Enhanced Diabetic Rat Wound Healing by Platelet-Rich Plasma Adhesion Zwitterionic Hydrogel.

BACKGROUND: The skin is the largest organ in the human body and serves as a barrier for protective, immune, and sensory functions. Continuous and permanent exposure to the external environment results in different levels of skin and extracellular matrix damage. During skin wound healing, the use of good dressings and addition of growth factors to the wound site can effectively modulate the rate of wound healing. A dressing containing bioactive substances can absorb wound exudates and reduce adhesion between the wound and dressing, whereas growth factors, cytokines, and signaling factors can promote cell motility and proliferation. AIM AND OBJECTIVES: We prepared a functional wound dressing by combining platelet-rich plasma (PRP) and zwitterionic hydrogels. Functional wound dressings are rich in various naturally occurring growth factors that can effectively promote the healing process in various types of tissues and absorb wound exudates to reduce adhesion between wounds and dressings. Furthermore, PRP-incorporated zwitterionic hydrogels have been used to repair full-thickness wounds in Sprague-Dawley rats with diabetes (DM SD). MATERIALS AND METHODS: Fibroblasts and keratinocytes were cultured with PRP, zwitterionic hydrogels, and PRP-incorporated zwitterionic hydrogels to assess cell proliferation and specific gene expression. Furthermore, PRP-incorporated zwitterionic hydrogels were used to repair full-thickness skin defects in DM SD rats. RESULTS: The swelling ratio of hydrogel, hydrogel + PRP1000 (108 platelets/mL), and hydrogel + PRP1000 (109 platelets/mL) groups were similar (~07.71% ± 1.396%, 700.17% ± 1.901%, 687.48% ± 4.661%, respectively) at 144 hours. The tensile strength and Young modulus of the hydrogel and hydrogel + PRP10000 groups were not significantly different. High concentrations of PRP (approximately 108 and 109 platelets/mL) effectively promoted the proliferation of fibroblasts and keratinocytes. The zwitterionic hydrogels were not cytotoxic to any cell type. High PRP concentration-incorporated zwitterionic hydrogels increased the rate of cell proliferation and significantly increased the expression of characteristic genes such as collagen, fibronectin, involucrin, and keratin. Subsequently, zwitterionic hydrogels with high PRP concentrations were used to repair full-thickness skin defects in DM SD rats, and a wound healing rate of more than 90% was recorded on day 12. CONCLUSIONS: PRP contains high concentrations of growth factors that promote cell viability, enhance specific gene expression, and have a high medical value in cell therapy. Zwitterionic hydrogels have a 3-dimensional interconnected microporous structure and can resist cell adhesion without causing cytotoxicity. Platelet-rich plasma-incorporated zwitterionic hydrogels further enhance the cellular properties and provide an effective therapeutic option for wound healing.

Schizophrenia patients discharged on antipsychotic polypharmacy from a public psychiatric hospital in Taiwan, 2006-2021.

The aim of this study was to identify the factors associated with antipsychotic polypharmacy (APP), investigate whether APP could affect the risk of rehospitalization, and explore temporal trends in APP use. Schizophrenia patients discharged from the study hospital between 2006 and 2021 (n = 16,722) were included in the analysis. The logistic regression model was employed to determine the predictors significantly associated with APP use. Survival analysis was used to compare time to rehospitalization between APP and antipsychotic monotherapy (AMT). The temporal trend of APP use was analyzed using the Cochran-Armitage Trend test. In comparison with the patients (n = 10,909) who were discharged on AMT, those (n = 5,813) on APP were significantly more likely to be male gender, to receive LAIs, to take clozapine, to take anticholinergic agents, to have a greater number of previous hospitalizations, and to have a higher CPZ equivalent dose of antipsychotic prescription. The prescription rate of APP significantly increased from 18.4 % in 2006 to 44.9 % in 2021. Compared with AMT, APP was associated with more clozapine use, more LAI use, higher doses of antipsychotics, and an increased risk of rehospitalization. In addition, the prescription of APP continued to increase during the study period.

