AKI after LRP (p < 0.05). CONCLUSIONS: The PI and RI of renal interlobar artery in the AKI group after LRP were significantly different from those in the non-AKI group. These two Doppler ultrasound parameters had good diagnostic efficacy in the early identification of AKI after LRP. Thus, they could provide reference and guidance for clinical practice.

Comprehensive analysis of consensus molecular subtypes for ovarian cancer from bulk to single-cell perspectives.

Molecular subtypes play a pivotal role in guiding preclinical and clinical risk assessment and treatment strategies in cancer. In this study, we extracted whole-tissue transcriptomic data from 1,987 ovarian cancer patients spanning 26 independent GEO cohorts. A total of four consensus subtypes (C1-C4) were identified, notably, subtype C1 samples exhibited a poor prognosis and higher M2 macrophages infiltration, whereas subtype C2 samples demonstrated the best prognosis and higher CD4 resting T cells infiltration. Additionally, we characterized cancer- and stromal-specific gene expression profiles, and conducted an analysis of ligand-receptor interactions within these compartments. Based on cancer compartment, subtype-specific interactions as well as gene signatures for each molecular subtype were identified. Leveraging single-cell transcriptomic data, we delineated malignant epithelial cells with four molecular subtypes and observed an increase in C1 cell proportions from primary to relapse to metastasis stages, with a corresponding decrease in C2 cell proportions. Furthermore, we investigated subtype-specific interaction with T cells through integrated analysis of bulk and single-cell datasets. Finally, we developed a robust 10-gene risk model based on subtype gene signatures for prognostic evaluation in ovarian cancer, demonstrating its efficacy across independent datasets. In summary, this study systematically explored ovarian cancer molecular subtypes and provided a framework for other cancer types.

Multiple myeloma exosomal miRNAs suppress cGAS-STING antiviral immunity.

DNA virus infection is a significant cause of morbidity and mortality in patients with multiple myeloma (MM). Monocyte dysfunction in MM patients plays a central role in infectious complications, but the precise molecular mechanism underlying the reduced resistance of monocytes to viruses in MM patients remains to be elucidated. Here, we found that MM cells were able to transfer microRNAs (miRNAs) to host monocytes/macrophages via MM cell-derived exosomes, resulting in the inhibition of innate antiviral immune responses. The screening of miRNAs enriched in exosomes derived from the bone marrow (BM) of MM patients revealed five miRNAs that negatively regulate the cGAS-STING antiviral immune response. Notably, silencing these miRNAs with antagomiRs in MM-bearing C57BL/KaLwRijHsd mice markedly reduced viral replication. These findings identify a novel mechanism whereby MM cells possess the capacity to inhibit the innate immune response of the host, thereby rendering patients susceptible to viral infection. Consequently, targeting the aberrant expression patterns of characteristic miRNAs in MM patients is a promising avenue for therapeutic intervention. Considering the miRNA score and relevant clinical factors, we formulated a practical and efficient model for the optimal assessment of susceptibility to DNA viral infection in patients with MM.

Clarifying the Direct Generation of •OH Radicals in Photocatalytic O2 Reduction: Theoretical Prediction Combined with Experimental Validation.

This work systematically studied thermocatalytic and photocatalytic pathways of formaldehyde degradation and H-assisted O2 reduction over a Pt13/anatase-TiO2(101) composite via DFT calculations together with constrained molecular dynamics (MD) simulations. We show that photocatalytic O2 reduction on Pt/TiO2 can directly generate •OH radicals (*O2 → *OOH → •OH) via two hydrogenation steps with small barriers, and the product selectivity (*H2O2 or •OH) is decided by the relative position between catalyst Fermi level and •OH/*H2O2 redox potential (theoretical determination of 0.07 V referencing to the SHE). Such a novel reaction channel was furthermore validated at the liquid-solid interface via constrained MD simulations and experimental electron paramagnetic resonance detections, and a wide range of H resources, e.g., *HCHO, *HCO, *H (H+ + e-), can always drive the direct •OH generation. The additional portion of e--triggered •OH radicals are prone to diffuse into solution or the TiO2 surface and furthermore cooperate with the conventional h+-driven photooxidations.

Interfacial Assembly of Free-Standing Polymer-Phenolic Films for Antibacterial and Antiultraviolet Applications.

