In this study, glucono-δ-lactone-induced cold-set emulsion gels stabilized by whey protein (WPI) and pea protein (PPI) at various mass ratios were formulated, characterized, and applied. Compared with WPI-stabilized emulsion, zeta potential of emulsion decreased but droplet size, apparent viscosity, and modulus increased with increasing PPI. Differences in the properties of emulsions led to differences in the structure and properties of gels formed. Compared with emulsion gel formed by single PPI, the addition of WPI was found to improve the microstructure, water-holding capacity, rheological, and texture properties of emulsion gel, and the synergistic effect of WPI and PPI was observed at a mixing ratio of 75/25. In vitro digestion experiments revealed that all emulsion gels demonstrated comparable encapsulation, but adding PPI reduced stability and bio-accessibility, regardless of ratio. Data indicated that this method could produce a stable emulsion gel with properties modulated by adjusting the whey and pea protein ratio.

Parkinson's disease (PD) is marked by a prolonged asymptomatic "window period" (several years). Early prediction and diagnosis during this window are crucial, as timely interventions can slow disease progression. In this study, a fully integrated wearable sweat-sensing patch capable of real-time detection of three key PD biomarkers: L-Dopa, ascorbic acid, and glucose is developed. The system includes a biomimetic microfluidic module for sedentary sweat collection, an advanced electrochemical sensing platform for biomarker analysis, on-site signal processing circuitry for data management, and custom software for real-time data visualization. A universal strategy is proposed to significantly extend the stability of oxidase enzymes without activity loss, achieved through the design of Cu-oxidase hybrid nanoflowers. The patch is successfully tested on dozens of volunteers (healthy and PD patients in various stages), demonstrating its capability to monitor biomarkers in real time, assess PD progression, and optimize medication management.

The mitochondrial unfolded protein response (UPRmt) is an intracellular retrograde signaling process that facilitates the restoration of mitochondrial homeostasis. Mitochondria are essential for neuronal signaling, and their dysfunction has been implicated as a significant mechanism in the development of chronic pain. Nevertheless, little is known about the exact function of UPRmt in bone cancer pain (BCP). This research intended to explore the connection between UPRmt and the progression of BCP. In BCP group, the ultrastructure of spinal cord mitochondria was disrupted, accompanied by a decline in ATP levels and a decrease in Mitochondrial membrane potential (MMP). Concurrently, mRNA and protein levels of UPRmt marker proteins (Atf5, Hsp60, LonP1, and ClpP) were upregulated, with the expression of Atf5, a key transcription factor of UPRmt, notably enhanced in spinal dorsal horn neurons. Nicotinamide riboside (NR)-mediated pharmacological augmentation of the UPRmt significantly alleviated BCP-induced nociceptive hypersensitivity, as demonstrated by elevated mechanical withdrawal thresholds and diminished spontaneous flinching behavior. Concomitant mitochondrial functional recovery was evidenced by restoration of MMP and normalization of ATP level. Notably, genetic knockdown of activating transcription factor 5 (Atf5) abolished both NR-induced UPRmt activation and the consequent protection against rotenone-mediated mitochondrial dysfunction. These findings establish UPRmt potentiation as an effective strategy for ameliorating mitochondrial dysfunction and attenuating BCP-associated nociception, proposing this pathway as a novel therapeutic target for clinical pain management.

Food industry has partially replaced animal proteins with plant-derived alternatives, and effects of combining these two types on properties of food systems need to be elucidated. This study fabricated and characterised emulsion gels of mixed whey and pea protein, varying protein mass ratios from 100:0 to 0:100 and oil volumes from 30% to 45%, induced by transglutaminase cross-linking. An increase in pea protein led to larger particle size and reduced surface charge in the solutions. Emulsion droplet size ranged from 0.60 to 15.17 mu m, increasing with higher levels of pea protein and oil. Mixed protein gels exhibited significantly greater hardness compared to gels with individual proteins. Water-holding capacity of pure whey protein emulsion gels exceeded 90%, while the value remained above 80% when pea protein was less than 50%. Partially replacing whey protein with pea protein may have potential applications in food products such as salad dressings and cheese. The whey protein/pea protein mixture emulsion gel with different protein mass ratio and different oil volume fraction was constructed by cross-linking with transglutaminase and characterised. image