Comparative effects of warming systems applied to different parts of the body on hypothermia in adults undergoing abdominal surgery: A systematic review and network meta-analysis of randomized controlled trials.

STUDY OBJECTIVE: The prevention of perioperative hypothermia after anesthesia induction is a critical concern in patients undergoing abdominal surgery. The effectiveness of various warming systems for preventing hypothermia and shivering when applied to specific areas of the body remains undetermined. DESIGN: Systematic review and network meta-analysis. SETTING: Operating room. INTERVENTION: Five electronic databases were searched, including only randomized control trials (RCTs) reporting the effects of warming systems applied to specific body sites on the intraoperative core temperature and postoperative risk of shivering in adults undergoing abdominal surgery. A multivariate random-effects network meta-analysis with a frequentist framework was implemented for data analysis. MEASUREMENTS: The primary outcome was the core body temperature 60 and 120 min after anesthesia induction for abdominal surgery. The secondary outcome was the incidence of postoperative shivering. RESULTS: This review comprised a total of 24 RCTs including 1119 patients. At 60 and 120 min after anesthesia induction, a forced-air warming system applied to the upper body (0.3 °C and 95% confidence intervals = [0.3 to 0.4], 1.0 °C [0.7 to 1.3]), lower body (0.4 °C [0.3 to 0.5], 0.9 °C [0.5 to 1.2]), and underbody (0.5 °C [0.5 to 0.6], 1.2 °C [0.9 to 1.6]) was superior to passive insulation in terms of core body temperature regulation. Compared with passive insulation, the forced-air warming system applied to the lower body (odds ratio = 0.06) or underbody (0.44) and the electric heating blanket to the lower body (0.02) or the whole body (0.07) significantly reduced the risk of shivering. CONCLUSIONS: The results of this NMA revealed that forced-air warming with an underbody blanket effectively elevates core body temperatures in 60 and 120 min after induction of anesthesia and prevents shivering in patients recovering from abdominal surgery.

Liposome-tethered supported lipid bilayer platform for capture and release of heterogeneous populations of circulating tumor cells.

Because of scarcity, vulnerability, and heterogeneity in the population of circulating tumor cells (CTCs), the CTC isolation system relying on immunoaffinity interaction exhibits inconsistent efficiencies for all types of cancers and even CTCs with different phenotypes in individuals. Moreover, releasing viable CTCs from an isolation system is of importance for molecular analysis and drug screening in precision medicine, which remains a challenge for current systems. In this work, a new CTC isolation microfluidic platform was developed and contains a coating of the antibody-conjugated liposome-tethered-supported lipid bilayer in a developed chaotic-mixing microfluidic system, referred to as the "LIPO-SLB" platform. The biocompatible, soft, laterally fluidic, and antifouling properties of the LIPO-SLB platform offer high CTC capture efficiency, viability, and selectivity. We successfully demonstrated the capability of the LIPO-SLB platform to recapitulate different cancer cell lines with different antigen expression levels. In addition, the captured CTCs in the LIPO-SLB platform can be detached by air foam to destabilize the physically assembled bilayer structures due to a large water/air interfacial area and strong surface tension. More importantly, the LIPO-SLB platform was constructed and used for the verification of clinical samples from 161 patients with different primary cancer types. The mean values of both single CTCs and CTC clusters correlated well with the cancer stages. Moreover, a considerable number of CTCs were isolated from patients' blood samples in the early/localized stages. The clinical validation demonstrated the enormous potential of the universal LIPO-SLB platform as a tool for prognostic and predictive purposes in precision medicine.

Is there a role for lung surgery in initially unresectable non-small cell lung cancer after tyrosine kinase inhibitor treatment?

