Acute calcitriol treatment mitigates vitamin D deficiency-associated mortality after intracerebral haemorrhage.

OBJECTIVE: Vitamin D deficiency (VDD) is emerging as a predictor of poor prognosis in various neurological conditions, where clinical outcomes are often worse in stroke patients with VDD. This study aimed to provide experimental evidence on whether and how pre-existing VDD would affect survival and neurofunctional outcomes in intracerebral haemorrhage (ICH), and to evaluate whether acute vitamin D (VD) supplementation would improve post-stroke outcomes. METHODS: Experimental ICH models were induced in mice with and without VDD. Haematoma size was measured using T2*-weighted MRI and haemoglobin concentration. Post-ICH mortality, neurofunctional outcomes and the extent of blood-brain barrier (BBB) leakage were assessed to identify their correlations with VD status. Therapeutic benefits of acute VD administration were also evaluated. RESULTS: Mice with VDD exhibited significantly higher acute mortality rates and more severe motor deficits than mice without VDD post-ICH. Marked haematoma expansion and increased Evans blue extravasation were observed in VDD mice, suggesting that VDD was associated outcomes with increased BBB disruption. Acute treatment with a loading dose of VD (calcitriol) significantly improved outcomes in VDD mice. CONCLUSION: This study provides novel insights into the pathophysiological mechanisms at play in ICH concomitant with VDD and a scientific rationale for acute treatment with VD.

Effect of Remote Ischemic Conditioning on Organ Transplantation: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Remote ischemic conditioning (RIC) has shown great advantages in protecting organs from ischemia-reperfusion loss and applied research on RIC continues to increase. We performed a systematic review and meta-analysis to comprehensively investigate the value of RIC for different organ transplantation. METHODS: We searched PubMed, EMBASE, and the Cochrane Library from inception to November 1, 2023, for randomized controlled trials investigating whether RIC has an advantage in organ transplantation (including heart, lung, liver, and kidney) compared with controls. The primary outcomes varied according to the transplanted organ, including liver transplantation (graft loss, early allograft dysfunction, acute kidney injury, days in hospital, and mortality); kidney transplantation (delayed graft function, acute rejection (AR), graft loss, 50% decrease in serum creatinine, glomerular filtration rate, days in hospital, and mortality); heart and lung transplantation (AR, mortality). Two investigators independently selected suitable trials, assessed trial quality, and extracted the data. RESULTS: A total of 11 randomized controlled trials were included in this study, including six kidney transplants, three liver transplants, and one heart and lung transplant each, with 561 RIC cases and 564 controls, and a total of 1125 patients. The results showed that RIC did not reduce mortality in transplant patients compared with controls (liver transplant: RR0.9, 95% confidence interval [0.31-2.66]; kidney transplant: RR 0.76, 95% confidence interval [0.17-3.33]), graft failure rate (liver transplantation: RR 0.3, 95% confidence interval [0.07, 1.19]; kidney transplantation: RR 0.89, 95% confidence interval [0.35, 2.27]), length of hospital stay (liver transplantation: standard mean difference [SMD] 0.14, 95% confidence interval [-0.15, 0.42]; kidney transplantation: SMD -0.1, 95% confidence interval [-0.3, 0.11]). In addition, RIC did not improve early liver function after liver transplantation (RR 0.97, 95% confidence interval [0.55,1.7]), acute kidney injury after liver transplantation (RR 1.17 95% confidence interval [0.9, 1.54]), delayed functional recovery after renal transplantation (RR 0.84, 95% confidence interval [0.62, 1.15]), AR rate (RR 1.04, 95% confidence interval [0.72, 1.49]), 50% serum creatinine decline rate (RR 1.1, 95% confidence interval [0.88, 1.37]), glomerular filtration rate 3 months after surgery (SMD 0.13, 95% confidence interval [-0.05, 0.31]) and postoperative 12 months glomerular filtration rate (SMD 0.13, 95% confidence interval [-0.06, 0.31]). CONCLUSION: Remote ischemic modulation does not improve clinical outcomes in patients undergoing organ transplantation (heart, lung, liver, and kidney).

