Pyroptosis,ferroptosis,and autophagy in spinal cord injury:regulatory mechanisms and therapeutic targets

Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.

Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

Mechanisms and therapeutic targets of ferroptosis: Implications for nanomedicine design

Ferroptosis is a nonapoptotic form of cell death and differs considerably from the well-known forms of cell death in terms of cell morphology,genetics,and biochemistry.The three primary pathways for cell ferroptosis are system Xc^(-)/glutathione peroxidase 4(GPX4),lipid metabolism,and ferric metabolism.Since the discovery of ferroptosis,mounting evidence has revealed its critical regulatory role in several diseases,especially as a novel potential target for cancer therapy,thereby attracting increasing attention in the fields of tumor biology and anti-tumor therapy.Accordingly,broad prospects exist for identifying ferroptosis as a potential therapeutic target.In this review,we aimed to systematically summarize the activation and defense mechanisms of ferroptosis,highlight the therapeutic targets,and discuss the design of nanomedicines for ferroptosis regulation.In addition,we opted to present the advantages and disadvantages of current ferroptosis research and provide an optimistic vision of future directions in related fields.Overall,we aim to provide new ideas for further ferroptosis research and inspire new strategies for disease diagnosis and treatment.

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Mitophagy in intracerebral hemorrhage:a new target for therapeutic intervention

Intracerebral hemorrhage is a life-threatening condition with a high fatality rate and severe sequelae.However,there is currently no treatment available for intracerebral hemorrhage,unlike for other stroke subtypes.Recent studies have indicated that mitochondrial dysfunction and mitophagy likely relate to the pathophysiology of intracerebral hemorrhage.Mitophagy,or selective autophagy of mitochondria,is an essential pathway to preserve mitochondrial homeostasis by clearing up damaged mitochondria.Mitophagy markedly contributes to the reduction of secondary brain injury caused by mitochondrial dysfunction after intracerebral hemorrhage.This review provides an overview of the mitochondrial dysfunction that occurs after intracerebral hemorrhage and the underlying mechanisms regarding how mitophagy regulates it,and discusses the new direction of therapeutic strategies targeting mitophagy for intracerebral hemorrhage,aiming to determine the close connection between mitophagy and intracerebral hemorrhage and identify new therapies to modulate mitophagy after intracerebral hemorrhage.In conclusion,although only a small number of drugs modulating mitophagy in intracerebral hemorrhage have been found thus far,most of which are in the preclinical stage and require further investigation,mitophagy is still a very valid and promising therapeutic target for intracerebral hemorrhage in the long run.

Research advancements in nanoparticles and cell-based drug delivery systems for the targeted killing of cancer cells

Nanotechnology in cancer therapy has significantly advanced treatment precision,effectiveness,and safety,improving patient outcomes and personalized care.Engineered smart nanoparticles and cell-based therapies are designed to target tumor cells,precisely sensing the tumor microenvironment(TME)and sparing normal cells.These nanoparticles enhance drug accumulation in tumors by solubilizing insoluble compounds or preventing their degradation,and they can also overcome therapy resistance and deliver multiple drugs simultaneously.Despite these benefits,challenges remain in patient-specific responses and regulatory approvals for cell-based or nanoparticle therapies.Cell-based drug delivery systems(DDSs)that primarily utilize the immune-recognition principle between ligands and receptors have shown promise in selectively targeting and destroying cancer cells.This review aims to provide a comprehensive overview of various nanoparticle and cell-based drug delivery system types used in cancer research.It covers approved and experimental nanoparticle therapies,including liposomes,micelles,protein-based and polymeric nanoparticles,as well as cell-based DDSs like macrophages,T-lymphocytes,dendritic cells,viruses,bacterial ghosts,minicells,SimCells,and outer membrane vesicles(OMVs).The review also explains the role of TME and its impact on developing smart DDSs in combination therapies and integrating nanoparticles with cell-based systems for targeting cancer cells.By detailing DDSs at different stages of development,from laboratory research to clinical trials and approved treatments,this review provides the latest insights and a collection of valuable citations of the innovative strategies that can be improved for the precise treatment of cancer.