BACKGROUND: The role of lung surgery in initially unresectable non-small cell lung cancer (NSCLC) after tyrosine kinase inhibitor (TKI) treatment remains unclear. We aimed to assess the survival benefits of patients who underwent surgery for regressed or regrown tumors after receiving TKI treatment. METHODS: The details of patients diagnosed with unresectable NSCLC treated with TKI followed by lung resection from 2010 to 2020 were retrieved from our database. The primary endpoint was 3-year overall survival (OS), whereas the secondary endpoints were a 2-year progression-free survival (PFS), feasibility, and the safety of pulmonary resection. The statistical tests used were Fisher's exact test, Kruskal Wallis test, Kaplan-Meier method, Cox proportional hazards model, and Firth correction. RESULTS: Nineteen out of thirty-two patients were selected for the study. The patients underwent lung surgery after confirmed tumor regression (17 [89.5%]) and regrowth (two [10.5%]). All surgeries were performed via video-assisted thoracoscopic surgery: 14 (73.7%) lobectomies and five (26.3%) sublobar resections after a median duration of 5 months of TKI. Two (10.5%) postoperative complications and no 30-day postoperative mortality were observed. The median postoperative follow-up was 22 months. The 2-year PFS and 3-year OS rates were 43.9% and 61.5%, respectively. Patients who underwent surgery for regressed disease showed a significantly better OS than for regrowth disease (HR=0.086, 95% CI 0.008-0.957, p=0.046). TKI-adjuvant demonstrated a better PFS than non-TKI adjuvant (HR=0.146, 95% CI 0.027-0.782, p=0.025). CONCLUSION: Lung surgery after TKI treatment is feasible and safe and prolongs survival via local control and directed consequential therapy. Lung surgery should be adopted in multimodality therapy for initially unresectable NSCLC.

Activation of Nrf2 by Esculetin Mitigates Inflammatory Responses through Suppression of NF-κB Signaling Cascade in RAW 264.7 Cells.

Inflammation is a major root of several diseases such as allergy, cancer, Alzheimer's, and several others, and the present state of existing drugs provoked researchers to search for new treatment strategies. Plants are regarded to be unique sources of active compounds holding pharmacological properties, and they offer novel designs in the development of therapeutic agents. Therefore, this study aimed to explore the anti-inflammatory mechanism of esculetin in lipoteichoic acid (LTA)-induced macrophage cells (RAW 264.7). The relative expression of inducible nitric oxide synthase (iNOS), nitric oxide (NO) production and COX-2 expression were intensified in LTA-induced RAW cells. The phosphorylation status of mitogen-activated protein kinases (extracellular signal-regulated kinase (ERK)1/2, p38 MAPK, and c-Jun N-terminal kinase (JNK)) and nuclear factor kappa B (NF-κB) p65 were detected by using Western blot assay. The nuclear translocation of p65 was assessed by confocal microscopic image analysis. Esculetin significantly and concentration-dependently inhibited LTA-induced NO production and iNOS expression, but not COX-2 expression, in RAW cells. Esculetin was not effective in LTA-induced MAPK molecules (ERK, p38 and JNK). However, esculetin recovered LTA-induced IκBα degradation and NF-κB p65 phosphorylation. Moreover, esculetin at a higher concentration of 20 µM evidently inhibited the nuclear translocation of NF-κB p65. At the same high concentration, esculetin augmented Nrf2 expression and decreased DPPH radical generation in RAW 264.7 cells. This study exhibits the value of esculetin for the treatment of LTA-induced inflammation by targeting NF-κB signaling pathways via its antioxidant properties.

Quantitative and amplification-free detection of SOCS-1 CpG methylation percentage analyses in gastric cancer by fiber optic nanoplasmonic biosensor.

