A traditional Chinese medicine (TCM) monomer is a bioactive compound extracted from Chinese herbal medicines possessing determined biological activity and pharmacological effects, and has gained much attention for treating neuronal diseases. However, the application of TCM monomers is limited by their low solubility and poor ability to cross the blood-brain barrier (BBB). Exosomes are small extracellular vesicles (EVs) ranging in size from 30 to 150 nm in diameter and can be used as drug delivery carriers that directly target cells or tissues with unique advantages, including low toxicity, low immunogenicity, high stability in blood, and the ability to cross the BBB. This review discusses the biogenesis, components, stability, surface modification, isolation technology, advantages, and disadvantages of exosomes as drug carriers and compares exosomes and other similar drug delivery systems. Furthermore, exosome-encapsulated TCM monomers exert neuroprotective roles, such as anti-inflammation, anti-apoptosis, anti-mitophagy, and anti-oxidation, in various neuronal diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and cerebral ischemia and reperfusion (CI/R) injury, as well as anti-drug resistance, anti-tumorigenesis, anti-angiogenesis, and promotion of apoptosis in brain tumors, providing more inspiration to promote the development of an exosome-based delivery tool in targeted therapy for neuronal diseases.

The microstructures of pharmaceutical preparations play a pivotal role in determining their critical quality attributes (CQAs), such as drug release, content uniformity, and stability, which greatly impact the safety and efficacy of drugs. Unlike the inherent molecular structures of active pharmaceutical ingredients (APIs) and excipients, the microstructures of pharmaceutical preparations are developed during the formulation process, presenting unique analytical challenges. In this review, we primarily focus on presenting the research methods used to elucidate the microstructures of pharmaceutical preparations, including X-ray imaging (XRI), scanning electron microscopy (SEM), atomic force microscopy (AFM), Raman spectroscopy, infrared (IR) spectroscopy, and rheometer technology. Subsequently, we highlight the applications, advantages, and limitations of these methods. Finally, we discuss the current challenges and future perspectives in this field. This review aims to provide a comprehensive reference for understanding the microstructures of pharmaceutical preparations, offering new insights and potential advancements in their development.

Diabetes, a metabolic disease stemming from impaired or defective insulin secretion, ranks among the most severe chronic illnesses globally. While several approved drugs exist for its treatment, they often come with multiple side effects. Therefore, there is a pressing need for safe and effective anti-diabetic medications. Traditional Chinese medicine has recognized Lycium barbarum (LB; goji berry) plant, commonly known as “wolfberry fruit” in China, for over 2,000 years. Natural compounds derived from LB show promise in reducing diabetes levels. Although research on the impact of LB on diabetes is still limited, our review aims to explore the potential of LB in reducing the risk of diabetes and examine the underlying mechanisms involved. LB can modulate diabetes through various pathways, such as inhibiting α-amylase and α-glucosidase activities, promoting β-cell proliferation, stimulating insulin secretion, inhibiting glucagon secretion, improving insulin resistance and glucose tolerance, and enhancing antioxidant and anti-inflammatory activities. Additionally, LB improves gut flora and immunomodulation, further aiding diabetes management. These findings highlight the potential clinical utility of LB in managing diabetes and its complications within the framework of evidence-based modern medicine.

Neddylation is a crucial posttranslational modification that involves the attachment of neural precursor cell-expressed developmentally downregulated protein 8 (NEDD8) to a lysine residue in the substrate via the sequential actions of the E1 NEDD8-activating enzyme (NAE) (E1), E2 NEDD8-conjugating enzyme (E2), and E3 NEDD8-ligase (E3). The most extensively studied substrates of neddylation are members of the cullin family, which act as scaffold components for cullin ring E3 ubiquitin ligases (CRLs). Since cullin neddylation activates CRLs, which are frequently overactive in tumors, inhibiting neddylation has emerged as a promising strategy for developing novel antitumor therapies. This review explores the antitumor effects of inhibiting neddylation that leads to the inactivation of CRLs and provides a summary of known inhibitors that target protein-protein interactions (PPIs) within the neddylation enzymatic cascade.