Three modifications (pH shift, ultrasound, combined pH shift and ultrasound) induced alterations in pure whey protein isolate (WPI), pea protein isolate (PPI), and mixed whey and pea protein (WPI-PPI) were investigated. The processing effect was related to the protein type and technique used. Solubility of WPI remained unchanged by various treatments. Particle size was enlarged by pH shift while reduced by ultrasound and combined approach. All methods exposed more surface hydrophobic groups on WPI, while pH shift and joint processing was detrimental to its emulsifying activity. The PPI and mixture exhibited similar responses toward the modifications. Solubility of PPI and the blend enhanced in the sequence of pH shift and ultrasound > ultrasound > pH shift. Individual approach expanded while co-handling diminished the particle diameter. Treatments also caused more disclosure of hydrophobic regions in PPI and WPI-PPI and emulsifying activity was ameliorated in the order of pH shift and ultrasound > ultrasound > pH shift.

Background: The growing demand for surgical resection in elderly patients with hepatocellular carcinoma highlights the need to understand the impact of preoperative frailty on surgical outcomes. The aim of this multicentre cohort study was to investigate the association between frailty and short- and long-term outcomes after hepatic resection among elderly patients with hepatocellular carcinoma. Methods: A multicentre analysis was conducted on elderly patients with hepatocellular carcinoma (aged greater than or equal to 70 years) who underwent curative-intent resection at ten Chinese hospitals from 2012 to 2021. Frailty was assessed using the Clinical Frailty Scale (with frailty defined as a Clinical Frailty Scale score greater than or equal to 5). The primary outcomes were overall survival and recurrence-free survival; secondary outcomes encompassed postoperative 30-day morbidity and mortality, and 90-day mortality. The outcomes between patients with and without preoperative frailty were compared. Results: Of the 488 elderly patients, 148 (30.3%) were considered frail. Frail patients experienced significantly higher 30-day morbidity (68.9% (102 of 148) versus 43.2% (147 of 340)), 30-day mortality (4.1% (6 of 148) versus 0.6% (2 of 340)), and 90-day mortality (6.1% (9 of 148) versus 0.9% (3 of 340)) compared with non-frail patients (all P < 0.010). During a median follow-up of 37.7 (interquartile range 20.4-57.8) months, frail patients demonstrated significantly worse median overall survival (41.6 (95% c.i. 32.0 to 51.2) versus 69.7 (95% c.i. 55.6 to 83.8) months) and recurrence-free survival (27.6 (95% c.i. 23.1 to 32.1) versus 42.7 (95% c.i. 34.6 to 50.8) months) compared with non-frail patients (both P < 0.010). Multivariable Cox regression analysis revealed frailty as an independent risk factor for decreased overall survival (HR 1.61; P = 0.001) and decreased recurrence-free survival (HR 1.32; P = 0.028). Conclusion: Frailty is significantly associated with adverse short-term and long-term outcomes after resection in elderly patients with hepatocellular carcinoma. The findings suggest that frailty assessment should be incorporated into perioperative and postoperative evaluation for elderly patients undergoing hepatocellular carcinoma resection.

Depression is a neurological disorder that profoundly affects human physical and mental health, resulting in various changes in the central nervous system. Despite several prominent hypotheses, such as the monoaminergic theory, hypothalamic-pituitary-adrenal (HPA) axis theory, neuroinflammation, and neuroplasticity, the current understanding of depression's pathogenesis remains incomplete. Importantly, depression is a gender-dimorphic disorder, with women exhibiting higher incidence rates than men. Given estrogen's pivotal role in the menstrual cycle, it is reasonable to postulate that its fluctuating levels could contribute to the pathogenesis of depression. Estrogen acts by binding to a diversity of receptors, which are widely distributed in the central nervous system. An abundance of research has established that estrogen and its receptors play a crucial role in depression, spanning pathogenesis and treatment. In this comprehensive review, we provide an in-depth analysis of the fundamental role of estrogen and its receptors in depression, with a focus on neuroinflammation, neuroendocrinology, and neuroplasticity. Furthermore, we discuss potential mechanisms underlying the therapeutic effects of estrogen in the treatment of depression, which may pave the way for new antidepressant drug development and alternative treatment options.