A new innovative approach is essential for early and effective diagnosis of gastric cancer, using promoter hypermethylation of the tumor suppressor, SOCS-1, that is frequently inactivated in human cancers. We have developed an amplification-free fiber optic nanoplasmonic biosensor for detecting DNA methylation of the SOCS-1 human genome. The method is based on the fiber optic nanogold-linked sorbent assay of PCR-free DNA from human gastric tumor tissue and cell lines. We designed a specific DNA probe fabricated on the fiber core surface while the other probe is bioconjugated with gold nanoparticles in free form to allow percentage determination and differentiating the methylated and unmethylated cell lines, further demonstrating the SOCS-1 methylation occurs in cancer patients but not in normal cell lines. The observed detection limit is 0.81 fM for methylated DNA, and the detection time is within 15 min. In addition, our data were significantly correlated to the data obtained from PCR-based pyrosequencing, and yet with superior accuracy. Hence our results provide new insight to the quantitative evaluation of methylation status of the human genome and can act as an alternative to PCR with a great potential.

Exosomes from Human Placenta Choriodecidual Membrane-Derived Mesenchymal Stem Cells Mitigate Endoplasmic Reticulum Stress, Inflammation, and Lung Injury in Lipopolysaccharide-Treated Obese Mice.

Endoplasmic reticulum (ER) stress mediates the effects of obesity on aggravating sepsis-induced lung injury. We investigated whether exosomes from human placenta choriodecidual membrane-derived mesenchymal stem cells (pcMSCs) can mitigate pulmonary ER stress, lung injury, and the mechanisms of inflammation, oxidation, and apoptosis in lipopolysaccharide-treated obese mice. Diet-induced obese (DIO) mice (adult male C57BL/6J mice fed with a 12-week high-fat diet) received lipopolysaccharide (10 mg/kg, i.p.; DIOLPS group) or lipopolysaccharide plus exosomes (1 × 108 particles/mouse, i.p.; DIOLPSExo group). Our data demonstrated lower levels of ER stress (upregulation of glucose-regulated protein 78, phosphorylated eukaryotic initiation factor 2α, and C/EBP homologous protein; p = 0.038, <0.001, and <0.001, respectively), inflammation (activation of nuclear factor-kB, hypoxia-inducible factor-1α, macrophages, and NLR family pyrin domain containing 3; upregulation of tumor necrosis factor-α, interleukin-1ß, and interleukin-6; p = 0.03, <0.001, <0.001, <0.001, <0.001, <0.001, and <0.001, respectively), lipid peroxidation (p < 0.001), and apoptosis (DNA fragmentation, p = 0.003) in lung tissues, as well as lower lung injury level (decreases in tidal volume, peak inspiratory flow, and end expiratory volume; increases in resistance, injury score, and tissue water content; p < 0.001, <0.001, <0.001, <0.001, <0.001, and =0.002, respectively) in the DIOLPSExo group than in the DIOLPS group. In conclusion, exosomes from human pcMSCs mitigate pulmonary ER stress, inflammation, oxidation, apoptosis, and lung injury in lipopolysaccharide-treated obese mice.

Tumor Necrosis Factor-α Mediates Lung Injury in the Early Phase of Endotoxemia.

Endotoxemia induces lung injury. We assessed the therapeutic efficacy between triple cytokine (tumor necrosis factor-α [TNF-α], interleukin-1ß [IL-1ß], and IL-6) inhibition (mediated by KCF18 peptide) and single cytokine (TNF-α) inhibition (mediated by SEM18 peptide) on alleviating lung injury in the early phase of endotoxemia. Mice receiving endotoxin (Endo group), endotoxin plus KCF18 (EKCF group), or endotoxin plus SEM18 (ESEM) were monitored and euthanized at 24 h after endotoxin. Our data demonstrated altered lung function (decreases in tidal volume, minute ventilation, and dynamic compliance; and by contrast, increases in airway resistance and end expiration work) and histology (increases in injury scores, leukocyte infiltration, vascular permeability, and tissue water content) in the Endo group with significant protection observed in the EKCF and ESEM groups (all p < 0.05). Levels of inflammation (macrophage activation and cytokine upregulations), oxidation (lipid peroxidation), necroptosis, pyroptosis, and apoptosis in EKCF and ESEM groups were comparable and all were significantly lower than in the Endo group (all p < 0.05). These data demonstrate that single cytokine TNF-α inhibition can achieve therapeutic effects similar to triple cytokines TNF-α, IL-1ß, and IL-6 inhibition on alleviating endotoxin-induced lung injury, indicating that TNF-α is the major cytokine in mediating lung injury in the early phase of endotoxemia.

