Lipid nanoparticles as the drug carrier for targeted therapy of hepatic disorders.

The liver, a complex and vital organ in the human body, is susceptible to various diseases, including metabolic disorders, acute hepatitis, cirrhosis, and hepatocellular carcinoma. In recent decades, these diseases have significantly contributed to global morbidity and mortality. Currently, liver transplantation remains the most effective treatment for hepatic disorders. Nucleic acid therapeutics offer a selective approach to disease treatment through diverse mechanisms, enabling the regulation of relevant genes and providing a novel therapeutic avenue for hepatic disorders. It is expected that nucleic acid drugs will emerge as the third generation of pharmaceuticals, succeeding small molecule drugs and antibody drugs. Lipid nanoparticles (LNPs) represent a crucial technology in the field of drug delivery and constitute a significant advancement in gene therapies. Nucleic acids encapsulated in LNPs are shielded from the degradation of enzymes and effectively delivered to cells, where they are released and regulate specific genes. This paper provides a comprehensive review of the structure, composition, and applications of LNPs in the treatment of hepatic disorders and offers insights into prospects and challenges in the future development of LNPs.

Enhancing precision medicine: Bispecific antibody-mediated targeted delivery of lipid nanoparticles for potential cancer therapy.

The precise delivery of therapeutic agents to specific cell populations, including cancer cells, remains a target in modern medicine, to enhance treatment efficacy, while minimizing unintended side effects. This study presents a strategy utilizing bispecific antibodies for the targeted delivery of nucleic acid drugs to the surface of glucose-regulated protein 78 (GRP78)-overexpressing cancer cells. Strong binding affinity of the bispecific antibodies to GRP78-overexpressing cancer cells, including HEPG2 cells, confirmed the tumor-targeting potential of this platform. Functional analyses demonstrated the role of the bispecific antibodies in enhancing lipid nanoparticle (LNP) uptake, causing increased gene expression levels of nucleic acid drugs loaded within LNPs. In vivo imaging confirmed the potency of the bispecific-antibody-modified LNPs in delivering nucleic acid drugs to tumors and sustaining therapeutic expression levels. In vivo therapy results indicated that the bispecific antibodies improved the antitumor activity of PE38-loaded LNPs in tumors overexpressing surface GRP78. This study pioneered a bispecific-antibody-centered platform for the targeted delivery of nucleic acid drugs. The robust antigen-antibody binding affinity, tumor-selective interactions, enhanced cellular uptake, and proficient gene expression promise to advance precision therapeutics in oncology. Continued refinement and translation of this drug delivery strategy are important to unlock its full clinical potential.

Prevention of limb function deterioration in patients with cerebral infarction by clinical nursing pathway management.

Objective: To analyze the application effect of clinical nursing pathway in patients with cerebral infarction (CI) and its influence on the deterioration of limb function, so as to find effective prevention methods.Methods: A total of 80 patients with CI admitted to our hospital from November 2020 to May 2022 were included in the study. The subjects were divided into two groups based on different nursing interventions, with one group receiving clinical nursing pathway intervention, referred to as the nursing group (n = 40), and the other group receiving standard nursing care, referred to as the routine group (n = 40). The limb function, neurological function, mobility and quality of life before and after intervention were analyzed, and the incidence of safety endpoints after 3 months of follow-up was observed.Results: The results showed that before the intervention, there were no significant differences in each function and index of the study subjects (p>0.05). After the intervention, the limb function, neurological function, mobility and quality of life of the two groups were higher than those before the intervention, and the degree of improvement was higher in the nursing group (p<0.05). At the same time, the adverse events in the nursing group were significantly less than those in the conventional group (p<0.05).Conclusion: It is suggested that clinical nursing management pathway can significantly reduce the deterioration of limb function of patients with CI, improve their mobility and quality of life, which is worthy of clinical promotion.

Creation of a ready-to-use brexpiprazole suspension and the inflammation-mediated pharmacokinetics by intramuscular administration.

Brexpiprazole (BPZ), which is approved for the treatment of schizophrenia and major depressive disorder, has the potential to meet diverse clinical needs. This study aimed to develop a long-acting injectable (LAI) formulation of BPZ that could provide sustained therapeutic benefits. A library of BPZ prodrugs was screened through esterification, and BPZ laurate (BPZL) was identified as an optimal candidate. To achieve stable aqueous suspensions, a pressure- and nozzle size-controlled microfluidization homogenizer was utilized. The pharmacokinetics (PK) profiles, considering dose and particle size modulation, were investigated following a single intramuscular injection in beagles and rats. BPZL treatment resulted in sustained plasma concentrations above the median effective concentration (EC50) for 2 âˆ¼ 3 weeks, without exhibiting an initial burst release. Histological examination of foreign body reaction (FBR) in rats revealed the morphological evolution of an inflammation-mediated drug depot, confirming the sustained release mechanism of BPZL. These findings provide strong support for the further development of a ready-to-use LAI suspension of BPZL, which could potentially enhance treatment outcomes, improve patient adherence, and address the clinical challenges associated with long-term regimens of schizophrenia spectrum disorders (SSD).

