👤 Adeline J H Yong

Precise toxicological mechanism of atherosclerosis (AS) induced by environmental hazardous substance nicotine exposure remains unclear, impeding its prevention strategies and antagonist development. Additionally, it is yet unknown whether Dendrobium officinale's active components can antagonize nicotine-induced AS. This study aimed to elucidate nicotine exposure-induced AS toxicological mechanisms and identify Dendrobium officinale's active components-derived antagonists. Firstly, using ApoE Show less

The protein corona formed upon systemic administration critically modulates the pharmacokinetics, biodistribution, and therapeutic efficacy of the nanomedicines. While emerging evidence links obesity to heightened chemosensitivity, the underlying nanobio-interfacial mechanisms remain poorly understood. Herein, we demonstrate that pegylated liposomal doxorubicin (PLD) exhibits significantly enhanced antitumor and antimetastatic efficacy in obese breast tumor-bearing mice compared to normal controls. Mechanistic investigations reveal that obesity confers PLD with prolonged systemic circulation and improved tumor accumulation. Notably, preincubation of PLD with plasma from obese mice reduces macrophage uptake while promoting internalization by breast cancer cells compared to that from normal mice. Genetic ablation of apolipoprotein E (ApoE) in obese mice abolishes obesity-associated improvements in PLD blood circulation, tumor accumulation, and uptake by cancer cells. Conversely, supplementation with recombinant ApoE restores these effects in ApoE-deficient mice and potentiates PLD's antitumor efficacy. Collectively, our findings demonstrate obesity-induced ApoE as a pivotal regulator of the protein corona that actively enhances tumor-targeted delivery of PLD, which offers a rational strategy for engineering protein-corona-mediated tumor-targeted nanomedicines. Show less

Neurodegenerative diseases, which pose significant challenges for effective treatment, often involve risk variants of lysosomal gene products that disrupt lysosomal function, leading to the accumulation of indigestible materials and damage to brain cells. The lysosome is a degradative organelle and a signaling hub that senses nutrient availability. How lysosomal dysfunction contributes to neurodegenerative diseases is an important open question. In this study, we identified CLN3 (ceroid lipofuscinosis, neuronal 3), an endolysosomal protein that is linked to Batten disease, as an evolutionarily conserved protein that facilitates lysosomal chloride efflux. Additionally, we report that a natural compound with anti-inflammatory properties-the curcumin analog C1, which is a TFEB (transcription factor EB) activator-could enhance CLN3 activity and improve lysosomal function. These findings provide new insight into the role of CLN3 in lysosomal ion homeostasis and raise the possibility that modulation of the TFEB-CLN3 signaling axis may hold therapeutic potential for lysosomal storage disorders. Show less