Healthcare burden and factors of type 2 diabetes mellitus with Schizophrenia.

This study investigated healthcare utilization and expenditure for patients with type 2 diabetes mellitus and schizophrenia and associated factors. Healthcare utilization (outpatient visits and hospitalization) and expenditure (outpatient, inpatient, and total medical expenditure) between 2002 and 2013 of patients with T2DM with schizophrenia (case group) and without (control group) were examined using the Taiwan National Health Insurance Research Database. (1) The average total numbers of outpatient visits and hospital admissions of the case group were 35.14 outpatient visits and 1.09 hospital admissions significantly higher than those of the control group in the whole study period (based on every 3-year period). Nonpsychiatric outpatient visits and nonpsychiatric hospital admissions were significantly more numerous for the case group. (2) The total outpatient expenditure, total inpatient expenditure, and total medical expenditure of the case group were NT$65,000, NT$170,000, and NT$235,000 significantly higher than those of the control group, respectively. Nonpsychiatric outpatient expenditure was significantly lower for the case group, but the inpatient and total nonpsychiatric medical expenditure were similar between groups. (3) Patients who were elder of low income, with complications, and high diabetes mellitus complication severity index had higher total numbers of outpatient visits and hospitalizations and medical expenditure. (4) Women had a higher number of outpatient visits but a lower number of hospitalization and medical expenditure. Lower non-psychiatric outpatient expenditure despite more visits indicated non-psychiatrist may not understand schizophrenia patients and cannot communicate well with them, leading to neglect of medical evaluation and treatment that should be carried out.

Beneficial effects of preoperative oral nutrition supplements on postoperative outcomes in geriatric hip fracture patients: A PRISMA-compliant systematic review and meta-analysis of randomized controlled studies.

BACKGROUND: Geriatric hip fracture patients often present malnutrition during admission, which leads to higher morbidity and mortality. Protein-based oral nutrition supplements may improve nutritional status. We conducted this systematic review and meta-analysis of randomized controlled trials (RCTs) according to the PRISMA guidelines to elucidate whether preoperative nutrition supplements can improve postoperative outcomes in geriatric hip fracture patients. METHODS: Only RCTs conducted to compare postoperative outcomes between geriatric hip fracture patients (>60 years old) receiving preoperative oral protein-based nutrition supplement (ONS group) and those who receiving regular diet (Control group) were included. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched from inception until August, 2021. Postoperative outcomes, including complications, length of hospital stay, and in-hospital mortality, were assessed. RESULTS: A total of 5 RCTs with 654 geriatric hip fracture patients (ONS group: 320 subjects; Control group 334 subjects) were included. Our data revealed that postoperative complications risk in the ONS group was significantly lower than in the Control group (odd's ratio: 0.48, 95% confidence intervals [CI]: 0.26-0.89, P = .02, I2 = 64%). However, no significant differences in the length of hospital stay (standardized mean difference: -0.35 days, 95% CI: -1.68 to 0.98 days, P = .61, I2 = 0%) and the risk of having postoperative in-hospital mortality (odd's ratio: 1.07, 95% CI: 0.43-2.63, P = .89, I2 = 54%) between these 2 groups were observed. Quality assessment revealed high risk of bias and significant data heterogeneity (I2>50%) in most included RCTs. CONCLUSION: Preoperative protein-based oral nutrition supplements exert beneficial, but limited, effects on postoperative outcomes in geriatric patients with hip fracture undergoing surgery.

Rutaecarpine, an Alkaloid from Evodia rutaecarpa, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3ß Signal Axis through a Cyclic Nucleotides/VASP-Independent Mechanism.