Visible and infrared photodiode based on γ-InSe/Ge van der Waals heterojunction for polarized detection and imaging.

Broadband photodetectors are a category of optoelectronic devices that have important applications in modern communication information. γ-InSe is a newly developed two-dimensional (2D) layered semiconductor with an air-stable and low-symmetry crystal structure that is suitable for polarization-sensitive photodetection. Herein, we report a P-N photodiode based on 3D Ge/2D γ-InSe van der Waals heterojunction (vdWH). A built-in electric field is introduced at the p-Ge/n-InSe interface to suppress the dark current and accelerate the separation of photogenerated carriers. Moreover, the heterojunction belongs to the accumulation mode with a well-designed type-II band arrangement, which is suitable for the fast separation of photogenerated carriers. Driven by these advantages, the device exhibits excellent photovoltaic performance within the detection range of 400 to 1600 nm and shows a double photocurrent peak at around 405 and 1550 nm. In particular, the responsivity (R) is up to 9.78 A W-1 and the specific detectivity (D*) reaches 5.38 × 1011 Jones with a fast response speed of 46/32 µs under a 1550 nm laser. Under blackbody radiation, the room temperature R and D* in the mid-wavelength infrared region are 0.203 A W-1 and 5.6 × 108 Jones, respectively. Moreover, polarization-sensitive light detection from 405-1550 nm was achieved, with the dichroism ratios of 1.44, 3.01, 1.71, 1.41 and 1.34 at 405, 635, 808, 1310 and 1550 nm, respectively. In addition, high-resolution single-pixel imaging capability is demonstrated at visible and near-infrared wavelengths. This work reveals the great potential of the γ-InSe/Ge photodiode for high-performance, broadband, air-stable and polarization-sensitive photodetection.

Network topology-directed design of molecular CPU for cell-like dynamic information processing.

Natural cells (NCs) can automatically and continuously respond to fluctuant external information and distinguish meaningful stimuli from weak noise depending on their powerful genetic and protein networks. We herein report a network topology-directed design of dynamic molecular processing system (DMPS) as a molecular central processing unit that powers an artificial cell (AC) able to process fluctuant information in its immediate environment similar to NCs. By constructing a mixed cell community, ACs and NCs have synchronous response to fluctuant extracellular stimuli under physiological condition and in a blood vessel-mimic circulation system. We also show that fluctuant bioinformation released by NCs can be received and processed by ACs. The molecular design of DMPS-powered AC is expected to allow a profound understanding of biological systems, advance the construction of intelligent molecular systems, and promote more elegant bioengineering applications.

Novel Self-Assembled Micelles With Increased Tumor Penetration and Anti-Tumor Efficiency Against Breast Cancer.

PURPOSE: Recently, docetaxel (DTX) micelles based on retinoic acid derivative surfactants showed lower systemic toxicity and bioequivalence to polysorbate-solubilized docetaxel (Taxotere®) in a phase II clinical study. However, the poor stability of these surfactants in vitro and in vivo led to extremely harsh storage conditions with methanol, and the formed micelles were quickly disintegrated with rapid drug burst release in vivo. To further enhance the stability and accumulation in tumors of DTX micelles, a novel surfactant based on acitretin (ACMeNa) was synthesized and used to prepare DTX micelles to improve anti-tumor efficiency. METHODS: Novel micelle-forming excipients were synthesized, and the micelles were prepared using the thin film hydration technique. The targeting effect in vitro, distribution in the tumor, and its mechanism were observed. Pharmacokinetics and anti-tumor effect were further investigated in rats and tumor-bearing female mice, respectively. RESULTS: The DTX-micelles prepared with ACMeNa (ACM-DTX) exhibited a small size (21.9 ± 0.3 nm), 39% load efficiency, and excellent stability in vitro and in vivo. Long circulation time, sustained and steady accumulation, and strong penetration in the tumor were observed in vivo, contributing to a better anti-tumor effect and lower adverse effects. CONCLUSIONS: The micelles formed by ACMeNa showed a better balance between anti-tumor and adverse effects. It is a promising system for delivering hydrophobic molecules for cancer therapy.

Pubertal exposure to bisphenol-A affects social recognition and arginine vasopressin in the brain of male mice.