Retinal degenerative diseases (RDDs) cause irreversible vision loss with limited treatment options. Traditional Chinese medicine (TCM) formulas have demonstrated neuroprotective effects, yet their overall efficacy lacks comprehensive meta-evidence. The aim of this study was to exploratively evaluate the neuroprotective effects of TCM formulas in animal RDD models. A comprehensive literature search was conducted across eight electronic databases to identify animal studies that evaluated the neuroprotective effects of TCM formulas on RDDs. Pairwise meta-analysis and Bayesian network meta-analysis (NMA) were performed to synthesize evidence on key outcomes: neural growth, glial activation, oxidative stress, apoptosis factors, and ophthalmological parameters. Treatment rankings were assessed using the surface under the cumulative ranking curve (SUCRA). Twenty-four studies were included. The compositions and bioactive compounds of the TCM formulas have been defined and identified. Pairwise meta-analysis demonstrated that specific TCM formulas might exert neuroprotective effects on RDDs by regulating key biomarkers. Specifically, Zhen-Bao-Wan, Bu-Shen-Yi-Jing-Fang, and Qi-Shen-Yi-Qi pills modulated neural growth and glial activation by upregulating BDNF, CNTF, and reducing GFAP, respectively. Furthermore, Yi-Qi-Wen-Yang-Tong-Luo decoction, Zi-Yin-Ming-Mu decoction, and Yishi-Tablet suppressed oxidative stress and apoptosis by reducing SOD, retinal apoptotic cells and caspase-3, respectively. Additionally, Bu-Yang-Huan-Wu decoction improved retinal function by elevating ERG-a and ERG-b wave amplitudes. Subgroup analyses indicated that Bu-Yang-Huan-Wu decoction and Qu-Yu-Tong-Luo prescription exhibited superior efficacy in restoring retinal ganglion cell (RGC) counts and retinal thickness in specific RDD models. The NMA results indicated that the included TCM formulas exhibited target-specific and dose‒response trends, with different formulas showing preferential efficacy for distinct biomarkers. Given the limitations identified in this study, these findings should be interpreted as preliminary evidence to guide future research rather than as conclusive results. Future studies with rigorous experimental designs are needed to address these limitations and enhance translational relevance. This study provides preclinical and exploratory evidence that the included TCM formulas might exert neuroprotective effects on animal models of RDDs by modulating glial activation, promoting neuronal growth, and inhibiting oxidative stress and apoptosis. Additional high-quality preclinical studies are essential to validate these effects and inform future clinical translation. https://www.crd.york.ac.uk/PROSPERO/view/CRD420251002491 identifier CRD420251002491. Show less

Intestinal immunity defends against enteric pathogens, mediates symbiotic relationships with the resident microbiota, and provides tolerance to food antigens, safeguarding critical nutrient absorption and barrier functions of this mucosal tissue. Despite the abundance of tissue resident activated T cells, their contributions to these various roles remains poorly understood. Here, we identify a dominant population of IL-10 producing, T-bet expressing CD4+ Tr1 T cells, residing in the small intestinal lamina propria at homeostasis. Remarkably, these intestinal Tr1 cells emerge at the time of weaning and accumulate independently of the microbiota displaying similar abundance, function and TCR repertoire under germ-free conditions. Instead, the small intestinal T-bet+ Tr1 program is driven and shaped by dietary antigens, and accumulates in a cDC1-IL-27 dependent manner. Upon activation, these cells robustly express IL-10 and multiple inhibitory receptors, establishing a distinct suppressive profile. Altogether, this work uncovers a previously unappreciated dominant player in homeostatic small intestinal immunity with the potential to play critical suppressive roles in this tissue, raising important implications for the understanding of immune regulation in the intestine. Establishing immunological tolerance to self and environmental antigens is critical to preserve tissue homeostasis and function. In the intestine, both dietary and microbiota derived antigens are routinely encountered by the immune system, which deploys a variety of mechanisms to maintain tolerance to these innocuous antigens. Understanding how immunological tolerance is established is critical, a when this process goes awry it can lead to severe inflammatory and autoimmune diseases such as food allergy and inflammatory bowel disease. However, how tolerance is established in the intestine is still poorly understood. In this study we describe a novel dominant T cell population in the small intestine shaped by dietary components with the potential to play important roles in immune tolerance at this site. back # IntroductionBarrier surfaces such as the gut and skin represent the first line of defense against the environment. These organs must strike a delicate balance between providing protection against environmental and infectious agents, maintaining tissue function, and establishing a homeostatic symbiotic relationship with resident microbes collectively known as the microbiota (1). The immune system plays a critical role in establishing these dynamic and carefully regulated relationships, as evidenced by the large number of immune cells present at these sites. Of particular note, activated T cells are very abundant at barrier tissues, where they orchestrate immune effector functions geared towards these varied tasks (1, 2). In the small intestine, the intraepithelial compartment harbors innate like natural CD8aa⁺ IELs, many of which are self reactive; as well as CD4⁺CD8aa⁺ and CD8ab⁺ IELs responding to dietary and microbial antigens (3). The underlying lamina propria (SILP) harbors predominantly CD4⁺ T cells, which participate in responses to commensal-derived and dietary antigens (2, 4). Despite the abundance of small intestinal CD4 T cells, only a handful of cognate immune interactions focusing on Type 17 and T regulatory helper subsets have been described. Thus, whether immune responses in this tissue are truly limited to a small number of antigenic triggers and effector functions remains to be fully elucidated. The small number of gut homeostatic CD4 T cell responses described thus far have been shown to primarily respond to specific commensal bacteria or dietary antigens (1, 2, 5-8): Among other examples, SFB induces cognate Th17 cells in the small intestine (9, 10), a consortium human commensal bacteria induces CD8b⁺ cells in the colon (11), and Show less