The Crumbs protein (CRB) family plays a crucial role in maintaining the apical-basal polarity and integrity of embryonic epithelia. The family comprises different isoforms in different animals and possesses diverse structural, localization, and functional characteristics. Mutations in the human CRB1 or CRB2 gene may lead to a broad spectrum of retinal dystrophies. Various CRB-associated experimental models have recently provided mechanistic insights into human CRB-associated retinopathies. The knowledge obtained from these models corroborates the importance of CRB in retinal development and maintenance. Therefore, complete elucidation of these models can provide excellent therapeutic prospects for human CRB-associated retinopathies. In this review, we summarize the current animal models and human-derived models of different CRB family members and describe the main characteristics of their retinal phenotypes.

Depression is a widespread disease, with high mortality and recurrence rates. Recent studies have shown that elevated cytokine levels are implicated in the molecular mechanisms of depression. Oxidative stress contributes to the stimulation of cytokine production. Growing evidence suggests that ginsenoside Re (Gs-Re) exerts a neuroprotective effect on the hippocampus by suppressing oxidative stress and inflammation. However, the effect and mechanism of Gs-Re in the treatment of depression remain understudied. This study aimed to evaluate the neuroprotective and antidepressant-like effects of Gs-Re and the possible underlying mechanisms. In this article, the antidepressant-like effect of the Gs-Re was studied both in vitro (H2O2-induced oxidative stress in HT-22 cells) and in vivo (reserpine-induced depressive model mice). Our results indicated that, at the cellular level, Gs-Re effectively enhanced cell survival following H2O2 stimulation, inhibited the mass production of oxidative stress markers (MDA and ROS), and prevented the occurrence of apoptosis. Moreover, Gs-Re significantly reduced the levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α and restored the abnormal mitochondrial membrane potential. Subsequently, Gs-Re treatment reversed reserpine-induced neuroinflammation and depressive-like behaviors in vivo and inhibited microglia overactivation. Furthermore, the alterations in the BDNF/TrkB/ERK/CREB signaling pathway induced by H2O2 or reserpine in HT-22 cells or in the mouse hippocampus were significantly reversed by Gs-Re. K252a blocked the improvement of Gs-Re on depression-like behavior and eliminated the inhibition of oxidative stress and neuroinflammation in vivo. This study suggested that Gs-Re produces neuroprotective and depressive effects by inhibiting oxidative stress and inflammation and activating the BDNF/TrkB/ERK/CREB pathway.

Herein, porous poly(lactic-co-glycolic acid) (PLGA) microspheres were prepared to load icariin and miR-23b for the treatment of metastatic lung cancer. The microspheres exhibited desirable aerodynamic diameter, high drug loading and encapsulation efficiency, as well as a favorable drug release profile, which was beneficial for the deposition and exposure of drugs in the lung tissues. The release solution from microspheres exhibited a favorable anti-proliferative effect by inducting cell apoptosis and arresting the cell cycle at G1 phase, and meanwhile inhibited the migration and invasion of cancer cells. More importantly, the microspheres could be effectively inhaled and accumulated in the lung tissues to trigger the in situ apoptosis of tumor cells and suppress metastasis, using mice bearing melanoma-metastatic lung cancer as a model. Furthermore, inhalation of the microspheres showed favorable biocompatibility, barely causing tissue damage. Overall, porous PLGA microspheres provide a promising platform for the inhalable co-delivery of drugs and genes to obtain ideal therapeutic efficacy in lung cancer and other pulmonary diseases.

ObjectiveTo evaluate the cardiovascular safety of anticancer drug immune checkpoint inhibitors (ICIs) used in patients with malignant tumors.MethodsFour clinical research databases that have been completed since their establishment were searched, and the odds ratios and 95% confidence intervals of each indicator were statistically calculated.Results62 randomized controlled trial and controlled trials were included. In single drug treatment ICIs group, the overall risk of cardio cerebral Vascular disease at all levels was higher than that in the placebo/chemotherapy group. Especially in all grades of Myocarditis and above grade 3 compared with normal controls, except for pericardial lesions, other indicators have no obvious side effects.ConclusionSingle drug use of an anti-tumor ICIs may increase cardiovascular side effects risk in cancer patients, so we need to strengthen monitoring, identification and management, and timely intervention to manage ICI induced adverse events.

