{"title":"Therapeutic potential of Parkin and its regulation in Parkinson's disease.","authors":"N Safreena, Indu C Nair, Goutam Chandra","doi":"10.1016/j.bcp.2024.116600","DOIUrl":"https://doi.org/10.1016/j.bcp.2024.116600","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the midbrain substantia nigra, resulting in motor and non-motor symptoms. While the exact etiology of PD remains elusive, a growing body of evidence suggests that dysfunction in the parkin protein plays a pivotal role in the pathogenesis of the disease. Parkin is an E3 ubiquitin ligase that ubiquitinates substrate proteins to control a number of crucial cellular processes including protein catabolism, immune response, and cellular apoptosis.While autosomal recessive mutations in the PARK2 gene, which codes for parkin, are linked to an inherited form of early-onset PD, heterozygous mutations in PARK2 have also been reported in the more commonly occurring sporadic PD cases. Impairment of parkin's E3 ligase activity is believed to play a pathogenic role in both familial and sporadic forms of PD.This article provides an overview of the current understanding of the mechanistic basis of parkin's E3 ligase activity, its major physiological role in controlling cellular functions, and how these are disrupted in familial and sporadic PD. The second half of the manuscript explores the currently available and potential therapeutic strategies targeting parkin structure and/or function in order to slow down or mitigate the progressive neurodegeneration in PD.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Interleukin-6 in non-infectious uveitis: Biology, experimental evidence and treatment strategies","authors":"","doi":"10.1016/j.bcp.2024.116605","DOIUrl":"10.1016/j.bcp.2024.116605","url":null,"abstract":"<div><div>Uveitis is the leading cause of visual impairment worldwide. Interleukin-6 (IL-6), which is upregulated in response to inflammation, is one of the most important inflammatory cytokines associated with uveitis. Two major IL-6 receptors (IL-6R) mediate the pro-inflammatory and anti-inflammatory biological effects of IL-6. This review summarized multiple perspectives on the mechanism of IL-6-mediated uveitis, based on experimental evidence from clinical and animal models. It includes discussions on the roles of the downstream IL-6 signaling pathway, immunocytes, and the blood-retinal barrier. Therapeutic strategies aimed at blocking the action of IL-6 have progressed in clinical practice. However, due to the adverse events associated with existing biologics including infections, drugs that selectively inhibit intraocular IL-6 still require further development. The novel concept of converting the pro-inflammatory effects of IL-6 into protective effects also requires further research. In addition, the relationship between the <em>trans</em>-presentation of IL-6R and T-helper17 cells in uveitis remains unexplored. This review aims to consolidate our current understanding of the biology, signaling pathways, experimental models, and immune pathogenesis related to IL-6 and uveitis. We also discuss clinical strategies focused on blocking IL-6 as a treatment for uveitis. Targeting IL-6 provides unlimited potential for improving the diagnosis, treatment, and prognosis of uveitis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting fibroblast activation protein with chimeric antigen receptor macrophages.","authors":"Yizhi Mao, Chen Yao, Shimeng Zhang, Qi Zeng, Jing Wang, Chunjie Sheng, Shuai Chen","doi":"10.1016/j.bcp.2024.116604","DOIUrl":"https://doi.org/10.1016/j.bcp.2024.116604","url":null,"abstract":"<p><p>Under the rapid advancement of chimeric antigen receptor T cell (CAR-T) technology, CAR-macrophages (CAR-Ms) are also being developed currently in the pre-clinical stage and have been shown to inhibit tumor growth in several mouse tumor models. Fibroblast activation protein (FAP) is a type II transmembrane serine protease, which is expressed in stromal fibroblasts of over 90 % of common human epithelial cancers and is upregulated in fibrotic diseases of the liver, lung and colon, etc. In this study, we firstly constructed FAP-CAR macrophages to target FAP<sup>+</sup> cells through in vitro phagocytosis assays. In subsequent in vivo assays, we discovered that FAP-CAR-ΔZETA bone marrow-derived macrophages (BMDMs) rather than FAP-CAR BMDMs, exhibited a pronounced anti-tumor effect in mouse subcutaneous MC38 colon cancer model. In addition, FAP-CAR and FAP-CAR-ΔZETA BMDMs therapy could effectively improve CCl<sub>4</sub>-induced liver fibrosis in mice. Collectively CAR-Ms targeting FAP demonstrated great therapeutic potential in cancer and liver fibrosis therapy.