Understanding of the evolution of metazoans from their unicellular ancestors is a fundamental question in biology. In contrast to fungi which utilize the Mon1-Ccz1 dimeric complex to activate the small GTPase RAB7A, metazoans rely on the Mon1-Ccz1-RMC1 trimeric complex. Here, we report a near-atomic resolution cryogenic-electron microscopy structure of the Show less

Regarding whether brain magnetic resonance imaging (MRI) should be routine in patients with suspected early-stage lung cancer, guideline recommendations are inconsistent. Therefore, we performed this study to evaluate the incidence of and risk factors for brain metastasis (BM) in patients with suspected early-stage non-small-cell lung cancer (NSCLC). A review of the medical charts of consecutive NSCLC patients diagnosed between January 2006 and May 2020 was performed. We identified 1,382 NSCLC patients with clinical staging of T1/2aN0M0 (excluding BM), and investigated the incidence, clinical predictors, and prognosis of BM in the cohort. We also performed RNA-sequencing differential expression analysis using transcriptome of 8 patients, using DESeq2 package (version 1.32.0) with R (version 4.1.0). Among 1,382 patients, nine hundred forty-nine patients (68.7%) underwent brain MRI during staging, and 34 patients (3.6%) were shown to have BM. Firth's bias-reduced logistic regression showed that tumor size (OR 1.056; 95% CI 1.009-1.106, p=0.018) was the only predictor of BM, and pathologic type was not a predictor of BM in our cohort (p>0.05). The median overall survival for patients with brain metastasis was 5.5 years, which is better than previously reported in the literature. RNA-sequencing differential expression analysis revealed the top 10 significantly upregulated genes and top 10 significantly downregulated genes. Among the genes involved in BM, Unc-79 homolog, non-selective sodium leak channel (NALCN) channel complex subunit (UNC79) was the most highly expressed gene in the lung adenocarcinoma tissues from the BM group, and an Given the incidence and favorable outcome of BM in patients with suspected early-stage NSCLC, selective screening with brain MRI may be considered, especially in patients with high-risk features. Show less

Experimental and clinical studies have conclusively demonstrated that lowering elevated low-density lipoprotein cholesterol levels results in fewer major adverse cardiac events. Over the past few decades, statins have become the mainstay of lipid-lowering therapy, contributing significantly to the reduction of lipids, and providing patients with a cost-effective approach. However, with growing evidence in support of combination therapies providing increased benefits to certain patient populations, such as those intolerant to statins, there is an urgent need to investigate the safety and efficacy of alternative lipid-lowering drugs. In this paper, we review the current alternative and adjuvant cholesterol targeting agents. We further discuss the clinical trials that have evaluated the safety and efficacy of these alternative and adjuvant therapies as well as their implications for practical use. These drugs target levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or lipoprotein(a) as treatments for hyperlipidemia and atherosclerotic cardiovascular disease. Show less