We report a facile interfacial assembly strategy for the preparation of flexible polyphenol-based films for antibacterial and antiultraviolet applications. The free-standing films can be instantaneously formed via spraying tannic acid (TA) at the surface of carboxymethyl chitosan (CMCS) solutions. Compared with the traditional casting-evaporation procedure on solid substrates, the liquid interfacial assembly method for the construction of free-standing films is rapid and facile, which prevents the interface separation procedure from the substrates. The thickness and mechanical properties of the films are well controlled by changing the incubation time. The low-field nuclear magnetic resonance was used to analyze the water distributions inside the films and to distinguish the cross-linked structure of CMCS-TA films with different thicknesses, revealing the dynamics of the film formation process. Importantly, the films exhibit outstanding antibacterial and antiultraviolet properties, which are promising in the applications of wound dressings. This study provides a new avenue for the assembly of flexible free-standing films with multifunctionality via a facile and low-cost fabrication process.

Orally administrated liquid metal agents for inflammation-targeted alleviation of inflammatory bowel diseases.

Rapid drug clearance and off-target effects of therapeutic drugs can induce low bioavailability and systemic side effects and gravely restrict the therapeutic effects of inflammatory bowel diseases (IBDs). Here, we propose an amplifying targeting strategy based on orally administered gallium (Ga)-based liquid metal (LM) nano-agents to efficiently eliminate reactive oxygen and nitrogen species (RONS) and modulate the dysregulated microbiome for remission of IBDs. Taking advantage of the favorable adhesive activity and coordination ability of polyphenol structure, epigallocatechin gallate (EGCG) is applied to encapsulate LM to construct the formulations (LM-EGCG). After adhering to the inflamed tissue, EGCG not only eliminates RONS but also captures the dissociated Ga to form EGCG-Ga complexes for enhancive accumulation. The detained composites protect the intestinal barrier and modulate gut microbiota for restoring the disordered enteral microenvironment, thereby relieving IBDs. Unexpectedly, LM-EGCG markedly decreases the Escherichia_Shigella populations while augmenting the abundance of Akkermansia and Bifidobacterium, resulting in favorable therapeutic effects against the dextran sulfate sodium-induced colitis.

TaqTth-hpRNA: a novel compact RNA-targeting tool for specific silencing of pathogenic mRNA.

Pathogenic allele silencing is a promising treatment for genetic hereditary diseases. Here, we develop an RNA-cleaving tool, TaqTth-hpRNA, consisting of a small, chimeric TaqTth, and a hairpin RNA guiding probe. With a minimal flanking sequence-motif requirement, in vitro and in vivo studies show TaqTth-hpRNA cleaves RNA efficiently and specifically. In an Alzheimer's disease model, we demonstrate silencing of mutant APPswe mRNA without altering the wild-type APP mRNA. Notably, due to the compact size of TaqTth, we are able to combine with APOE2 overexpression in a single AAV vector, which results in stronger inhibition of pathologies.

A disproportionality analysis of adverse events caused by GnRHas from the FAERS and JADER databases.