Social recognition is an ability of animals to identify and distinguish conspecifics, which is essential for nearly all social species to establish social relationships. Social recognition provides the basis for a variety of social behaviors. Because of modulated by gonadal hormones, it is possible that social cognition is affected by environmental endocrine disruptors (EEDs). In the present study, after being pubertal exposed to bisphenol A (BPA, 0.04, 0.4, and 4 mg/kg) for 18 days, adult male mice did not show significant dishabituation to a novel female stimulus in habituation-dishabituation task. The capacity for discriminating the odors between familiar and novel female urine or between male and female urine was suppressed in BPA-exposed male. In addition, BPA (0.4, 4 mg/kg) decreased the number of immunoreaction of AVP (AVP-ir) neurons in both the bed nucleus of the stria terminalis (BNST) and the medial amygdala (MeA), and BPA (0.04, 0.4, 4 mg/kg) reduced the level of V1αR in the lateral septum (LS) of adult male. Further, BPA decreased the levels of testosterone (T) in the brain and androgens receptor (AR) in the LS, the amygdala, and BNST, as well the levels of estrogen receptor α and ß (ERα/ß) in the amygdala and BNST. These results indicate that pubertal exposure to BPA affected the actions of both androgens and estrogens in the brain and inhibited AVP system of social circuits, and these alterations may be associated with impaired social recognition of adult male mice.

Systemic Corticosteroid Administration in Coronavirus Disease 2019 Outcomes: An Umbrella Meta-Analysis Incorporating Both Mild and Pulmonary Fibrosis-Manifested Severe Disease.

Background: Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed. The real role of corticosteroid use in COVID-19 has long been of interest and is disputable. Methods: We aimed to quantitatively reevaluate the efficacy of corticosteroids on COVID-19. Databases were searched for eligible meta-analyses/systematic reviews with available outcome data. For each association, we estimated the summary effect size with fixed- and random-effects models, 95% confidence intervals, and 95% prediction intervals. Heterogeneity, Egger's test, evidence of small-study effects and excess significance bias, and subgroup analyses were rigorously evaluated. Results: Intended outcomes of 12 eligible studies were mortality, clinical improvement, hospitalization, mechanical ventilation (MV), adverse events (AEs), intensive care unit (ICU) stay, hospital stay, virus clearance time (VCT), and negative conversion. Corticosteroid administration was associated with a 27% risk reduction in MV [hazard ratio (HR): 0.73 (0.64-0.83)] and a 20% reduction in mortality of critically ill/severe COVID-19 patients [HR: 0.80 (0.65-0.98)]. Interestingly, shorter ICU stays and, conversely, potentially longer hospital stays, a longer VCT, and a longer time to negative conversion were associated with corticosteroid use. There was no significant impact of different corticosteroid doses on mortality. Only one study showed slightly excess significant bias. Caution should be applied given the weak nature of the evidence, and it has been confirmed by sensitivity analyses too. Conclusion: This umbrella study found benefits from corticosteroids on MV and especially the mortality of critically ill/severe patients with shorter ICU stays but prolonged hospital stays and VCT. The benefits and harms should be reevaluated and balanced before corticosteroids are cautiously prescribed in clinical practice.

Molecular mechanisms associated with the antidepressant effects of the class I histone deacetylase inhibitor MS-275 in the rat ventrolateral orbital cortex.

Histone modifications mediated by histone acetylation are thought to play an important role in the pathogenesis and treatment of depression. Recent studies have revealed that histone deacetylase inhibitors (HDACis), such as sodium valproate (VPA) and MS-275, may be involved in the pathogenesis of depression and in the underpinnings of antidepressant therapeutic action in several brain regions, including the ventrolateral orbital cortex (VLO). In the present study, we investigated whether the class I histone deacetylase inhibitor MS-275 exerts antidepressant-like effects when infused bilaterally into the VLO of a rat, using the forced swimming test (FST) and tail suspension test (TST) as behavioral measures. We found that chronic intra-VLO infusion of MS-275 significantly reduced immobility time in the FST and TST compared with vehicle-treated controls, similar to the effects of systemically administered fluoxetine. These antidepressant-like effects of MS-275 are associated with an increase in H3 acetylation and elevated CREB and BDNF levels in the VLO. Our findings suggest the possibility that alterations in gene expression due to chromatin remodeling, including upregulation of CREB and BDNF, may be involved in the antidepressant-like effect of HDACis in the VLO.

[Expression of connective tissue growth factor in skin lesions in patients with scleroderma].

OBJECTIVE: To identify the role of connective tissue growth factor (CTGF) in the pathogenesis of scleroderma (SD) and its association with different types and stages of SD. METHODS: The expression of CTGF mRNA and proteins in the skin lesions of 36 patients with SD (including 29 SSc, 7 localized SD; 28 cases at edema and sclerosis stage, and 8 cases at atrophy stage) was detected with in situ RT-PCR and immuno-histochemical SABC respectively. Twenty normal skin tissues served as controls. RESULTS: The SD patients had higher positive rate and field-strength score of the expression of CTGF mRNA and proteins than the controls. No significant differences were found in the positive rate and field-strength score of the expression of CTGF mRNA and proteins between localized SD and SSc. The SD patients at the edema and sclerosis stage had higher positive rate and field-strength score of the expression of CTGF mRNA and proteins than those at the atrophy stage. CONCLUSION: CTGF plays an important role in the pathogenesis of SD and it is closely associated with the development of the pathologic fibrotic process. Localized SD and SSc may have similar pathogenesis.