Pharmacology & Therapeutics最新文献

Due to the contribution of highly homologous acetyltransferases CBP and p300 to transcription elevation of oncogenes and other cancer promoting factors, these enzymes emerge as possible epigenetic targets of anticancer therapy. Extensive efforts in search for small molecule inhibitors led to development of compounds targeting histone acetyltransferase catalytic domain or chromatin-interacting bromodomain of CBP/p300, as well as dual BET and CBP/p300 inhibitors. The promising anticancer efficacy in in vitro and mice models led CCS1477 and NEO2734 to clinical trials. However, none of the described inhibitors is perfectly specific to CBP/p300 since they share similarity of a key functional domains with other enzymes, which are critically associated with cancer progression and their antagonists demonstrate remarkable clinical efficacy in cancer therapy. Therefore, we revise the possible and clinically relevant off-targets of CBP/p300 inhibitors that can be blocked simultaneously with CBP/p300 thereby improving the anticancer potential of CBP/p300 inhibitors and pharmacokinetic predicting data such as absorption, distribution, metabolism, excretion (ADME) and toxicity.

Cytochrome P450 2 J2 (CYP2J2) is primarily expressed extrahepatically and is the predominant epoxygenase in human cardiac tissues. This highlights its key role in the metabolism of endogenous substrates. Significant scientific interest lies in cardiac CYP2J2 metabolism of arachidonic acid (AA), an omega-6 polyunsaturated fatty acid, to regioisomeric bioactive epoxyeicosatrienoic acid (EET) metabolites that show cardioprotective effects including regulation of cardiac electrophysiology. From an in vitro perspective, the accurate characterization of the kinetics of CYP2J2 metabolism of AA including its inhibition and inactivation by drugs could be useful in facilitating in vitro-in vivo extrapolations to predict drug-AA interactions in drug discovery and development. In this review, background information on the structure, regulation and expression of CYP2J2 in human heart is presented alongside AA and EETs as its endogenous substrate and metabolites. The in vitro and in vivo implications of the kinetics of this endogenous metabolic pathway as well as its perturbation via inhibition and inactivation by drugs are elaborated. Additionally, the role of CYP2J2-mediated metabolism of AA to EETs in cardiac electrophysiology will be expounded.

Chronic Obstructive Pulmonary Disease (COPD) is a multifaceted respiratory disorder characterized by progressive airflow limitation and systemic implications. It has become increasingly apparent that COPD exerts its influence far beyond the respiratory system, extending its impact to various organ systems. Among these, the musculoskeletal system emerges as a central player in both the pathogenesis and management of COPD and its associated comorbidities. Muscle dysfunction and osteoporosis are prevalent musculoskeletal disorders in COPD patients, leading to a substantial decline in exercise capacity and overall health. These manifestations are influenced by systemic inflammation, oxidative stress, and hormonal imbalances, all hallmarks of COPD. Recent research has uncovered an intricate interplay between COPD and musculoskeletal comorbidities, suggesting that muscle and bone tissues may cross-communicate through the release of signalling molecules, known as “myokines” and “osteokines”. We explored this dynamic relationship, with a particular focus on the role of the immune system in mediating the cross-communication between muscle and bone in COPD. Moreover, we delved into existing and emerging therapeutic strategies for managing musculoskeletal disorders in COPD. It underscores the development of personalized treatment approaches that target both the respiratory and musculoskeletal aspects of COPD, offering the promise of improved well-being and quality of life for individuals grappling with this complex condition. This comprehensive review underscores the significance of recognizing the profound impact of COPD on the musculoskeletal system and its comorbidities. By unravelling the intricate connections between these systems and exploring innovative treatment avenues, we can aspire to enhance the overall care and outcomes for COPD patients, ultimately offering hope for improved health and well-being.

The study aims to evaluate the benefits and potential adverse effects of transarterial chemoembolization (TACE) combined with lenvatinib and programmed cell death 1 (PD-1) protein inhibitors in the treatment of advanced hepatocellular carcinoma (HCC). A systematic literature search of several databases for relevant studies, published from inception up to May 2023, was performed. Clinical trials investigating TACE combined with lenvatinib and PD-1 inhibitors compared with other treatment regimens for advanced HCC were included. Data were pooled using fixed- or random-effects models and expressed as hazard ratios (HRs) or risk ratios (RRs) with corresponding 95% confidence interval (CI). Trial sequential analysis was used to determine whether the study results were sufficiently conclusive. Totally thirteen cohort studies comprising 1279 patients were included. The combined use of TACE, lenvatinib, and PD-1 inhibitors significantly improved overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) compared with other treatment regimens. The incidences of all-grade or grade ≥ 3 adverse events were comparable and did not differ significantly between the two groups. Prognostic factor analysis identified treatment options, portal vein tumor thrombus, extrahepatic metastasis, and Barcelona Clinic Liver Cancer (BCLC) stage as independent prognostic factors for OS. Extrahepatic metastasis, Child–Pugh score, and hepatic vein invasion emerged as independent prognostic factors for PFS. TSA suggested that the available data were adequate for drawing numerical conclusions regarding ORR and DCR. An approach combining TACE, lenvatinib, and PD-1 inhibitors appeared to offer significant improvements in OS, PFS, ORR, and DCR in patients with advanced HCC without significantly increasing the risk for all-grade adverse events.

Mouse models of disease play a pivotal role at all stages of cancer drug development. Cell-line derived subcutaneous tumour models are predominant in early drug discovery, but there is growing recognition of the importance of the more complex orthotopic and metastatic tumour models for understanding both target biology in the correct tissue context, and the impact of the tumour microenvironment and the immune system in responses to treatment. The aim of this review is to highlight the value that orthotopic and metastatic models bring to the study of tumour biology and drug development while pointing out those models that are most likely to be encountered in the literature. Important developments in orthotopic models, such as the increasing use of early passage patient material (PDXs, organoids) and humanised mouse models are discussed, as these approaches have the potential to increase the predictive value of preclinical studies, and ultimately improve the success rate of anticancer drugs in clinical trials.