Age-related macular degeneration (AMD) is a disease that affects the vision of elderly individuals worldwide. Although current therapeutics have shown effectiveness against AMD, some patients may remain unresponsive and continue to experience disease progression. Therefore, in-depth knowledge of the mechanism underlying AMD pathogenesis is urgently required to identify potential drug targets for AMD treatment. Recently, studies have suggested that dysfunction of mitochondria can lead to the aggregation of reactive oxygen species (ROS) and activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) innate immunity pathways, ultimately resulting in sterile inflammation and cell death in various cells, such as cardiomyocytes and macrophages. Therefore, combining strategies targeting mitochondrial dysfunction and inflammatory mediators may hold great potential in facilitating AMD management. Notably, emerging evidence indicates that natural products targeting mitochondrial quality control (MQC) and the cGAS/STING innate immunity pathways exhibit promise in treating AMD. Here, we summarize phytochemicals that could directly or indirectly influence the MQC and the cGAS/STING innate immunity pathways, as well as their interconnected mediators, which have the potential to mitigate oxidative stress and suppress excessive inflammatory responses, thereby hoping to offer new insights into therapeutic interventions for AMD treatment.

CD8⁺ T cell-based immune-therapeutics, including immune checkpoint inhibitors and adoptive cell therapies (tumor-infiltrating lymphocytes (TILs), T cell receptor-engineered T cells (TCR-T), chimeric antigen receptor T cells (CAR-T)), have achieved significant successes and prolonged patient survival to varying extents and even achieved cure in some cases. However, immunotherapy resistance and tumor insusceptibility frequently occur, leading to treatment failure. Recent evidences have highlighted the ponderance of tumor cells metabolic reprogramming in establishing an immunosuppressive milieu through the secretion of harmful metabolites, immune-inhibitory cytokines, and alteration of gene expression, which suppress the activity of immune cells, particularly CD8⁺ T cells to evade immune surveillance. Therefore, targeting tumor cell metabolic adaptations to reshape the immune microenvironment holds promise as an immunomodulatory strategy to facilitate immunotherapy. Here, we summarize recent advances in the crosstalk between immunotherapy and tumor reprogramming, focusing on the regulatory mechanisms underlying tumor cell glucose metabolism, amino acid metabolism, and lipid metabolism in influencing CD8⁺ T cells to provide promising metabolic targets or combinational strategies for immunotherapy.

Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases and remains the leading cause of cancer-related mortality worldwide. Firstly, this review explores the limitations of conventional therapies, chemotherapy, radiotherapy, and surgery, focusing on the development of drug resistance and significant toxicity that often hinder their efficacy. Thereafter, advancements in targeted therapies, such as immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs), are discussed, highlighting their impact on improving outcomes for patients with specific genetic mutations, including c-ros oncogene 1 receptor tyrosine kinase (ROS1), anaplastic lymphoma kinase (ALK), and epidermal growth factor receptor (EGFR). Additionally, the emergence of novel immunotherapies and phytochemicals is examined, emphasizing their potential to overcome therapeutic resistance, particularly in advanced-stage diseases. The review also delves into the role of next-generation sequencing (NGS) in enabling personalized treatment approaches and explores the clinical potential of innovative agents, such as bispecific T-cell engagers (BiTEs) and antibody-drug conjugates (ADCs). Finally, we address the socioeconomic barriers that limit the accessibility of these therapies in low-resource settings and propose future research directions aimed at improving the long-term efficacy and accessibility of these treatments.