Infant's gender may have influences on composition of breastmilk. This study investigated differences in whey fractions from milk of mothers ( n = 12, 3 biological repeats) with male or female babies using a 4D label‐free proteomics. Altogether, 1572 proteins were identified and 42 of them were differentially expressed. Majority of the different proteins are located in extracellular position and possessed domain of immunoglobulin V‐set. The screened proteins were observed to contribute greatly to functions of cellular process, binding, and cell part; and pathways of immune system and immune disease. The findings may afford beneficial knowledge for understanding differences in breastmilk composition.

Liver cancer is one of the most common malignant tumors globally. Not only is it difficult to diagnose, but treatments are scarce and the prognosis is generally poor. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Aggressive cancer cells, such as those found in HCC, undergo extensive metabolic rewiring as tumorigenesis, the unique feature, ultimately causes adaptation to the neoplastic microenvironment. Intratumoral heterogeneity (ITH) is defined as the presence of distinct genetic features and different phenotypes in the same tumoral region. ITH, a property unique to malignant cancers, results in differences in many different features of tumors, including, but not limited to, tumor growth and resistance to chemotherapy, which in turn is partly responsible for metabolic reprogramming. Moreover, the different metabolic phenotypes might also activate the immune response to varying degrees and help tumor cells escape detection by the immune system. In this review, we summarize the reprogramming of glucose metabolism and tumoral heterogeneity and their associations that occur in HCC, to obtain a better understanding of the mechanisms of HCC oncogenesis.

Pancreatic cancer is a kind of aggressive tumor famous for its lethality and intractability, and pancreatic ductal adenocarcinoma is the most common type. Patients with pancreatic cancer often suffer a rapid loss of weight and abdominal neuropathic pain in their early stages and then go through cachexia in the advanced stage. These features of patients are considered to be related to metabolic reprogramming of pancreatic cancer and abundant nerve innervation responsible for the pain. With increasing literature certifying the relationship between nerves and pancreatic ductal adenocarcinoma (PDAC), more evidence point out that innervation’s role is not limited to neuropathic pain but explore its anti/pro-tumor functions in PDAC, especially the neural–metabolic crosstalks. This review aims to unite pancreatic cancer’s innervation and metabolic rearrangements with terminated published articles. Hopefully, this article could explore the pathogenesis of PDAC and further promote promising detecting or therapeutic measurements for PDAC according to the lavish innervation in PDAC.

Abstract Autism spectrum disorder (ASD) is a series of neurodevelopmental disorders with two core symptoms, repetitive behavioral phenotype, and social impairments, yet the underlying cellular and molecular mechanisms are still obscure. KLF4 (Kruppel-like factor 4) is a zinc finger protein transcription factor that has been widely reported in the regulation of cell proliferation, differentiation, survival, and apoptosis. Recently, increasing evidence demonstrated its critical role in neurodevelopment, microglia activating, and neuroinflammation in the central nervous system (CNS). Little is known about the effect of KLF4 in the medial prefrontal cortex (mPFC) on autism and autism-like behaviors. Here, we found that high and low expression levels of KLF4 in mPFC induced significant social novelty impairments. The molecular mechanisms might be associated with overexpression of KLF4 in mPFC promote activation of microglia and altered synaptic E/I ratio by affecting the expression of GluA1 and GABA-related proteins, the specific molecular mechanisms still need more investigations.

A new type of fluorescent silicon nanoparticles (SiNPs) were prepared via a facile one-pot hydrothermal method by using N-[3-(trimethoxysilyl)propyl]-ethylenediamine (DAMO) and glucose as reagents, and were subsequently applied to construct a ratiometric fluorescence assay for sensitive and rapid determination of xanthine in human serum. Two catalytic oxidation reactions were employed to induce a fluorescence response of the testing system towards xanthine. Under the catalysis of xanthine oxidase (XOD), xanthine in serum samples was oxidized and produced hydrogen peroxide (H2O2). By utilizing o-phenylenediamine (OPD) as the substrate for horseradish peroxidase (HRP) in the presence of H2O2, fluorescent 2,3-diaminophenazine (DAP) was finally generated. A ratiometric fluorescence assay for xanthine was established by determining the ratio of the green-yellow fluorescence emission of DAP and the blue fluorescence emitted from SiNPs under the inner filter effect (IFE) of DAP. Instead of traditional multi-step procedures for adding reacting reagents to the testing solution, all the reaction reagents were mixed with serum samples in a single step for this assay to shorten the total reaction time. This assay demonstrates superiority over a solo DAP fluorescence-based assay as well as other reported methods, with excellent sensitivity and reduced testing time. The strategies proposed in this work for both synthesis and application of fluorescent SiNPs can be used in future fabrication of novel fluorescent probes, especially for sensing biological metabolites involved in H2O2-generation or consumption reactions.

