查看更多>>摘要：The APOBEC3(A3)family plays a pivotal role in the immune system by performing DNA/RNA single-strand deamination.Cancers mostly arise from the accumulation of chronic mutations in so-matic cells,and recent research has highlighted the A3 family as a major contributor to tumor-associated mutations,with A3A being a key driver gene leading to cancer-related mutations.A3A helps to defend the host against virus-induced tumors by editing the genome of cancer-associated viruses that invade the host.However,when it is abnormally expressed,it leads to persistent,chronic mutations in the genome,thereby fueling tumorigenesis.Notably,A3A is prominently expressed in innate immune cells,particu-larly macrophages,thereby affecting the functional state of tumor-infiltrating immune cells and tumor growth.Furthermore,the expression of A3A in tumor cells may directly affect their proliferation and migration.A growing body of research has unveiled that A3A is closely related to various cancers,which signifies the potential significance of A3A in cancer therapy.This paper mainly classifies and summarizes the evidence of the relationship between A3A and tumorigenesis based on the potential mechanisms,aim-ing to provide valuable references for further research on the functions of A3A and its development in the area of cancer therapy.
查看更多>>摘要：Immunocytokines,employing targeted antibodies to concentrate cytokines at tumor sites,have shown potential advantages such as prolonged cytokine half-lives,mitigated adverse effects,and synergistic antitumor efficacy from both antibody and cytokine components.First,we present an in-depth analysis of the advancements of immunocytokines evaluated in preclinical and clinical applica-tions.Notably,anti-PD-1-based immunocytokines can redirect cytokines to intratumoral CD8+T cells and reinvigorate them to elicit robust antitumor immune responses.Then,we focus on their molecular structures and action mechanisms,striving to elucidate the correlations between diverse molecular struc-tures and their antitumor efficacy.Moreover,our exploration extends to the realm of novel cytokines,including IL-10,IL-18,and IL-24,unraveling their potential in the construction of immunocytokines.However,safety concerns remain substantial barriers to immunocytokines'development.To address this challenge,we explore potential strategies,such as cytokine engineering and prodrug design,which can foster next-generation immunocytokines development.Overall,this review concentrates on the design of molecular structures in immunocytokines,underscoring the direction and focus of ongoing efforts to improve safety profiles while maximizing therapeutic efficacy.
查看更多>>摘要：Aluminum adjuvants(Alum),approved by the US Food and Drug Administration,have been extensively used in vaccines containing recombinant antigens,subunits of pathogens,or toxins for almost a century.While Alums typically elicit strong humoral immune responses,their ability to induce cellular and mucosal immunity is limited.As an alternative,layered double hydroxide(LDH),a widely used antacid,has emerged as a novel class of potent nano-aluminum adjuvants(NanoAlum),demonstrating advantageous physicochemical properties,biocompatibility and adjuvanticity in both humoral and cellular immune responses.In this review,we summarize and compare the advantages and disadvantages of Alum and NanoAlum in these properties and their performance as adjuvants.Moreover,we propose the key features for ideal adjuvants and demonstrate that LDH NanoAlum is a promising candidate by sum-marizing its current progress in immunotherapeutic cancer treatments.Finally,we conclude the review by offering our integrated perspectives about the remaining challenges and future directions for NanoAlum's application in preclinical/clinical settings.
查看更多>>摘要：About 40％of approved drugs and nearly 90％of drug candidates are poorly water-soluble drugs.Low solubility reduces the drugability.Effectively improving the solubility and bioavailability of poorly water-soluble drugs is a critical issue that needs to be urgently addressed in drug development and application.This review briefly introduces the conventional solubilization techniques such as solubili-zers,hydrotropes,cosolvents,prodrugs,salt modification,micronization,cyclodextrin inclusion,solid dispersions,and details the crystallization strategies,ionic liquids,and polymer-based,lipid-based,and inorganic-based carriers in improving solubility and bioavailability.Some of the most commonly used approved carrier materials for solubilization techniques are presented.Several approved poorly water-soluble drugs using solubilization techniques are summarized.Furthermore,this review summa-rizes the solubilization mechanism of each solubilization technique,reviews the latest research advances and challenges,and evaluates the potential for clinical translation.This review could guide the selection of a solubilization approach,dosage form,and administration route for poorly water-soluble drugs.Moreover,we discuss several promising solubilization techniques attracting increasing attention worldwide.