Non-coding RNAs as therapeutic targets in cancer and its clinical application

Cancer genomics has led to the discovery of numerous oncogenes and tumor suppressor genes that play critical roles in cancer development and progression.Oncogenes promote cell growth and proliferation,whereas tumor suppressor genes inhibit cell growth and division.The dysregulation of these genes can lead to the development of cancer.Recent studies have focused on non-coding RNAs(ncRNAs),including circular RNA(circRNA),long non-coding RNA(lncRNA),and microRNA(miRNA),as therapeutic targets for cancer.In this article,we discuss the oncogenes and tumor suppressor genes of ncRNAs associated with different types of cancer and their potential as therapeutic targets.Here,we highlight the mechanisms of action of these genes and their clinical applications in cancer treatment.Understanding the molecular mechanisms underlying cancer development and identifying specific therapeutic targets are essential steps towards the development of effective cancer treatments.

Gene targets with therapeutic potential in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the third leading cause of cancer-related deaths worldwide.Major treatments include liver transplantation,resection,and chemotherapy,but the 5-year recurrence rate remains high.Late diagnosis often prevents surgical intervention,contributing to poor patient survival rates.Carcinogenesis in HCC involves genetic alterations that drive the transformation of normal cells into malignant ones.Enhancer of zeste homolog 2(EZH2),a key regulator of cell cycle progression,is frequently upregulated in HCC and is associated with advanced stages and poor prognosis,making it a potential biomarker.Additionally,signal transducer and activator of transcription 3,which binds to EZH2,affects disease staging and outcomes.Targeting EZH2 presents a promising therapeutic strategy.On the other hand,abnormal lipid metabolism is a hallmark of HCC and impacts prognosis.Fatty acid binding protein 5 is highly expressed in HCC tissues and correlates with key oncogenes,suggesting its potential as a biomarker.Other genes such as guanine monophosphate synthase,cell division cycle associated 5,and epidermal growth factor receptor provide insights into the molecular mechanisms of HCC,offering potential as biomarkers and therapeutic targets.

A Medicinal and Edible Plant Crocus sativus L.and Its Therapeutic Effects on Cardiovascular and Cerebrovascular Diseases

This paper introduces the biological characteristics,medicinal value,chemical component,and pharmacological effects of Crocus sativus L.,and explores its therapeutic effects on cardiovascular and cerebrovascular diseases such as angina pectoris and coronary heart disease.

Promise and challenges on the horizon of MET-targeted cancer therapeutics

MET(MNNG HOS transforming gene) is one of the receptor tyrosine kinases whose activities are frequently altered in human cancers, and it is a promising therapeutic target. MET is normally activated by its lone ligand, hepatocyte growth factor(HGF), eliciting its diverse biological activities that are crucial for development and physiology. Alteration of the HGF-MET axis results in inappropriate activation of a cascade of intracellular signaling pathways that contributes to hallmark cancer events including deregulated cell proliferation and survival, angiogenesis, invasion, andmetastasis. Aberrant MET activation results from autocrine or paracrine mechanisms due to overexpression of HGF and/or MET or from a ligand-independent mechanism caused by activating mutations or amplification of MET. The literature provides compelling evidence for the role of MET signaling in cancer development and progression. The finding that cancer cells often use MET activation to escape therapies targeting other pathways strengthens the argument for MET-targeted therapeutics. Diverse strategies have been explored to deactivate MET signaling, and compounds and biologics targeting the MET pathway are in clinical development. Despite promising results from various clinical trials, we are still waiting for true MET-targeted therapeutics in the clinic. This review will explore recent progress and hurdles in the pursuit of METtargeted cancer drugs and discuss the challenges in such development.