The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1-5 µM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca2+]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)γ2/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3ß (GSK3ß) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLCγ2/PKC and PI3K/Akt/GSK3ß pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders.

Dual-functional gold-iron oxide core-satellite hybrid nanoparticles for sensitivity enhancement in biosensors via nanoplasmonic and preconcentration effects.

A common strategy to improve the sensitivity of a biosensor for the detection of a low abundance analyte is to preconcentrate the analyte molecules before detection. A dual-functional gold-iron oxide core-satellite hybrid nanoparticle structure is proposed in this work to overcome the drawbacks of traditional sample pretreatment methods and the methods using non-magnetic nanomaterials for sample pretreatment. The new dual-functional hybrid nanoparticle structure can simultaneously serve as a signal reporter of a biorecognition event and a preconcentrator of a target at an extremely low concentration in a nanoplasmonic biosensor. By utilizing a fiber optic nanogold-linked sorbent assay in the fiber optic particle plasmon resonance (FOPPR) biosensor and an arbitrary DNA sequence as a target, we have demonstrated that the use of the new hybrid nanoparticle structure with magnetic preconcentration improves the limit of detection (LOD) for the DNA by 18 times as compared to the same method without magnetic preconcentration, so that the LOD for detecting the DNA can be as low as 2.6 fM. The new hybrid nanoparticle structure is easy to prepare and its use in the high-sensitivity and low-cost FOPPR biosensor provides vast opportunities in point-of-care applications.

Therapeutic effect of modulating the NLRP3-regulated transforming growth factor-ß signaling pathway on interstitial cystitis/bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder with complex pathogenesis and lacks effective treatment. Chronic inflammation is the main pathogenesis of Hunner-type IC/BPS. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome-related transforming growth factor-ß (TGF-ß)/Smad signaling pathway plays a crucial role in inflammation-related tissue fibrosis. Lipopolysaccharide (LPS) and protamine sulfate (LPS/PS) were instilled into the mouse bladder twice a week for 5 consecutive weeks to establish a chronic inflammation-induced IC/BPS model (LPS/PS model). Following LPS/PS treatment, curcumin (oral, 100 mg/kg; a potent NLRP3 modulator) was administered for 2 weeks in the curcumin treatment group, and normal saline was used for the sham group. Bladder function was evaluated by performing the voiding spot assay and examining the status of urothelial denudation and fibrosis in bladder tissues. The expression of NLRP3 inflammasome, interleukin-1ß, TGF-ß, Smad, vimentin, and E-cadherin in bladder tissues was evaluated through immunohistochemistry staining. Results revealed that the repeated instillation of LPS/PS leads to voiding dysfunction, bladder urothelium denudation, and detrusor muscle fibrosis through the upregulation of the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway and the increased epithelial-mesenchymal transition process in bladder tissues. The downregulation of the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway in bladder tissues through curcumin effectively mitigated bladder injury in the LPS/PS model. In conclusion, the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway plays a crucial role in bladder injury in the LPS/PS model, and modulation of this pathway, such as by using curcumin, can effectively mitigate the sequelae of chronic inflammation-induced IC/BPS.

Simultaneous Inhibition of Three Major Cytokines and Its Therapeutic Effects: A Peptide-Based Novel Therapy against Endotoxemia in Mice.