查看更多>>摘要：Over the past decade,research has increasingly identified unique dysregulations in lipid metabolism within the tumor microenvironment(TME).Lipids,diverse biomolecules,not only constitute biological membranes but also function as signaling molecules and energy sources.Enhanced synthesis or uptake of lipids in the TME significantly promotes tumorigenesis and proliferation.Moreover,lipids secreted into the TME influence tumor-resident immune cells(TRICs),thereby aiding tumor survival against chemotherapy and immunotherapy.This review aims to highlight recent advancements in under-standing lipid metabolism in both tumor cells and TRICs,with a particular emphasis on exogenous lipid uptake and endogenous lipid de novo synthesis.Targeting lipid metabolism for intervention in anticancer therapies offers a promising therapeutic avenue for cancer treatment.Nano-drug delivery systems(NDDSs)have emerged as a means to maximize anti-tumor effects by rewiring tumor metabolism.This review provides a comprehensive overview of recent literature on the development of NDDSs targeting tumor lipid metabolism,particularly in the context of tumor immunotherapy.It covers four key aspects:reprogramming lipid uptake,reprogramming lipolysis,reshaping fatty acid oxidation(FAO),and reshuf-fling lipid composition on the cell membrane.The review concludes with a discussion of future prospects and challenges in this burgeoning field of research.
查看更多>>摘要：Intravesical drug delivery(IDD),as a noninvasive,local pathway of administration,has great clinical significance for bladder diseases,especially bladder cancer.Despite the many advantages of IDD such as enhanced focal drug exposure and avoidance of systemic adverse drug reactions,the effectiveness of drug delivery is greatly challenged by the physiological barriers of the bladder.In this review,the routes and barriers encountered in IDD are first discussed,and attention is paid to the potential internal/mucosal retention and absorption-transport mechanisms of drugs.On this basis,the avoidance,overcoming and utilization of the"three barriers"is further emphasized,and current design and fabrication strategies for intravesical drug delivery systems(IDDSs)are described mainly from the perspectives of constructing drug reservoirs,enhancing permeability and targeting,with the hope of providing systematic understanding and inspirations for the research of novel IDDSs and their treatment of bladder diseases.
查看更多>>摘要：Pancreatic fibrosis(PF)is primarily distinguished by the stimulation of pancreatic stellate cells(PSCs)and excessive extracellular matrix deposition,which is the main barrier impeding drug de-livery and distribution.Recently,nanomedicine,with efficient,targeted,and controllable drug release characteristics,has demonstrated enormous advantages in the regression of pancreas fibrotic diseases.Notably,paracrine signals from parenchymal and immune cells such as pancreatic acinar cells,islet cells,pancreatic cancer cells,and immune cells can directly or indirectly modulate PSC differentiation and acti-vation.The intercellular crosstalk between PSCs and these cells has been a critical event involved in fi-brogenesis.However,the connections between PSCs and other pancreatic cells during the progression of diseases have yet to be discussed.Herein,we summarize intercellular crosstalk in the activation of PSCs and its contribution to the development of common pancreatic diseases,including pancreatitis,pancreatic cancer,and diabetes.Then,we also examine the latest treatment strategies of nanomedicine and potential targets for PSCs crosstalk in fibrosis,thereby offering innovative insights for the design of antifibrotic nanomedicine.Ultimately,the enhanced understanding of PF will facilitate the development of more pre-cise intervention strategies and foster individually tailored therapeutic approaches for pancreatic diseases.