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Epoxytiglianes induce keratinocyte wound healing responses via classical protein kinase C activation to promote skin re-epithelialization","authors":"","doi":"10.1016/j.bcp.2024.116607","DOIUrl":"10.1016/j.bcp.2024.116607","url":null,"abstract":"<div><div>Epoxytiglianes are a novel class of diterpene esters. The prototype epoxytigliane, EBC-46 (tigilanol tiglate), is a potent anti-cancer agent in clinical development for local treatment of a range of human and animal tumors. EBC-46 also consistently promotes wound re-epithelialization at the treatment sites, mediated via activation of classical protein kinase C (PKC) isoforms. We have previously shown that epoxytiglianes stimulate proliferative and wound repopulation responses in immortalized human skin keratinocytes (HaCaTs) <em>in vitro</em>, abrogated by pan-PKC inhibitor, bisindolylmaleimide-1. In this study, we further investigate the specific PKC isoforms responsible for inducing such wound healing responses, following HaCaT treatment with 1.51 nM-15.1 µM EBC-46 or analogue, EBC-211. Classical PKC inhibition by GӦ6976 (1 μM), significantly attenuated epoxytigliane induced, HaCaT proliferation and wound repopulation at all epoxytigliane concentrations. PKC-βI/-βII isoform inhibition by enzastaurin (1 μM), significantly inhibited HaCaT proliferation and wound repopulation responses induced by both epoxytiglianes, especially at 1.51–151 nM. PKC-α inhibitor, Ro 31–8220 mesylate (10 nM), exerted lesser inhibitory effects on HaCaT responses. Epoxytigliane changes in key keratin (KRT17) and cell cycle (cyclin B1, CDKN1A) protein levels were partly attenuated by GӦ6976 and enzastaurin. GӦ6976 also inhibited increases in matrix metalloproteinase (MMP-1, MMP-7, MMP-10) activities. Phospho-PKC (p-PKC) studies confirmed that epoxytiglianes transiently activated classical PKC isoforms (p-PKCα, p-PKC-βI/-βII, p-PKCγ) in a dose- and time-dependent manner. By identifying how epoxytiglianes stimulate classical PKCs to facilitate keratinocyte healing responses and re-epithelialization, these findings support further epoxytigliane development as topical therapeutics for clinical situations involving impaired re-epithelialization, such as non-healing wounds in skin.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Acetyl tributyl citrate attenuates 5-fluorouracil-induced inflammation, oxidative stress, and apoptosis in human keratinocytes","authors":"","doi":"10.1016/j.bcp.2024.116606","DOIUrl":"10.1016/j.bcp.2024.116606","url":null,"abstract":"<div><div>5-Fluorouracil (5-FU) is a commonly used chemotherapy drug that effectively destroys cancer cells. Despite its widespread use and efficacy, it also presents considerable challenges, particularly with adverse effects on rapidly dividing normal cells, such as keratinocytes. These detrimental effects are attributed to inflammatory, oxidative, and apoptotic potentials, leading to severe skin disorders. Due to the lack of specific remedies for 5-FU-induced dermatological side effects, conventional treatments are applied instead, which provide limited relief and have drawbacks. This study investigated the impact of acetyl tributyl citrate (ATBC) in 5-FU-treated human keratinocytes. The findings indicated that ATBC substantially reduced inflammation caused by 5-FU, as demonstrated by nuclear translocation of nuclear factor kappa B and expression of its downstream genes, including tumor necrosis factor, interleukin 1 beta (IL1B), and IL6. ATBC also markedly decreased oxidative stress, indicated by reactive oxygen species levels and the antioxidant gene expression such as superoxide dismutase 1 (SOD1), SOD2, and heme oxygenase 1 in 5-FU-treated cells. Furthermore, ATBC attenuated 5-FU-induced apoptosis, as determined by lactate dehydrogenase release and Annexin V/propidium iodide flow cytometry, with the potential involvement of interferon-related genes. Following this, protein kinase C delta was predicted as a possible molecular target of ATBC. These findings propose ATBC as a therapeutic agent for managing the cutaneous side effects associated with 5-FU treatment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting IL-17 and its receptors: A feasible way for natural herbal medicines to modulate fibroblast-like synoviocytes in rheumatoid arthritis","authors":"","doi":"10.1016/j.bcp.2024.116598","DOIUrl":"10.1016/j.bcp.2024.116598","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is characterized by processive synovial hyperplasia and abnormal proliferation of fibroblast-like synoviocytes (FLSs), and can eventually lead to progressive joint destruction. Increasing evidence has demonstrated that cytokines play pivotal roles in the pathogenesis of RA. In particular, the production of interleukin (IL)-17 by T helper 17 (Th17) cells is closely associated with the development of RA, and inhibition of IL-17/IL-17R could regulate the production of inflammatory factors by FLSs, which may be a feasible way to reduce inflammation and bone destruction in RA. Currently, accumulating evidence suggests that the utilization of natural herbal medicines is advantageous in the management of RA. In our present paper, a comprehensive reference search was conducted of the classic Materia Medica books, literature, online databases, academic search engines, and MS. or Ph. D theses. In conclusion, natural herbal medicines with antirheumatic activities that modulate FLSs by targeting IL-17/IL-17R were summarized. Furthermore, we also discuss the limitations and potential research directions for the future development of natural herbal medicines as candidate drugs for RA management in the clinic.