A clue to potential therapeutic targets: application of integrative medicine and bioinformatics

More and more evidence show that the targets of traditional Chinese medicine are a resource pool that contributes to the modern medicine. A key aspect of medicine research is to address the issue how to look for a clue of potential therapeutic molecular targets by interdisciplinary approaches. With the development of high throughput technology, a considerable amount of data has been emerging. The application of these big data is not so efficient as the generation of them. This paper attempts to show that interdisciplinary analysis contributes to the discovery of targets at the initial stage of drug research, indicating that it is necessary to explore the drug research and development with interdisciplinary approaches between integrative medicine and bioinformatics.

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches.Molecular neuro-oncologyhas now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targetedtherapy.Activity of the phosphoinositide 3;kinase(PI3K)/Akt pathway is often upregulated in brain tumors due to excessive stimu-lation by growth factor receptors and Ras.Loss of function of the tumor suppressor gene PTEN also frequently contributesto

Push forward LC-MS-based therapeutic drug monitoring and pharmacometabolomics for anti-tuberculosis precision dosing and comprehensive clinical management

The spread of tuberculosis(TB),especially multidrug-resistant TB and extensively drug-resistant TB,has strongly motivated the research and development of new anti-TB drugs.New strategies to facilitate drug combinations,including pharmacokinetics-guided dose optimization and toxicology studies of first-and second-line anti-TB drugs have also been introduced and recommended.Liquid chromatography-mass spectrometry(LC-MS)has arguably become the gold standard in the analysis of both endo-and exo-genous compounds.This technique has been applied successfully not only for therapeutic drug monitoring(TDM)but also for pharmacometabolomics analysis.TDM improves the effectiveness of treatment,reduces adverse drug reactions,and the likelihood of drug resistance development in TB patients by determining dosage regimens that produce concentrations within the therapeutic target window.Based on TDM,the dose would be optimized individually to achieve favorable outcomes.Pharmacometabolomics is essential in generating and validating hypotheses regarding the metabolism of anti-TB drugs,aiding in the discovery of potential biomarkers for TB diagnostics,treatment monitoring,and outcome evaluation.This article highlighted the current progresses in TDM of anti-TB drugs based on LC-MS bioassay in the last two decades.Besides,we discussed the advantages and disadvantages of this technique in practical use.The pressing need for non-invasive sampling approaches and stability studies of anti-TB drugs was highlighted.Lastly,we provided perspectives on the prospects of combining LC-MS-based TDM and pharmacometabolomics with other advanced strategies(pharmacometrics,drug and vaccine developments,machine learning/artificial intelligence,among others)to encapsulate in an all-inclusive approach to improve treatment outcomes of TB patients.

MicroRNAs in Parkinson's disease and emerging therapeutic targets

Parkinson＇s disease（PD） is the second most common age-related neurodegenerative disorder, with the clinical main symptoms caused by a loss of dopaminergic neurons in the substantia nigra, corpus striatum and brain cortex. Over 90% of patients with PD have sporadic PD and occur in people with no known family history of the disorder. Currently there is no cure for PD. Treatment with medications to increase dopamine relieves the symptoms but does not slow down or reverse the damage to neurons in the brain. Increasing evidence points to inflammation as a chief mediator of PD with inflammatory response mechanisms, involving microglia and leukocytes, activated following loss of dopaminergic neurons. Oxidative stress is also recognized as one of the main causes of PD, and excessive reactive oxygen species（ROS） and reactive nitrogen species can lead to dopaminergic neuron vulnerability and eventual death. Micro RNAs control a range of physiological and pathological functions, and may serve as potential targets for intervention against PD to mitigate damage to the brain. Several studies have demonstrated that micro RNAs can regulate oxidative stress and prevent ROS-mediated damage to dopaminergic neurons, suggesting that specific micro RNAs may be putative targets for novel therapeutic strategies in PD. Recent human and animal studies have identified a large number of dysregulated micro RNAs in PD brain tissue samples, many of which were downregulated. The dysregulated micro RNAs affect downstream targets such as SNCA, PARK2, LRRK2, TNFSF13 B, LTA, SLC5 A3, PSMB2, GSR, GBA, LAMP-2 A, HSC. Apart from one study, none of the studies reviewed had used agomirs or antagomirs to reverse the levels of downregulated or upregulated micro RNAs, respectively, in mouse models of PD or with isolated human or mouse dopaminergic cells. Further large-scale studies of brain tissue samples collected with short postmortem interval from human PD patients are warranted to provide more information on the micro RNA profiles in different brain regions and to test for gender differences.