Depression stands as a prominent contributor to global disability, entailing an elevated risk of suicide. Substantial evidence supports the notion that immune dysregulation may play a role in the development of depression and impede responses to antidepressant treatments. Immune dysregulation may cause depression in susceptible individuals through raising inflammatory responses. Differences in immune cell types and the release of pro-inflammatory mediators are observed in the blood and cerebrospinal fluid of patients with major depressive disorder, which is associated with neuroimmune dysfunction. Therefore, the interaction of peripheral and central immune targets in depression needs to be understood. Urgent attention is required for the development of innovative therapeutics directed at modulating immune responses for the treatment of depression. This review delineates the immune mechanisms involved in the pathogenesis of depression, assesses the therapeutic potential of immune system targeting for depression treatment, and deliberates on the merits and constraints of employing immunotherapy in the management of depression.

Histone methylation reader domains are protein modules that recognize specific histone methylation marks, such as methylated or unmethylated lysine or arginine residues on histones. These reader proteins play crucial roles in the epigenetic regulation of gene expression, chromatin structure, and DNA damage repair. Dysregulation of these proteins has been linked to various diseases, including cancer, neurodegenerative diseases, and developmental disorders. Therefore, targeting these proteins with chemical inhibitors has emerged as an attractive approach for therapeutic intervention, and significant progress has been made in this area. In this review, we will summarize the development of inhibitors targeting histone methylation readers, including MBT domains, chromodomains, Tudor domains, PWWP domains, PHD fingers, and WD40 repeat domains. For each domain, we will briefly discuss its identification and biological/biochemical functions, and then focus on the discovery of inhibitors tailored to target this domain, summarizing the property and potential application of most inhibitors. We will also discuss the structural basis for the potency and selectivity of these inhibitors, which will aid in further lead generation and optimization. Finally, we will also address the challenges and strategies involved in the development of these inhibitors. It should facilitate the rational design and development of novel chemical scaffolds and new targeting strategies for histone methylation reader domains with the help of this body of data.

Oncolytic adenoviruses (OAds), engineered Ads preferentially infect and lyse tumor cells, have attracted remarkable attention as immunotherapy weapons for the treatment of various malignancies. Despite hopeful successes in preclinical investigations and translation into clinical phases, they face some challenges that thwart their therapeutic effectiveness, including low infectivity of cancer cells, liver sequestration, pre-existing neutralizing antibodies, physical barriers to the spread of Ads, and immunosuppressive TME. Nanotechnology and nano-sized tools provide several advantages to overcome these limitations of OAds. Nano-sized tools could improve the therapeutic efficacy of OAds by enhancing infectivity and cellular uptake, targeting and protecting from pre-existing immune responses, masking and preventing liver tropism, and co-delivery with other therapeutic agents. Herein, we reviewed the constructs of various OAds and their application in clinical trials, as well as the limitations they have faced. Furthermore, we emphasized the potential applications of nanotechnology to solve the constraints of OAds to improve their anti-tumor activities.

Owing to renal reabsorption and the loss of uricase activity, uric acid (UA) is strictly maintained at a higher physiological level in humans than in other mammals, which provides a survival advantage during evolution but increases susceptibility to certain diseases such as gout. Although monosodium urate (MSU) crystal precipitation has been detected in different tissues of patients as a trigger for disease, the pathological role of soluble UA remains controversial due to the lack of causality in the clinical setting. Abnormal elevation or reduction of UA levels has been linked to some of pathological status, also known as U-shaped association, implying that the physiological levels of UA regulated by multiple enzymes and transporters are crucial for the maintenance of health. In addition, the protective potential of UA has also been proposed in aging and some diseases. Therefore, the role of UA as a double-edged sword in humans is determined by its physiological or non-physiological levels. In this review, we summarize biosynthesis, membrane transport, and physiological functions of UA. Then, we discuss the pathological involvement of hyperuricemia and hypouricemia as well as the underlying mechanisms by which UA at abnormal levels regulates the onset and progression of diseases. Finally, pharmacological strategies for urate-lowering therapy (ULT) are introduced, and current challenges in UA study and future perspectives are also described.

Melanoma is the most aggressive form of skin cancer, representing approximately 4% of all cutaneous neoplasms and accounting for up to 80% of deaths. Advanced stages of melanoma involve metastatic processes and are associated with high mortality and morbidity, mainly due to the rapid dissemination and heterogeneous responses to current therapies, including immunotherapy. Immune checkpoint inhibitors (ICIs) are currently used in the treatment of metastatic melanoma (MM) and despite being linked to an increase in patient survival, a high percentage of them still do not benefit from it. Accordingly, the number of therapeutic regimens for MM patients using ICIs either alone or in combination with other therapies has increased, together with the need for reliable biomarkers that can both predict and monitor response to ICIs.

In this context, circulating biomarkers, such as DNA, RNA, proteins, and cells, have emerged due to their ability to reflect disease status. Moreover, blood tests are minimally invasive and provide an attractive option to detect biomarkers, avoiding stressful medical procedures.

This systematic review aims to evaluate the possibility of a non-invasive biomarker signature that can guide therapeutic decisions. The studies reported here offer valuable insight into how circulating biomarkers can have a role in personalized treatments for melanoma patients receiving ICIs therapy, emphasizing the need for rigorous clinical trials to confirm findings and establish standardized procedures.