The prevalence and associated factors of sleep deprivation among healthy college students in China: a cross-sectional survey.

Background: The prevalence of sleep deprivation among college students is increasing and has a few associated factors. Methods: The present study analyzed 2,142 college students from 28 provinces in China. The Chinese version of the Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep duration. Binary logistic regression was conducted to explore the sleep deprivation related factors. Age and gender were controlled as covariates. Results: Among the 2,142 college students (27.7% male, 72.3% female), 1,620 (75.6%) reported the average sleep duration was below 7 h per day for one month, 49.3% (1,055/2,142) slept 6∼7 h (contains 6 h), 21.0% (449/2,142) slept 5∼6 h (contains 5 h), and 5.4% (116/2,142) slept <5 h. Age increased the risk of sleep deprivation, the adjusted odds ratio = 1.05 (95% CI [1.01∼1.10]). The adjusted odds ratio (A-OR) for sleep deprivation was higher for students of more than 60 min nap duration per day (A-OR = 2.35, 95% CI [1.45∼3.80]), and age growth (A-OR = 1.05, 95% CI [1.01∼1.10]). In contrast, A-ORs were lower among sleeping inconsistency between work and rest days (A-OR = 0.61, 95% CI [0.49∼0.75]), accustomed to staying up late (A-OR = 0.45, 95% CI [0.36∼0.57]), staying up late to work or study (A-OR = 0.62, 95% CI [0.49∼0.78]), stress (A-OR = 0.75, 95% CI [0.58∼0.98]), and repeated thoughts in bed had (A-OR = 0.79, 95% CI [0.62∼0.99]). Conclusions: Sleep deprivation is extremely common among healthy college students in China. It is necessary to perform methods maintaining enough sleep due to the current high incidence of sleep deprivation. Controlling the nap duration and getting enough sleep on rest days to replace missing hours of sleep on workdays might improve college students' sleep.

Development of a prognostic nomogram for metastatic pancreatic ductal adenocarcinoma integrating marital status.

Previous studies have shown that marital status can affect the overall survival (OS) of cancer patients yet its role in metastatic pancreatic ductal adenocarcinoma (mPDAC) remains unclear. This study aimed to explore the impact of marital status on the OS of mPDAC patients and to construct a prognostic nomogram to predict OS outcomes. Data from patients diagnosed with mPDAC were obtained from the Surveillance, Epidemiology, and End Results database between 1973 and 2015. The patients were randomized into primary and validation cohorts. Kaplan-Meier survival analysis was performed to compare differences in survival depending on marital status. Univariate and multivariate analyses were conducted to identify independent prognostic factors and a nomogram was established based using Cox regression analyses. Validation of the prognostic nomogram was evaluated with a calibration curve and concordance index (C-index). Our data showed significant differences in the OS of mPDAC patients with different marital status by Kaplan-Meier analysis (P < 0.05). Univariate and multivariate analyses confirmed that marital status was an independent OS-related factor in mPDAC patients. Based on the multivariate models of the primary cohort, a nomogram was developed that combined marital status, age, grade, tumor size, surgery of primary site, surgery of lymph node and metastatic. The nomogram showed that marital status had a moderate influence on predicting the OS of mPDAC patients. Moreover, the internally and externally validated C-indexes were 0.633 and 0.619, respectively. A calibration curve confirmed favorable consistency between the observed and predicted outcomes. Marital status was identified as an independent prognostic factor for OS of mPDAC patients and is a reliable and valid parameter to predict the survival of patients with mPDAC. This prognostic model has value and may be integrated as a tool to inform decision-making in the clinic.

Dual-Mode Avocado-like All-Iron Nanoplatform for Enhanced T1/T2 MRI-Guided Cancer Theranostic Therapy.