CXC chemokines and chemokine receptors in gastric cancer: From basic findings towards therapeutic targeting

Gastric cancer is the fourth most common cancer,and the second-highest cause of cancer-related deaths worldwide.Despite extensive research to identify novel diagnostic and therapeutic agents,patients with advanced gastric cancer suffer from a poor quality of life and poor prognosis,and treatment is dependent mainly on conventional cytotoxic chemotherapy.To improve the quality of life and survival of gastric cancer patients,a better understanding of the underlying molecular pathologies,and their application towards the development of novel targeted therapies,is urgently needed.Chemokines are a group of small proteins associated with cytoskeletal rearrangements,the directional migration of several cell types during development and physiology,and the host immune response via interactions with G-protein coupled receptors.There is also growing evidence to suggest that chemokines not only play a role in the immune system,but are also involved in the development and progression of tumors.In gastric cancer,CXC chemokines and chemokine receptors regulate the trafficking of cells in and out of the tumor microenvironment.CXC chemokines and their receptors can also directly influence tumorigenesis by modulating tumor transformation,survival,growth,invasion and metastasis,as well as indirectly by regulating angiogenesis,and tumor-leukocyte interactions.In this review,we will focus on the roles of CXC chemokines and their receptors in the development,progression,and metastasis of gastric tumors,and discuss their therapeutic potential for gastric cancer.

Exosomes: a novel therapeutic target for Alzheimer's disease?

Extracellular exosomes are formed inside the cytoplasm of cells in compartments known as multivesicular bodies. Thus, exosomes contain cytoplasmic content. Multivesicular bodies fuse with the plasma membrane and release exosomes into the extracellular environment. Comprehensive research suggests that exosomes act as both inflammatory intermediaries and critical inducers of oxidative stress to drive progression of Alzheimer＇s disease. An important role of exosomes in Alzheimer＇s disease includes the formation of neurofibrillary tangles and beta-amyloid production, clearance, and accumulation. In addition, exosomes are involved in neuroinflammation and oxidative stress, which both act as triggers for beta-amyloid pathogenesis and tau hyperphosphorylation. Further, it has been shown that exosomes are strongly associated with beta-amyloid clearance. Thus, effective measures for regulating exosome metabolism may be novel drug targets for Alzheimer＇s disease.

Aryl hydrocarbon receptor dynamics in esophageal squamous cell carcinoma:From immune modulation to therapeutic opportunities

Esophageal squamous cell carcinoma(ESCC)is a substantial global health burden.Immune escape mechanisms are important in ESCC progression,enabling cancer cells to escape the surveillance of the host immune system.One key player in this process is the Aryl Hydrocarbon Receptor(AhR),which influences multiple cellular processes,including proliferation,differentiation,metabolism,and immune regulation.Dysregulated AhR signaling participates in ESCC development by stimulating carcinogenesis,epithelial-mesenchymal transition,and immune escape.Targeting AhR signaling is a potential therapeutic approach for ESCC,with AhR ligands showing efficacy in preclinical studies.Additionally,modification of AhR ligands and combination therapies present new opportunities for therapeutic intervention.This review aims to address the knowledge gap related to the role of AhR signaling in ESCC pathogenesis and immune escape.