查看更多>>摘要：Alcoholic steatohepatitis(ASH)is a liver disease characterized by steatosis,inflammation,and necrosis of the liver tissue as a result of excessive alcohol consumption.Pregnane X receptor(PXR)is a xenobiotic nuclear receptor best known for its function in the transcriptional regulation of drug metabolism and disposition.Clinical reports suggested that the antibiotic rifampicin,a potent human PXR activator,is a contraindication in alcoholics,but the mechanism was unclear.In this study,we showed that the hepatic expression of fatty acid binding protein 4(FABP4)was uniquely elevated in ASH patients and a mouse model of ASH.Pharmacological inhibiting FABP4 attenuated ASH in mice.Furthermore,treat-ment of mice with the mouse PXR agonist pregnenolon-16α-carbonitrile(PCN)induced the hepatic and circulating levels of FABP4 and exacerbated ASH in a PXR-dependent manner.Our mechanism study established FABP4 as a transcriptional target of PXR.Treatment with andrographolide,a natural com-pound and dual inhibitor of PXR and FABP4,alleviated mice from ASH.In summary,our results showed that the PXR-FABP4 gene regulatory axis plays an important role in the progression of ASH,which may have accounted for the contraindication of rifampicin in patients of alcoholic liver disease.Pharmacolog-ical inhibition of PXR and/or FABP4 may have its promise in the clinical management of ASH.
查看更多>>摘要：Anxiety disorders are one of the most epidemic and chronic psychiatric disorders.An incom-plete understanding of anxiety pathophysiology has limited the development of highly effective drugs against these disorders.GPR17 has been shown to be involved in multiple sclerosis and some acute brain injury disorders.However,no study has investigated the role of GPR17 in psychiatric disorders.In a well-established chronic restraint stress(CRS)mouse model,using a combination of pharmacological and molecular biology techniques,viral tracing,in vitro electrophysiology recordings,in vivo fiber photom-etry,chemogenetic manipulations and behavioral tests,we demonstrated that CRS induced anxiety-like behaviors and increased the expression of GPR17 in basolateral amygdala(BLA)glutamatergic neurons.Inhibition of GPR17 by cangrelor or knockdown of GPR17 by adeno-associated virus in BLA glutama-tergic neurons effectively improved anxiety-like behaviors.Overexpression of GPR17 in BLA glutama-tergic neurons increased the susceptibility to anxiety-like behaviors.What's more,BLA glutamatergic neuronal activity was required for anxiolytic-like effects of GPR17 antagonist and GPR17 modulated anxiety-like behaviors via BLA to ventral hippocampal CA1 glutamatergic projection.Our study finds for the first and highlights the new role of GPR17 in regulating anxiety-like behaviors and it might be a novel potential target for therapy of anxiety disorders.
查看更多>>摘要：TROP-2,a tumor-associated antigen,has been implicated in the progression of various epithelial tumors.Due to its favorable expression profile,TROP-2 has emerged as a promising target for antibody-drug conjugates(ADCs)based anti-tumor therapies.Although ADCs have shown efficacy in cancer treatment,their application in solid tumors is hindered by their high molecular weight,poor tumor penetration,and release of cytotoxic molecules.Therefore,a recombinant immunotoxin was devel-oped based on a shark-derived variable domain of immunoglobulin new antigen receptor(VNAR)anti-body.VNARs are only one-tenth the size of IgG antibodies and possess remarkable tissue penetration capabilities and high stability.In this study,a shark VNAR phage display library was created,leading to the identification of shark VNAR-5G8 that targets TROP-2.VNAR-5G8 exhibited a high affinity and cellular internalization ability towards cells expressing high levels of TROP-2.Epitope analysis revealed that VNAR-5G8 recognizes a hidden epitope consisting of CRD and TY-1 on TROP-2.Subsequently,VNAR-5G8 was fused with a truncated form of Pseudomonas exotoxin(PE38)to create the recombinant immunotoxin(5G8-PE38),which exhibited significant anti-tumor activity in vitro and in vivo.Overall,this study highlights the promise of 5G8-PE38 as a valuable candidate for cancer therapy.
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