The incomplete degradation of tumour cells by macrophages (Mϕ) is a contributing factor to tumour progression and metastasis, and the degradation function of Mϕ is mediated through phagosomes and lysosomes. In our preliminary experiments, we found that overactivation of NADPH oxidase 2 (NOX2) reduced the ability of Mϕ to degrade engulfed tumour cells. Above this, we screened out liquiritin from Glycyrrhiza uralensis Fisch, which can significantly inhibit NOX2 activity and inhibit tumours, to elucidate that suppressing NOX2 can enhance the ability of Mϕ to degrade tumour cells. We found that the tumour environment could activate the NOX2 activity in Mϕ phagosomes, causing Mϕ to produce excessive reactive oxygen species (ROS), thus prohibiting the formation of phagolysosomes before degradation. Conversely, inhibiting NOX2 in Mϕ by liquiritin can reduce ROS and promote phagosome-lysosome fusion, therefore improving the enzymatic degradation of tumour cells after phagocytosis, and subsequently promote T cell activity by presenting antigens. We further confirmed that liquiritin down-regulated the expression of the NOX2 specific membrane component protein gp91 phox, blocking its binding to the NOX2 cytoplasmic component proteins p67 phox and p47 phox, thereby inhibiting the activity of NOX2. This study elucidates the specific mechanism by which Mϕ cannot degrade tumour cells after phagocytosis, and indicates that liquiritin can promote the ability of Mϕ to degrade tumour cells by suppressing NOX2.

Ferroptosis of chondrocytes is a significant contributor to osteoarthritis (OA), for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis. Here, we screen for anti-ferroptotic drugs in Food and Drug Administration (FDA)-approved drug library via a high-throughput manner in chondrocytes. We identified a group of FDA-approved anti-ferroptotic drugs, among which vitamin K showed the most powerful protective effect. Further study demonstrated that vitamin K effectively inhibited ferroptosis and alleviated the extracellular matrix (ECM) degradation in chondrocytes. Intra-articular injection of vitamin K inhibited ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus (DMM) mouse model. Mechanistically, transcriptome sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest-specific 6 (Gas6). Furthermore, exogenous expression of Gas6 was found to inhibit ferroptosis through the AXL receptor tyrosine kinase (AXL)/phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) axis. Together, we demonstrate that vitamin K inhibits ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of AXL/PI3K/AKT axis, indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and other ferroptosis-related diseases.

The “hallmarks of cancer” concept provides a valuable framework for understanding fundamental organizing principles common to various cancers. However, without a consensus gene set for cancer hallmarks, data comparison and integration result in diverse biological interpretations across studies. Therefore, we aimed to form a consensus cancer hallmark gene set by merging data from available mapping resources and establishing a framework for mining these gene sets. By consolidating data from seven projects, 6763 genes associated with 10 cancer hallmarks were identified. A cancer hallmarks enrichment analysis was performed for prognostic genes associated with overall survival across 12 types of solid tumors. “Tissue invasion and metastasis” was most prominent in cancers of the stomach (P = 2.2 × 10^-11), pancreas (P = 4.2 × 10^-9), bladder (P = 3.3 × 10^-8), and ovaries (P = 0.0007), aligning with their heightened potential to spread. “Sustained angiogenesis” was most prominent in squamous cell carcinomas of the lung (P = 2.5 × 10^-7), while “genome instability” showed strong enrichment in lung adenocarcinomas (LUADs) (P = 1.5 × 10^-8) and cancers of the liver (P = 5.5 × 10^-10), pancreas (P = 2.1 × 10^-5), and kidney (P = 0.018). Pancreatic cancers displayed the highest enrichment of hallmarks, emphasizing the disease's complexity, while in melanomas and cancers of the liver, prostate, and kidney, a single hallmark was enriched among the prognostic markers of survival. Additionally, an online tool (www.cancerhallmarks.com) that allows the identification of cancer-associated hallmarks from new gene sets was established. In summary, our aim of establishing a consensus list of cancer hallmark genes was achieved. Furthermore, the analysis of survival-associated genes revealed a unique pattern of hallmark enrichment with potential pharmacological implications in different tumor types.