Three major cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6, mediate endotoxemia-induced liver injury. With the similar structures to the binding domains of the three cytokines to their cognate receptors, the novel peptide KCF18 can simultaneously inhibit TNF-α, IL-1ß, and IL-6. We elucidated whether KCF18 can alleviate injury of liver in endotoxemic mice. Adult male mice (BALB/cJ) were intraperitoneally (i.p.) administered lipopolysaccharide (LPS, 15 mg/kg; LPS group) or LPS with KCF18 (LKCF group). Mice in the LKCF group received KCF18 (i.p.) at 2 h (0.6 mg/kg), 4 h (0.3 mg/kg), 6 h (0.3 mg/kg), and 8 h (0.3mg/kg) after LPS administration. Mice were sacrificed after receiving LPS for 24 h. Our results indicated that the binding levels of the three cytokines to their cognate receptors in liver tissues in the LKCF group were significantly lower than those in the LPS group (all p < 0.05). The liver injury level, as measured by performing functional and histological analyses and by determining the tissue water content and vascular permeability (all p < 0.05), was significantly lower in the LKCF group than in the LPS group. Similarly, the levels of inflammation (macrophage activation, cytokine upregulation, and leukocyte infiltration), oxidation, necroptosis, pyroptosis, and apoptosis (all p < 0.05) in liver tissues in the LKCF group were significantly lower than those in the LPS group. In conclusion, the KCF18 peptide-based simultaneous inhibition of TNF-α, IL-1ß, and IL-6 can alleviate liver injury in mice with endotoxemia.

Bio-Inspired Amphoteric Polymer for Triggered-Release Drug Delivery on Breast Cancer Cells Based on Metal Coordination.

Nanoscale coordination polymers are promising vehicles for anticancer drug delivery because their surface composition and particle size can be tuned to exploit the enhanced permeability and retention effect, and their reversible interaction with metal cations enables triggered drug release at the tumor site. Here, we develop a novel nanoscale coordination polymer using the diblock copolymer poly(2-methacryloyloxyethyl phosphorylcholine)-block-poly(serinyl acrylate) (PMPC-b-PserA) and demonstrate its use for encapsulation of a hydrophobic drug and triggered drug release to induce breast cancer cell apoptosis in vitro. The zwitterionic PMPC block was inspired by the antifouling structure of cell membranes, and the PserA block was inspired by the amphoteric amino acids of proteins. The polymer was synthesized by reversible addition-fragmentation chain transfer polymerization, and a mixture of the polymer and FeCl3 self-assembled into nanoparticles via complexation of Fe3+ with PserA, with the hydrophilic PMPC block at the particle surface. At a molar ratio of Fe3+ to serA of 3:1, the hydrodynamic diameter of the particles was 22.2 nm. Curcumin, a natural water-insoluble polyphenol used to enhance the effects of chemotherapeutics, was encapsulated in the particles as an oil-in-water emulsion, with an encapsulation efficiency of 99.6% and a particle loading capacity of 32%. Triggered release of curcumin was achieved by adding deferoxamine, an FDA-approved Fe3+ chelating agent; curcumin release efficiency increased at higher deferoxamine concentrations and lower pH. Triggered release of curcumin induced apoptosis in human triple-negative breast cancer cells; cell viability decreased to 34.3% after 24 h of treatment with the curcumin-loaded nanoparticles and deferoxamine, versus >80% viability without deferoxamine to trigger drug release. The biocompatibility, tunable composition and size, high hydrophobic drug loading, and triggered-release capability of this nanoscale coordination polymer make it well-suited for use in anticancer drug delivery.

Anticlogging Hemofiltration Device for Mass Collection of Circulating Tumor Cells by Ligand-Free Size Selection.

A new hemofiltration system was developed to continuously capture circulating tumor cells (CTCs) from a large volume of whole blood using a column that was packed with antifouling zwitterionized silica microspheres. The silica microspheres were modified with sulfobetaine silane (SBSi) to inhibit fouling, resist clogging, and give a high surface wettability and prolonged operation time. Packed microspheres with different diameters formed size-controllable interstitial pores that effectively captured CTCs by ligand-free size selection. For optimized performance of the hemofiltration system, operational factors, including the size of microspheres, flow rate, and cross-sectional area of the column, were considered with respect to the removal rate for colorectal cancer cells and the retention rate for white blood cells and red blood cells. The captured CTCs were collected from the column by density sedimentation. A large quantity of colorectal cancer cells was spiked into sheep blood, and the sample was circulated for 5 h with a total operational volume of 2 L followed by collection and culture in vitro. The results showed that the proposed hemofiltration device selectively removed abundant CTCs from in vitro circulatory blood. The viable cells were harvested for amplification and potential applications for precision medicine.