Development of T1/T2 dual-mode MRI contrast agents that can also treat cancer is an attractive prospect for personalized precision medicine. Unfortunately, conventional contrast agents can suffer from toxicity and lack any ability to treat cancer. An all-iron T1/T2 MR imaging agent with photothermal and drug delivery capability would overcome these issues. Here, an avocado-like Fe3+/Fe2O3 composed T1-T2 dual-mode contrast agent based on Fe-TA coordination network (CNMN) is developed. This material possesses suitable longitudinal and transverse relaxation coefficients. Moreover, the strong heat generation property of Fe-TA endows CNMN with the capability to act as a potent photothermal agent. Furthermore, CNMN can also act as an effective delivery platform for the chemotherapeutic drug doxorubicin (DOX) to achieve high effective chemo-photothermal combination therapy. The work demonstrates reliable T1-T2 MRI-guided chemo-photothermal therapy for safe and effective clinical application.

A pH-sensitive coordination polymer network-based nanoplatform for magnetic resonance imaging-guided cancer chemo-photothermal synergistic therapy.

Developing various kinds of nanoplatforms with integrated diagnostic and therapeutic functions would be significant for imaging-guided precision treatment of cancer. However, it is still a challenge to organically integrate therapeutic and imaging components into a single nano-system rather than simply mixing. Herein, an iron-gallic acid network-based nanoparticle (Fe-GA@PEG-PLGA) was designed for magnetic resonance imaging (MRI)-guided chemo-photothermal synergistic therapy of tumors. The tumor spatial location and size information can be accurately achieved due to T1 MRI based on Fe3+ coordination with GA in Fe-GA network. Furthermore, the nanoparticle exhibited extraordinary photostability and photothermal therapy capacity exceeded 42 °C within 100 s under 808 nm laser irradiation. Meanwhile, the Fe-GA polymeric network can be disassembled in tumor acidic environment and the released drug GA can induce apoptosis. This study demonstrated that the Fe-GA network-based nanoparticle is a promising diagnostic and therapeutic agent for theranostic application and further clinic translation.

A nanoscale photothermal agent based on a metal-organic coordination polymer as a drug-loading framework for effective combination therapy.

Metallic materials are widely emerging as photothermal agents owing to their superior photothermal transduction efficiency and satisfactory photostability. In this study, an iron-based coordination polymer (Fe-CNP) loaded with doxorubicin (DOX) was assessed as a dual-function agent for photothermal therapy (PTT) and tumor-targeted chemotherapy. Fe-CNPs were synthesized by a one-step coordination reaction between Fe3+, hydrocaffeic acid, and dopamine-modified hyaluronic acid. A drug-loading method was developed to entrap DOX within Fe-CNPs through the formation of coordination bonds by Fe3+ and DOX (Scheme 1). DOX release was rapidly triggered in the cellular acidic environment and further enhanced by hyperpyrexia in the part of tumor, which will kill the remaining tumor cells after PTT. Animal experiments demonstrated complete inhibition of tumor growth without recurrence in 21 days after injection of DOX@Fe-CNPs with NIR laser irradiation. These results confirmed the enhanced anti-tumor efficiency of the chemo-photothermal nanosystem. Our work may reveal a photothermal coordination polymer as a drug-loading framework and highlight the development of metal-organic materials in combined chemo-photothermal therapy. STATEMENT OF SIGNIFICANCE: Photothermal therapy (PTT), which could directly act on tumors, has been considered as a promising treatment method for cancer. The combination of PTT with chemotherapy is attracting tremendous attention because such advanced application can achieve personalized precise medicine. Unfortunately, most PTT materials have photobleaching property, which results in reduced photothermal efficiency. Furthermore, their clinical applications also suffer from low loading capacity of chemotherapeutic drugs or nonbiodegradability in the biological system. In this study, we hypothesized that iron-based coordination polymers (Fe-CNPs) could function dually as agents to deliver both PTT and tumor-targeted chemotherapy by coordination loading of the chemotherapeutic drug doxorubicin (DOX). Our work may open up new avenues to rationally design versatile platforms for photothermal-chemotherapy to obtain synergistically enhanced therapeutic efficacy.

A multifunctional ternary Cu(II)-carboxylate coordination polymeric nanocomplex for cancer thermochemotherapy.