Hypothalamic regulation of feeding and energy expenditure is a fundamental and evolutionarily conserved neurophysiological process critical for survival. Dysregulation of these processes, due to environmental or genetic causes, can lead to a variety of pathological conditions ranging from obesity to anorexia. Melanocortins and endogenous cannabinoids (eCBs) have been implicated in the regulation of feeding and energy homeostasis; however, the interaction between these signaling systems is poorly understood. Here, we show that the eCB 2-arachidonoylglycerol (2-AG) regulates the activity of melanocortin 4 receptor (MC4R) cells in the paraventricular nucleus of the hypothalamus (PVN Show less

Long non-coding RNA is an endogenous non-coding RNA that has currently been proved to be an important player in cancer cell biology. In the present study, we investigated the biological role of PHACTR2-AS1 in tongue squamous cell carcinoma (TSCC). PHACTR2-AS1 was preferentially localized in the cytoplasm, and was notably upregulated in TSCC tissues. High PHACTR2-AS1 was correlated with tumour differentiation, metastatic clinical features, relapse and shortened survival time. Depletion of PHACTR2-AS1 did not affect TSCC cell viability and colony formation ability, whereas substantially inhibited cell migration and invasion in vitro and lung metastasis in vivo. Mechanistically, PHACTR2-AS1 could sponge miR-137 to increase Snail expression, resulting in triggering epithelial-mesenchymal transition process, thereby promoting TSCC cell metastasis. Taken together, our data for the first time elucidate the metastasis-promoting role of PHACTR2-AS1 in TSCC, hinting a new therapeutic target for metastatic TSCC patients. Show less

EIF4E is the rate-limiting factor in the mRNA translation of specific set of oncogenes. Snail is the core transcription factor of epithelial-mesenchymal transition (EMT), a key step of cancer metastasis. The connection between the two oncoproteins has not been well established in the human cancer tissues and in nasopharyngeal carcinoma (NPC). Here we showed that the positive correlative over-expression was seen between eIF4E and Snail in NPC tissues, and the expression was significantly higher in the metastatic NPC than in the un-metastatic NPC. In NPC cells, eIF4E knockdown significantly reduced Snail mRNA and protein levels, increased the mRNA level of E-cad (a direct downstream gene of Snail and a negative EMT marker), attenuated the invasive ability of the cells, and sensitized the cells to cisplatin in invasion. In contrast, enforced the expression of eIF4E significantly increased Snail mRNA and protein levels, and promoted the invasive ability in NPC cells. Under the condition of the high eIF4E expression, Snail knockdown significantly increased E-cad mRNA level and weaken the invasive ability of NPC cells. Finally, eIF4E directly bound Snail mRNA for translation initiation displayed by the RIP assay. Therefore, the results firstly suggested that eIF4E enhanced the Snail expression in both transcription and translation manner in human cancer tissues and targeting the eIF4E/Snail axis might intervene with the EMT and metastasis of NPC. This finding provided a new clue for further understanding the metastatic mechanism of human cancers and for preventing and treating NPC metastasis. Show less

In multiple sclerosis, physiological repair mechanisms can help the nervous system to recover from tissue injury. Enhancing such repair mechanisms is an important, and increasingly realistic, therapeutic goal in multiple sclerosis. With respect to remyelination, several promising therapeutic avenues are currently being explored, including stem cell transplantation, LINGO-1, prolactin and glatiramer acetate. Glatiramer acetate is believed to act by the induction of specific populations of anti-inflammatory Th2 cells or Type 2 monocytes which infiltrate sites of injury in the nervous system where they release anti-inflammatory cytokines leading to bystander suppression of inflammation. In addition, these cells can release neurotrophic factors such as BDNF and IGF-1 which have been shown to stimulate the differentiation of oligodendrocyte precursor cells and thus enhance remyelination. In addition, neurotrophic factors released in response to glatiramer acetate may stimulate the differentiation of neuronal progenitor cells into mature neurones that can replace neurones lost through the disease process. This repair capacity of glatiramer acetate may contribute to the long-term well-being of patients with multiple sclerosis treated with glatiramer acetate. Show less