MicroRNAs and liver cancer associated with iron overload:Therapeutic targets unravelled

Primary liver cancer is a global disease that is on the increase.Hepatocellular carcinoma(HCC)accounts for most primary liver cancers and has a notably low survival rate,largely attributable to late diagnosis,resistance to treatment,tumour recurrence and metastasis.MicroRNAs(miRNAs/miRs)are regulatory RNAs that modulate protein synthesis.miRNAs are involved in several biological and pathological processes including the development and progression of HCC.Given the poor outcomes with current HCC treatments,miRNAs represent an important new target for therapeutic intervention.Several studies have demonstrated their role in HCC development and progression.While many risk factors underlie the development of HCC,one process commonly altered is iron homeostasis.Iron overload occurs in several liver diseases associated with the development of HCC including Hepatitis C infection and the importance of miRNAs in iron homeostasis and hepatic iron overload is well characterised.Aberrant miRNA expression in hepatic fibrosis and injury response have been reported,as have dysregulated miRNA expression patterns affecting cell cycle progression,evasion of apoptosis,invasion and metastasis.In2009,miR-26a delivery was shown to prevent HCC progression,highlighting its therapeutic potential.Several studies have since investigated the clinical potential of other miRNAs with one drug,Miravirsen,currently in phaseⅡclinical trials.miRNAs also have potential as biomarkers for the diagnosis of HCC and to evaluate treatment efficacy.Ongoing studies and clinical trials suggest miRNA-based treatments and diagnostic methods will have novel clinical applications for HCC in the coming years,yielding improved HCC survival rates and patient outcomes.

MicroRNAs as diagnostic markers and therapeutic targets for traumatic brain injury

Traumatic brain injury （TBI） is characterized by primary damage to the brain from the external mechanical force and by subsequent secondary injury due to various molecular and pathophysiological responses that eventually lead to neuronal cell death. Secondary brain injury events may occur minutes, hours, or even days after the trauma, and provide valuable therapeutic targets to prevent further neuronal degeneration. At the present time, there is no effective treatment for TBI due, in part, to the widespread impact of numerous complex secondary biochemical and pathophysiological events occurring at different time points following the initial injury. MicroRNAs control a range of physiological and pathological functions such as develop- ment, differentiation, apoptosis and metabolism, and may serve as potential targets for progress assessment and intervention against TBI to mitigate secondary damage to the brain. This has implications regarding improving the diagnostic accuracy of brain impairment and long-term outcomes as well as potential novel treatments. Recent human studies have identified specific microRNAs in serum/plasma （miR-425-p, -21, -93, -191 and -499） and cerebro-spinal fluid （CSF） （miR-328, -362-3p, -451, -486a） as possible indicators of the diagnosis, severity, and prognosis of TBI. Experimental animal studies have examined specific microRNAs as biomarkers and therapeutic targets for moderate and mild TBI （e.g., miR-21, miR-23b）. MicroRNA profil- ing was altered by voluntary exercise. Differences in basal microRNA expression in the brain of adult and aged animals and alterations in response to TBI （e.g., miR-21） have also been reported. Further large-scale studies with TBI patients are needed to provide more information on the changes in microRNA profiles in different age groups （children, adults, and elderly）.

MicroRNAs as disease progression biomarkers and therapeutic targets in experimental autoimmune encephalomyelitis model of multiple sclerosis

Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination.Focal demyelination is associated with relapsing-remitting multiple sclerosis,while progressive forms of the disease show axonal degeneration and neuronal loss.The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity.MicroRNAs(miRNAs)are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases.A review of recent studies with the experimental autoimmune encephalomyelitis animal model(mostly female mice 6–12 weeks of age)has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset(asymptomatic)stage when assessed in blood plasma and urine exosomes,and spinal cord tissue.The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes,brain and spinal cord tissue,and at the post-peak(chronic)stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue.Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease.Interestingly,experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a,miR-23b,miR-497,miR-26a,and miR-20b,or by suppression of miR-182,miR-181c,miR-223,miR-155,and miR-873.Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course.Additionally,studies should be performed with male mice of a similar age,and with aged male and female mice.