Background: Gonadotrophin-releasing hormone analogs (GnRHas) play a significant role in addressing gynecological diseases, central precocious puberty, and cancer. However, ensuring the safety of GnRHas in real-world applications requires continuous vigilance. In light of this, we undertook a disproportionality analysis focused on adverse events (AEs) associated with GnRHas using data from both the FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER). We evaluated GnRHas-associated AEs and characterized the clinical priority of unlisted AEs caused by each GnRHa from the different databases. Methods: In the disproportionality analysis, we applied two adjusted algorithms to identify signals related to GnRHas in the FAERS and JADER databases from 2004 to 2023. Additionally, we utilized the Statistical Analysis System (SAS, 9.4) to examine potential and high-aROR (adjusted reporting odds ratio) signals associated with GnRHas. We performed clinical priority assessment for suspicious PTs and an analysis of serious/non-serious outcomes. We also gathered information on the onset times of AEs linked with GnRHas from both databases. Results: From January 2004 to September 2023, FAERS and JADER recorded a total of 50,360,413 and 1,440,200 AEs, respectively. Employing two algorithms, the suspicious preferred terms (PTs) related to leuprolide (Leu) were 562 potential PTs (44 unlisted in specifications), followed by goserelin (Gos) with 189 PTs (28 unlisted), triptorelin (Tri) with 172 PTs (28 unlisted), and Leu-JADER with 85 PTs (10 unlisted). At the same PT level, the differences in GnRHas between the two databases were observed, such as cardiac failure, diabetes mellitus, liver disorder, dementia, suicidal ideation, interstitial lung disease, urinary disorders, and hypertensive crisis. In an analysis of serious vs. non-serious outcomes, a total of 43 AEs of Leu were more likely to be reported as serious AEs with p < 0.05 (such as asthenia, urinary retention, diabetes mellitus, interstitial lung disease, gait disturbance, and so on), following by Tri (6 AEs), and Gos (4 AEs). Based on the clinical priority score, 41 PTs of Leu, 26 PTs of Tri, 24 PTs of Gos, and 8 PTs of Leu-JADER were graded as weak. There were 3 PTs of Leu, 2 PTs of Tri, 4 PTs of Gos, and 2 PTs of Leu-JADER that were graded as moderate. Notably, in the assessment of the relevant evidence, 2 PTs (loss of libido and urinary tract toxicity caused by Leu), 1 PT (electrolyte imbalance caused by Tri), and 2 PTs (anorexia and suicidal ideation caused by Gos) showed a strong level of evidence with "++." The differences in the signal strength of the same PTs from two databases were also worth noting. Moreover, the median onset time for GnRHas (Leu, Tri, and Gos) was 23 days (0, 298), 22 days (0, 181), and 217 days (29, 706), respectively, as median (Q1, Q3). Conclusion: An examination of two databases revealed suspicious AEs associated with GnRHas. Our study found potential new AE signals of GnRHas and supported continuous clinical monitoring, pharmacovigilance, regional differences, and further studies of GnRHas.

Jujuboside A through YY1/CYP2E1 signaling alleviated type 2 diabetes-associated fatty liver disease by ameliorating hepatic lipid accumulation, inflammation, and oxidative stress.

Non-alcoholic fatty liver disease (NAFLD) was a chronic complication of type 2 diabetes mellitus (T2DM), and this comorbid disease lacked therapeutic drugs. Semen Ziziphi Spinosae (SZS) was the seed of Ziziphus jujuba var. Spinosa (Bunge) Hu ex H.F. Chow, and it could alleviate the symptoms of T2DM patients. As a triterpene saponin, Jujuboside A (Ju A) was the main active substance isolated from SZS and could improve hyperglycemia of diabetic mice. However, it was still unknown whether Ju A has protective effects on T2DM-associated NAFLD. Our study showed that Ju A attenuated T2DM-associated liver damage by alleviating hepatic lipid accumulation, inflammatory response, and oxidative stress in the liver of db/db mice, and high glucose (HG) and free fatty acid (FFA) co-stimulated human hepatocellular carcinomas (HepG2) cells. Along with the improved hyperglycemia and liver injury, Ju A restrained Yin Yang 1 (YY1)/cytochrome P450 2E1 (CYP2E1) signaling in vivo and in vitro. YY1 overexpression intercepted the protective effects of Ju A on T2DM-induced liver injury via promoting hepatic lipid accumulation, inflammatory response, and oxidative stress. While, the blocking effect of YY1 overexpression on Ju A's hepatoprotective effect was counteracted by further treatment of CYP2E1 specific inhibitor diethyldithiocarbamate (DDC) in vitro. In-depth mechanism research showed that Ju A through YY1/CYP2E1 signaling promoted hepatic fatty acid ß-oxidation, and inhibited inflammatory response and oxidative stress by activating peroxisome proliferator-activated receptor alpha (PPARα), leading to the improvement of T2DM-associated NAFLD. Ju A might be a potential agent in the treatment and health care of T2DM-associated liver disease, especially NAFLD.

Scorpion venom heat-resistant synthesized peptide ameliorates epileptic seizures and imparts neuroprotection in rats mediated by NMDA receptors.