Colorectal inflammatory cancer transformation poses a major risk to patients with colitis. Patients with chronic intestinal inflammation have an approximately 2–3 fold increased risk of developing colorectal cancer (CRC). Unfortunately, there is currently no effective intervention available. Huangqin decoction (HQD), a well-known traditional Chinese medicine (TCM) formula, is frequently clinically prescribed for treating patients with colitis, and its active ingredients have effective antitumour efficacy. Nonetheless, the mechanism of HQD-mediated prevention of colorectal inflammatory cancer transformation remains unclear. A strategy integrating metagenomic, lipidomic, and messenger RNA (mRNA) sequencing analysis was used to investigate the regulatory effects of HQD on the gut microbiome, metabolism and potential mechanisms involved in colorectal inflammatory cancer transformation. Our study revealed that HQD suppressed colorectal inflammatory cancer transformation, which was associated with enhanced intestinal barrier function, decreased the inflammatory response, and regulation of the gut microbiome. Notably, cohousing experiments revealed that the transfer of the gut microbiome from HQD-treated mice largely inhibited the pathological transformation of colitis. Moreover, gut microbiome transfer from HQD-treated mice primarily resulted in the altered regulation of fatty acid metabolism, especially the remodeling of arachidonic acid metabolism, which was associated with the amelioration of pathological transformation. Arachidonic acid metabolism and the key metabolic enzyme arachidonic acid 12-lipoxygenase (ALOX12) were affected by HQD treatment, and no obvious protective effect of HQD was observed in Alox12^-/- mice, which revealed that ALOX12 was a critical mediator of HQD protection against colorectal inflammatory cancer transformation. In summary, multiple omics analyses were applied to produce valuable data and theoretical support for the application of HQD as a promising intervention for the transformation of inflammatory CRC.

This study investigates the molecular complexities of non-alcoholic fatty liver disease (NAFLD)-induced brain dysfunction, with a focus on the liver-intestine-brain axis and potential therapeutic interventions. The main objectives include understanding critical microbiota shifts in NAFLD, exploring altered metabolites, and identifying key regulatory molecules influencing brain function. The methods employed encompassed 16S ribosomal RNA (rRNA) sequencing to scrutinize stool microbiota in NAFLD patients and healthy individuals, non-targeted metabolomics using LC-MS to uncover elevated levels of deoxycholic acid (DCA) in NAFLD mice, and single-cell RNA sequencing (scRNA-seq) to pinpoint the pivotal gene Hpgd in microglial cells and its downstream Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. Behavioral changes and brain function were assessed in NAFLD mice with and without fecal microbiota transplantation (FMT) treatment, utilizing various assays and analyses. The results revealed significant differences in microbiota composition, with increased levels of Bacteroides in NAFLD patients. Additionally, elevated DCA levels were observed in NAFLD mice, and FMT treatment demonstrated efficacy in ameliorating liver function and brain dysfunction. Hpgd inhibition by DCA activated the JAK2/STAT3 pathway in microglial cells, leading to inflammatory activation, inhibition of mitochondrial autophagy, induction of neuronal apoptosis, and reduction in neuronal action potentials. This study elucidates the intricate molecular mechanisms underlying the liver-gut-brain axis in NAFLD, and the identification of increased DCA and the impact of JAK2/STAT3 signaling on microglial cells highlight potential therapeutic targets for addressing NAFLD-induced brain dysfunction.