Lung ischemia reperfusion (IR) is known to occur after lung transplantation or cardiac bypass. IR leads to tissue inflammation and damage and is also associated with increased morbidity and mortality. Various receptors are known to partake in activation of the innate immune system, but the downstream mechanism of tissue damage and inflammation is yet unknown. MicroRNAs (miRNAs) are in the forefront in regulating ischemia reperfusion injury and are involved in inflammatory response. Here, we have identified by high-throughput approach and evaluated a distinct set of miRNAs that may play a role in response to IR in rat lung tissue. The top three differentially expressed miRNAs were validated through quantitative PCRs in the IR rat lung model and an in vitro model of IR of hypoxia and reoxygenation exposed type II alveolar cells. Among the miRNAs, miR-18a-5p showed consistent downregulation in both the model systems on IR. Cellular and molecular analysis brought to light a crucial role of this miRNA in ischemia reperfusion. miR-18a-5p plays a role in IR-mediated apoptosis and ROS production and regulates the expression of neuropeptide Galanin. It also influences the nuclear localization of transcription factor: nuclear factor-erythroid 2-related factor (Nrf2) which in turn may regulate the expression of the miR-18a gene. Thus, we have not only established a rat model for lung IR and enumerated the important miRNAs involved in IR but have also extensively characterized the role of miR-18a-5p. This study will have important clinical and therapeutic implications for and during transplantation procedures.

Background Doxil® (PEGylated liposomal doxorubicin, PLD) has been widely used in cancer treatment due to its excellent therapeutic efficacy, but it can simultaneously cause severe adverse effects such as hand-foot syndrome (HFS). To date, the pathophysiologic mechanism of HFS development induced by PLD administration has not been well understood. Materials and Methods The histological features of skin lesion in PLD-induced HFS model were characterized by hematoxylin and eosin (H&E) staining and picrosirius red staining, and the induction of inflammation and apoptosis in the epidermal layer was detected by immunohistochemical and TUNEL staining. Moreover, the generation of reactive oxygen species (ROS) was determined to elucidate the potential mechanism of skin lesion in the development of HFS. Results The administration of PLD has been demonstrated to induce the histological damage of skin tissues including the destruction of collagen fibers and the induction of severe inflammation and apoptosis of epidermal cells. The mechanism was probably attributed to the accumulation of PLD in the skin tissues during the long-term circulation and further the induction of ROS to cause the oxidative damage of keratinocytes owing to the sustained release of doxorubicin from PLD. Conclusion The ROS generation induced by the administration of PLD has been identified to be a crucial factor in the development of HFS, which could be used as a potential therapeutic target to alleviate the HFS symptom of PLD administration.

BACKGROUND:Multidrug resistance (MDR) has emerged to be a major hindrance in cancer therapy, which contributes to the reduced sensitivity of cancer cells toward chemotherapeutic drugs mainly owing to the over-expression of drug efflux transporters. The combination of gene therapy and chemotherapy has been considered as a potential approach to improve the anti-cancer efficacy by reversing the MDR effect.MATERIALS AND METHODS:The AS1411 aptamer-functionalized micelles were constructed through an emulsion/solvent evaporation strategy for the simultaneous co-delivery of doxorubicin and miR-519c. The therapeutic efficacy and related mechanism of micelles were explored based on the in vitro and in vivo active targeting ability and the suppression of MDR, using hepatocellular carcinoma cell line HepG2 as a model.RESULTS:The micelle was demonstrated to possess favorable cellular uptake and tumor penetration ability by specifically recognizing the nucleolin in an AS1411 aptamer-dependent manner. Further, the intracellular accumulation of doxorubicin was significantly improved due to the suppression of ABCG2-mediated drug efflux by miR-519c, resulting in the efficient inhibition of tumor growth.CONCLUSION:The micelle-mediated co-delivery of doxorubicin and miR-519c provided a promising strategy to obtain ideal anti-cancer efficacy through the active targeting function and the reversion of MDR.