Finding new and effective natural products for designing antiepileptic drugs is highly important in the scientific community. The scorpion venom heat-resistant peptide (SVHRP) was purified from Buthus martensii Karsch scorpion venom, and subsequent analysis of the amino acid sequence facilitated the synthesis of a peptide known as scorpion venom heat-resistant synthesis peptide (SVHRSP) using a technique for peptide synthesis. Previous studies have demonstrated that the SVHRSP can inhibit neuroinflammation and provide neuroprotection. This study aimed to investigate the antiepileptic effect of SVHRSP on both acute and chronic kindling seizure models by inducing seizures in male rats through intraperitoneal administration of pentylenetetrazole (PTZ). Additionally, an N-methyl-D-aspartate (NMDA)-induced neuronal injury model was used to observe the anti-excitotoxic effect of SVHRSP in vitro. Our findings showed that treatment with SVHRSP effectively alleviated seizure severity, prolonged latency, and attenuated neuronal loss and glial cell activation. It also demonstrated the prevention of alterations in the expression levels of NMDA receptor subunits and phosphorylated p38 MAPK protein, as well as an improvement in spatial reference memory impairment during Morris water maze (MWM) testing in PTZ-kindled rats. In vitro experiments further revealed that SVHRSP was capable of attenuating neuronal action potential firing, inhibiting NMDA receptor currents and intracellular calcium overload, and reducing neuronal injury. These results suggest that the antiepileptic and neuroprotective effects of SVHRSP may be mediated through the regulation of NMDA receptor function and expression. This study provides new insight into therapeutic strategies for epilepsy.

Oral microsphere formulation of M2 macrophage-mimetic Janus nanomotor for targeted therapy of ulcerative colitis.

Oral medication for ulcerative colitis (UC) is often hindered by challenges such as inadequate accumulation, limited penetration of mucus barriers, and the intricate task of mitigating excessive ROS and inflammatory cytokines. Here, we present a strategy involving sodium alginate microspheres (SAMs) incorporating M2 macrophage membrane (M2M)-coated Janus nanomotors (denominated as Motor@M2M) for targeted treatment of UC. SAM provides a protective barrier, ensuring that Motor@M2M withstands the harsh gastric milieu and exhibits controlled release. M2M enhances the targeting precision of nanomotors to inflammatory tissues and acts as a decoy for the neutralization of inflammatory cytokines. Catalytic decomposition of H2O2 by MnO2 in the oxidative microenvironment generates O2 bubbles, propelling Motor@M2M across the mucus barrier into inflamed colon tissues. Upon oral administration, Motor@M2M@SAM notably ameliorated UC severity, including inflammation mitigation, ROS scavenging, macrophage reprogramming, and restoration of the intestinal barrier and microbiota. Consequently, our investigation introduces a promising oral microsphere formulation of macrophage-biomimetic nanorobots, providing a promising approach for UC treatment.

Integrative analysis reveals different feature of intrahepatic cholangiocarcinoma subtypes.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) has two main histological subtypes: large and small duct-type iCCA, which are characterized by different clinicopathological features. This study was conducted with the purpose of expanding our understanding of their differences in molecular features and immune microenvironment. METHODS: We selected 132 patients who underwent radical surgery at our department between 2015 and 2021 for clinical and survival analyses. Whole-exome sequencing was performed to analyse mutational landscapes. Bulk RNA sequencing and single-cell RNA sequencing data were used for pathway enrichment and immune infiltration analyses based on differentially expressed genes. The function of PPP1R1B was analysed both in vitro and in vivo and the gene mechanism was further investigated. RESULTS: We found that large duct-type iCCA had worse overall survival and recurrence-free survival rates than small duct-type iCCA. Mutations in ARID1A, DOT1L and ELF3 usually occur in large duct-type iCCA, whereas mutations in IDH1 and BAP1 occur in small duct-type iCCA. Among the differentially expressed genes, we found that PPP1R1B was highly expressed in large duct-type iCCA tumour tissues. Expression of PPP1R1B promoted cell proliferation, migration and invasion and indicated a worse prognosis. A combination of USF2 with the promoter of PPP1R1B can enhance gene expression in iCCA, which may further affect the expression of genes such as AHNAK, C4BPA and activating the PI3K/AKT pathway. CONCLUSIONS: Our findings extend our understanding of large and small duct-type iCCA. In addition, PPP1R1B may serve as a potential marker and therapeutic target for large duct-type iCCA.

A study on the morphology of iliac crest based on the objectives of jaw bone defect reconstruction.