Increased risk of bladder cancer in young adult men with hyperlipidemia: A population-based cohort study.

ABSTRACT: A high-cholesterol diet increases the risk of bladder cancer. The purpose of this nationwide longitudinal population-based retrospective cohort study is to investigate whether hyperlipidemia is a risk factor for bladder cancer.Data from Taiwan National Health Insurance Database were analyzed. The primary study end point was the occurrence of newly diagnosed bladder cancer. The relative risk of bladder cancer in a hyperlipidemia cohort was compared with that in an age- and gender-matched non-hyperlipidemia cohort by using the Cox proportional hazards regression model. Cox regression analyses were further adjusted by the propensity score.Our data revealed that the hyperlipidemia cohort (n = 33,555) had a significantly higher subsequent risk of bladder cancer than did the non-hyperlipidemia cohort (n = 33,555) (adjusted hazard ratio [HR] = 1.37, P = .005) after propensity score adjustment. Subgroup analyses revealed that men in the hyperlipidemia cohort had a significantly higher subsequent risk of bladder cancer than did those in the non-hyperlipidemia cohort (adjusted HR = 1.36, P = .040). However, the risk of bladder cancer was not significantly different between women in the hyperlipidemia cohort and those in the non-hyperlipidemia cohort. Subgroup analyses further revealed that the risk of bladder cancer was significantly higher in men aged 20 to 39 years in the hyperlipidemia cohort than in those in the non-hyperlipidemia cohort (adjusted HR = 5.45, P = .029).In conclusion, hyperlipidemia is a risk factor for bladder cancer in young adult men.

Let-7i-5p Mediates the Therapeutic Effects of Exosomes from Human Placenta Choriodecidual Membrane-Derived Mesenchymal Stem Cells on Mitigating Endotoxin-Induced Mortality and Liver Injury in High-Fat Diet-Induced Obese Mice.

Obesity complicates sepsis and increases the mortality of sepsis. We examined the effects of exosomes (from human placenta choriodecidual membrane-derived mesenchymal stem cells, pcMSCs) on preventing sepsis in obesity and the mitigating role of hsa-let-7i-5p microRNA. Obese mice (adult male C57BL/6J mice fed a high-fat diet for 12 weeks) received normal saline (HFD), endotoxin (10 mg/kg, intraperitoneal (ip); HFDLPS), endotoxin with exosomes (1 × 108 particles/mouse, ip; HLE), or endotoxin with let-7i-5p microRNA inhibitor-pretreated exosomes (1 × 108 particles/mouse, ip; HLEi). Our data demonstrated that the 48-h survival rate in the HLE (100%) group was significantly higher than in the HFDLPS (50%) and HLEi (58.3%) groups (both p < 0.05). In the surviving mice, by contrast, levels of liver injury (injury score, plasma aspartate transaminase and alanine transaminase concentrations, tissue water content, and leukocyte infiltration in liver tissues; all p < 0.05), inflammation (nuclear factor-κB activation, hypoxia-inducible factor-1α activation, macrophage activation, and concentrations of tumor necrosis factor-α, interleukin-6, and leptin in liver tissues; all p < 0.05), and oxidation (malondialdehyde in liver tissues, with p < 0.001) in the HLE group were significantly lower than in the HFDLPS group. Levels of mitochondrial injury/dysfunction and apoptosis in liver tissues in the HLE group were also significantly lower than in the HFDLPS group (all p < 0.05). Inhibition of let-7i-5p microRNA offset the effects of the exosomes, with most of the aforementioned measurements in the HLEi group being significantly higher than in the HLE group (all p < 0.05). In conclusion, exosomes mitigated endotoxin-induced mortality and liver injury in obese mice, and these effects were mediated by let-7i-5p microRNA.