Metal-based photothermal therapy has been widely used in the biomedicine field and includes gold nanoparticles, silver nanoparticles and copper sulfide nanoparticles. Furthermore, the coordination bonding-based metal nanocomplex is a new generation of photothermal agents for cancer therapy due to its high photothermal transduction efficiency, good biocompatibility, biodegradation and bioactivity. In this study, we designed a coordination bonding-based copper (Cu(II))-carboxylate ternary architecture, which consists of a conjugate dopamine-modified nontoxic hyaluronic acid, copper ions and citric acid. When the Cu(II) coordinated with the carboxyl groups, the splitting d orbitals energy gap of Cu(II) and the capability of electron transition were enhanced, which can increase the extinction ability in the near-infrared region for enhancing photothermal therapy. Moreover, the degradation of hyaluronic acid by hyaluronidase highly expressed in the tumor microenvironment led to the release of Cu-citric acid complexes, thus exhibiting an additional chemotherapeutic effect. The nanocomplexes possessed high-performance photothermal conversion, determined to be 21.3%. The solution could be easily heated to above 42 °C, which was sufficient to ablate the cancer cells. An obvious decrease in cell viability was observed in B16F10 cells incubated with the nanocomplexes under laser at the lower concentration of 20 µg/mL Cu(II). Upon near-infrared laser irradiation, the nanocomplexes showed high photothermal therapy and chemotherapeutic efficacy for breast cancer in vivo. This study demonstrated that the Cu(II)-carboxylate coordination nanocomplex is a promising new effective and facilely prepared thermochemotherapy agent for combination therapy against cancer.

Coordination-driven assembly of catechol-modified chitosan for the kidney-specific delivery of salvianolic acid B to treat renal fibrosis.

Kidney-specific delivery is critically important for the treatment of renal fibrosis with drugs such as salvianolic acid B (Sal B). Here we report a kidney-specific nanocomplex formed by the coordination-driven assembly of catechol-modified low molecular weight chitosan (HCA-Chi), calcium ions and Sal B. The prepared HCA-Chi-Ca-Sal B (HChi-Ca-Sal B) nanocomplex reversed the TGF-ß1-induced epithelial-mesenchymal transition (EMT) in HK-2 cells. In vivo imaging demonstrated a kidney-specific biodistribution of the nanocomplex. The anti-fibrosis effect of HChi-Ca-Sal B was tested in a mouse model of unilateral ureteral obstruction (UUO). Significant attenuation of the morphological lesions and the levels of extracellular matrix (ECM) proteins in the tubulointerstitium was observed in mice treated with HChi-Ca-Sal B, suggesting that the nanocomplex was able to prevent fibrosis better than the treatment with free Sal B. It was concluded that the HChi-Ca-Sal B nanocomplex showed a specific renal targeting capacity and could be utilized to enhance Sal B delivery for treating renal fibrosis.

Arginine-Modified Nanostructured Lipid Carriers with Charge-Reversal and pH-Sensitive Membranolytic Properties for Anticancer Drug Delivery.

The ability to escape endo/lysosomal trafficking is critically important to prevent entrapment of nanomedicines in lysosomes and to achieve maximum therapeutic efficacy of drugs delivered to cells through endocytosis. In this study, a novel pH-sensitive chitosan carrier with the ability to reverse its charge during endo/lysosomal trafficking is developed as a way of improving lysosomal disruption. N-Arginine-N-octyl chitosan (AOCS) is synthesized by grafting l-arginine onto carboxymethyl chitosan. The AOCS is used to modify the surface of nanostructured lipid carriers (NLC) to prepare pH-sensitive charge-reversal lysosomolytic nanocarriers (ANLC). The ANLC is loaded with 10-hydroxycamptothecin (HCPT). The results show that ANLC is able to reverse surface zeta potential from negative to positive at lysosomal pH, which contributes to improved release of encapsulated drugs into cytoplasm. The lysosomolytic capability of ANLC is confirmed by confocal microscopy and transmission electron microscopy. In vitro studies demonstrate that the anticancer activity of HCPT-loaded ANLC is improved when compared with HCPT-NLC and free HCPT. In vivo pharmacokinetics and tissue distribution analysis show improved delivery of HCPT-ANLC to subcutaneous Heps mouse liver tumors and greatly improved antitumor activity. The results present ANLC as a promising drug delivery carrier for improved antitumor therapy.