Ferroptosis has been shown to mediate the development of fibrosis. Polyphyllin VII (PP7), a bioactive component of Paris polyphylla, exhibits potent anti-inflammatory activity and can significantly alleviate liver fibrosis. In this study, treatment with PP7 significantly inhibited the proliferation and activation of hepatic stellate cells (HSCs), which could be suppressed by a ferroptosis inhibitor. In addition, it promoted HSC ferroptosis by suppressing glutathione (GSH) peroxidase 4 (GPX4) and enhanced the expression of CX3C chemokine ligand 1 (CX3CL1). Depletion of CX3CL1 attenuated the effects of PP7 on the activation and ferroptosis of HSCs and the expression of GPX4. Notably, CX3CL1 directly interacted with GPX4, triggering HSC ferroptosis. The transcription factor hypermethylated in cancer 1 (Hic1), which binds to the Cx3cl1 promoter, increased the expression of CX3CL1. Its absence resulted in downregulation of CX3CL1, suppressing the GPX4-dependent ferroptosis of PP7-treated HSCs and promoting their activation. HIC1 was found to directly interact with PP7 at the GLY164 site. Co-culture experiments showed that PP7-induced HSC ferroptosis attenuated macrophage recruitment by regulating inflammation-related genes. HSC-specific inhibition of HIC1 counteracted PP7-induced collagen depletion and HSC ferroptosis in vivo. These findings suggest that PP7 induces HSC ferroptosis through the HIC1/CX3CL1/GPX4 axis.

Discoidin domain receptor 1 (DDR1) is overexpressed in various tumors, such as triple-negative breast cancer (TNBC), and is rarely expressed in normal tissues. These characteristics make DDR1 a preferable target candidate for the construction of an antibody-drug conjugate (ADC) for targeted therapy. Here, we investigated the preparation and preclinical efficacy of DDR1-DX8951, an ADC that includes an anti-DDR1 monoclonal antibody conjugated to DX8951 by a cleavable Gly-Gly-Phe-Gly (GGFG) linker. The anti-DDR1 monoclonal antibody was coupled to DX8951 (i.e., DDR1-DX8951), producing the targeted therapy ADC. The antitumor activities of DDR1-DX8951 monotherapy or DDR1-DX8951 plus pembrolizumab were assessed in TNBC mouse models. DDR1-DX8951 can specifically target DDR1, be quickly internalized by TNBC cells, and reduce the viability of TNBC cells in vitro. The potent antitumor activity of DDR1-DX8951 was revealed in TNBC xenograft models. Importantly, our investigation demonstrated that DDR1-DX8951 plus pembrolizumab not only revealed the inhibitory efficacy on tumor growth and metastasis but also played an important role in improving the immunosuppressive tumor microenvironment (TME) of TNBC. Taken together, this investigation provides justification for large-sample studies to further assess the safety and efficacy of DDR1-DX8951 plus pembrolizumab for TNBC clinical trials.

Endothelial dysfunction is a key factor linking obstructive sleep apnea hypopnea syndrome (OSAHS) with cardiovascular diseases. In this study, we used advanced proteomics and metabolomics approaches to investigate the impact of extracellular vesicles (EVs) derived from the serum of OSAHS patients on endothelial function. Our multi-omics analysis identified dysregulated pathways related to fatty acid metabolism, apoptosis regulation, and inflammatory responses, highlighting fatty acid synthase (FASN) as a crucial player in OSAHS-induced endothelial dysfunction. Both in vitro and in vivo experiments demonstrated that FASN-enriched EVs impair endothelial cell viability and disrupt metabolic homeostasis, offering new insights for the development of targeted therapies for cardiovascular complications associated with OSAHS.

Proteolysis-targeting chimeras (PROTACs) represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can, potentially revolutionizing drug discovery and treatment strategies. However, the links between in vitro and in vivo data are poorly understood, hindering a comprehensive understanding of the absorption, distribution, metabolism, and excretion (ADME) of PROTACs. In this work, ¹⁴C-labeled vepdegestrant (ARV-471), which is currently in phase III clinical trials for breast cancer, was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics (PK) by establishing a physiologically based pharmacokinetics (PBPK) model. For in vitro-in vivo extrapolation (IVIVE), hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did. PBPK models, which were initially developed and validated in rats, accurately simulate ARV-471's PK across fed and fasted states, with parameters within 1.75-fold of the observed values. Human models, informed by in vitro ADME data, closely mirrored postoral dose plasma profiles at 30 mg. Furthermore, no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans. This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.