OBJECTIVES: to understand the morphological characteristics of iliac crest and provide advice and assistance for jaw bone reconstruction with iliac bone flap by evaluating the thickness and curvature of iliac crest. MATERIALS AND METHODS: 100 patients who had taken Spiral CT of the Abdominal region before surgeries between 2020 and 2022 were included in this study. 3D reconstruction images of the iliac bones were created. 5 vertical planes perpendicular to the iliac crest were made every 2 cm along the centerline of the iliac crest (VP2 ~ VP10). On these vertical planes, 4 perpendicular lines were made every 1 cm along the long axis of the iliac crest (D1 ~ D4). The thicknesses at these sites, horizontal angle (HA) of iliac crest and the distance between inflection point and the central point of anterior superior iliac spine (DIA) were measured. RESULTS: The thickness of iliac bone decreased significantly from D1 ~ D4 on VP6 ~ VP10 and from VP2 ~ VP10 on D3 and D4 level (P<0.05). HA of iliac crests was 149.13 ± 6.92°, and DIA was 7.36 ± 1.01 cm. Iliac bone thickness, HA and DIA had very weak or weak correlation with patient's age, height and weight. CONCLUSIONS: The average thicknesses of iliac crest were decreased approximately from front to back, from top to bottom. The thickness and curvature of the iliac crest were difficult to predict by age, height and weight. CLINICAL RELEVANCE: Virtual surgical planning is recommended before jaw bone reconstruction surgery with iliac bone flap, and iliac crest process towards alveolar process might be a better choice.

Retrospective study of the deep circumflex iliac artery flap and the vascularized fibula free flap for maxillary defect repair.

OBJECTIVES: The deep circumflex iliac artery flap (DCIA) and vascularized fibular free flap (FFF) are mainstay flaps for maxillary defect reconstruction. This study compared the functional outcomes and success rates of these flaps to provide midface reconstruction strategies. MATERIALS AND METHODS: Maxillary defects reconstructed with DCIA or FFF at the Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology between May 2016 and May 2023 were retrospectively analyzed. The length, width, and height of the grafted bone segments; intermaxillary distance; buttress reconstruction rate (BRR); dental arch reconstruction rate (DAR); success rate; and dental implantation rate were compared. RESULTS: The DCIA and FFF groups had 33 and 27 patients, respectively. Success rate in the DCIA group was 93.94 % and 100 % in the FFF group. The DCIA length was less than that of FFF; however, the width and height were significantly larger. 87.10 % of cases in the DCIA group were classified as Brown class b and c, 51.85 % of cases in the FFF group were classified as Brown class d. The average BRR in the DCIA group was 69.89 % ± 16.05 %, which was significantly higher than that in the FFF group. A total of 38.7 % and 11.1 % patients in the DCIA and FFF groups, respectively, had completed implantation. CONCLUSION: DCIA has a greater width and height, and is more suitable for repairing Brown class b and c defects, providing sufficient bone for implantation, while the FFF is longer and more suitable for Brown class d defect reconstruction.

Post-marketing safety concerns with palbociclib: a disproportionality analysis of the FDA adverse event reporting system.

OBJECTIVES: To explore the association between palbociclib and related adverse events (AEs) in the real world through U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: The signal strength of palbociclib-related AEs was done by disproportionality analysis. Clinical priority of palbociclib-related AEs was scored and ranked by assessing five different features. Outcome analysis, time to onset analysis, dose-report /AEs number analysis, and stratification analysis were all performed. RESULTS: There were 61,821 'primary suspected (PS)' reports of palbociclib and 195,616 AEs associated with palbociclib. The four algorithms simultaneously detected 18 positive signals at the SOC level, and 65 positive signals at the PT level. Bone marrow failure, neuropathy, peripheral, pleural effusion, myelosuppression, pulmonary edema, and pulmonary thrombosis were also found to have positive signals. Gender (female vs male, χ2 = 5.287, p = 0.022) and age showed significant differences in serious and non-serious reports. Palbociclib-related AEs had a median onset time of 79 days (interquartile range [IQR] 20-264 days). CONCLUSIONS: The study identified potential Palbociclib-related AEs and offered warnings for special AEs, providing further data for palbociclib safety studies in breast cancer patients. Nonetheless, prospective clinical trials are needed to validate these results and explain their relationship.

Carbon Fiber Reinforced Recycled Polypropylene/Polyolefin Elastomer Composites with High Mechanical Properties.

The treatment of waste plastics has gradually become a hot topic in the current scientific community. In response to the needs for high-impact performance R-PP-based composites, carbon fiber (CF)-reinforced polyolefin elastomer (POE)/recycled polypropylene (R-PP) composite (CF/POE/R-PP) was prepared by the mechanical blending method, and its mechanical and thermal properties were systematically studied. It was found that the CF could effectively improve the bending and notch impact strength as well as enhance the thermal stability of POE/R-PP. Furthermore, a stable and dispersed composite interface formed by the combination of maleic anhydride-grafted polypropylene (PP-g-MAH) with the surface of CF and the fusion alkyl chains in R-PP and POE further enhanced the CF's reinforcing effect. As a result, the addition of 9 wt.% CF successfully improved the heat resistance of the composite material, and the residual carbon content increased by 97.84% after sintering. The composite toughening of POE and CF effectively improved the impact strength of the composite material, with a maximum increase of over 1000%. This study ultimately resulted in a high-impact-resistant composite material.

ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition.

The tumor microenvironment (TME) is restricted in metabolic nutrients including the semi-essential amino acid arginine. While complete arginine deprivation causes T cell dysfunction, it remains unclear how arginine levels fluctuate in the TME to shape T cell fates. Here, we find that the 20-µM low arginine condition, representing the levels found in the plasma of patients with cancers, confers Treg-like immunosuppressive capacities upon activated T cells. In vivo mouse tumor models and human single-cell RNA-sequencing datasets reveal positive correlations between low arginine condition and intratumoral Treg accumulation. Mechanistically, low arginine-activated T cells engage in metabolic and transcriptional reprogramming, using the ATF4-SLC7A11-GSH axis, to preserve their suppressive function. These findings improve our understanding of the role of arginine in human T cell biology with potential applications for immunotherapy strategies.

[Yeast extract improves the inflammatory response of HepG2 cells induced by ethyl alcohol and lipopolysaccharide].

OBJECTIVE: To explore the ameliorative effect of yeast extract(YE) on the inflammatory response of human hepatoma cells(HepG2) induced by ethyl alcohol(EtOH) and lipopolysaccharide(LPS), and further explore the potential molecular mechanism based on Toll-like receptor 4(TLR4)/nuclear factor kappa B(NF-κB) signaling pathway. METHODS: HepG2 cells were induced by 50 mmol/L EtOH and 1 µg/mL LPS combined with YE intervention. The expression level of inflammatory cytokines was detected by ELISA. The expression level of TLR4 and the nuclear translocation of NF-κB were detected by immunofluorescence staining. The expression levels of TLR4, NF-κB, phospho-NF-κB-P65(P-NF-κB-p65), nucleus-phospho-NF-κB-p65(N-P-NF-κB-p65), tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-1ß(IL-1ß) were detected by Western blot. RESULTS: Compared with the control group, the cells in EtOH+LPS group produced a large number of inflammatory factors and had a significant inflammatory response. YE intervention significantly alleviated EtOH+LPS induced hepatocyte inflammatory response. Further molecular mechanism studies showed that YE significantly reduced TLR4 expression level and inhibited NF-κB nuclear translocation in hepatocytes. CONCLUSION: YE can effectively inhibit the inflammatory response of HepG2 cells induced by EtOH and LPS, and its molecular mechanism may be related to the down-regulation of TLR4/NF-κB pathway.

Tumor Microenvironment-Activatable Nanosystem Capable of Overcoming Multiple Therapeutic Obstacles for Augmenting Immuno/Metal-Ion Therapy.

Abnormal tumor microenvironment (TME) imposes barriers to nanomedicine penetration into tumors and evolves tumor-supportive nature to provide tumor cell protection, seriously weakening the action of antitumor nanomedicines and posing significant challenges to their development. Here, we engineer a TME-activatable size-switchable core-satellite nanosystem (Mn-TI-Ag@HA) capable of increasing the effective dose of therapeutic agents in deep-seated tumors while reversing tumor-supportive microenvironment for augmenting immuno/metal-ion therapy. When activated by TME, the nanosystem disintegrates, allowing ultrasmall-sized Ag nanoparticles to become unbound and penetrate deep into solid tumors. Simultaneously, the nanosystem produces O2 and releases TGF-ß inhibitors in situ to drive macrophage M2-to-M1 polarization, increasing intratumoral H2O2 concentration, and ultimately augmenting metal-ion therapy by accelerating hypertoxic Ag+ production. The nanosystem can overcome multiple obstacles that aid in tumor resistance to nanomedicine, demonstrating effective tumor penetration, TME regulation, and tumor inhibition effects. It can provoke long-term immunological memory effects against tumor rechallenge when combined with immune checkpoint inhibitor anti-PD-1. This work provides a paradigm for designing efficient antitumor nanomedicines.