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Protective role of 2-aminothiazole derivative against ethanol-induced teratogenic effects in-vivo zebrafish","authors":"","doi":"10.1016/j.bcp.2024.116601","DOIUrl":"10.1016/j.bcp.2024.116601","url":null,"abstract":"<div><div>Teratology investigates the origins of congenital disabilities, often linked to environmental factors such as ethanol (EtOH) exposure. Ethanol at 150 μM has been associated with teratogenic effects, oxidative stress, immunological responses, and endocrine disruptions. Fetal alcohol spectrum disorder (FASD) arises from maternal alcohol consumption during pregnancy, leading to developmental delays and cognitive impairment. Due to their diverse therapeutic applications, amino thiazole derivatives are crucial in drug development. This study aimed to determine whether the 2-amino thiazole derivative, notably the 1-(4-chlorophenyl)-N-(6-nitrobenzo[d]thiazol-2-yl)ethan-1-imine (N4) compound, reduces teratogenic effects induced by embryonic EtOH exposure in a zebrafish model. Teratogenic effects, mortality, locomotion behaviour, oxidative stress, gene expression, and tissue damage were evaluated in larvae over a 7-day experimental period using three treatment concentrations (50, 100, and 150 μM). Results showed that EtOH induced morphological defects in the head, eyes, and body length of exposed larvae, along with behavioural abnormalities and oxidative damage. N4 effectively mitigated these toxic effects in a concentration-dependent manner, reducing oxidative damage, preventing teratogenic effects, and averting tissue damage induced by EtOH exposure. This study highlights the potential of N4 to enhance antioxidant and anti-inflammatory effects against ethanol-induced oxidative stress, offering promising therapeutic strategies for FASD treatment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Fat mass and obesity-associated protein alleviates cerebral ischemia/reperfusion injury by inhibiting ferroptosis via miR-320-3p/SLC7A11 axis","authors":"","doi":"10.1016/j.bcp.2024.116603","DOIUrl":"10.1016/j.bcp.2024.116603","url":null,"abstract":"<div><div>Fat mass and obesity-associated protein (FTO) is a demethylase and has recently been found to have a protective effect in acute ischemic stroke (AIS), but the underlying mechanism is unclear to a large extent. New studies have found that the expression of certain miRNAs may be affected by N6-methyladenosine (m6A) levels. Here, using high-throughput sequencing and quantitative polymerase chain reaction, we found miR-320-3p was significantly up-regulated in AIS patients. miR-320-3p aggravated the neurobehavioral manifestation, infarct volume and histopathology of middle cerebral artery occlusion/reperfusion model mice. Mechanically, miR-320-3p binds to the 3′ untranslated region of solute carrier family 7 member 11 (SLC7A11) mRNA, promoting oxidative stress and ferroptosis induced by oxygen-glucose deprivation/reoxygenation in neurons. FTO inhibited the m6A methylation of the primary transcript pri-miR-320 and the maturation of miR-320-3p, thus having a protective effect on cerebral ischemia/reperfusion injury after AIS. Clinically, we also confirmed the down-regulation of FTO and SLC7A11 mRNA in the peripheral blood of AIS patients and their correlation with the expression of miR-320-3p. Our study found that FTO inhibits ferroptosis through miR-320-3p/SLC7A11 axis in an m6A-dependent manner, and thus has a protective effect on cerebral ischemic reperfusion injury. Our results provided a promising therapeutic target of cerebral ischemia/reperfusion injury after AIS.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Insights into the modulatory effects of host-gut microbial xanthine co-metabolism on high-fat diet-fed mice","authors":"","doi":"10.1016/j.bcp.2024.116596","DOIUrl":"10.1016/j.bcp.2024.116596","url":null,"abstract":"<div><div>Gut microbiota-mediated endobiotic and xenobiotic metabolism play crucial roles in disease progression, and drug therapy/toxicity. Our recent study suggested that gut microbiota-mediated xanthine metabolism is correlated with resistance to high-fat diet (HFD)-induced obesity. Here, we explored the role of host-gut microbial xanthine co-metabolism in the prevention and treatment of HFD-induced obesity by orally administration of <em>Bifidobacterium longum</em>, xanthine, and a xanthine oxidase inhibitor (topiroxostat). The findings indicate that xanthine exhibits a significantly protective effect against HFD-induced obesity. While <em>B. longum</em>, xanthine, and topiroxostat did not alleviate the dysbiosis of the weight and glucose metabolism of HFD-induced obesity (DIO) and obesity resistance (DIR) mice. 16S rRNA sequencing analyses revealed that treatments with <em>B. longum</em> significantly altered gut microbiota composition in HFD-fed and DIO mice. Microbial interaction network analysis revealed several Bacteroidetes species, such as <em>Amulumruptor caecigallinarius</em> and <em>Muribaculum intestinale</em>, as keystone taxa that were notably enriched by <em>B. longum</em>. Untargeted metabolomics analysis implied that xanthine might serve as a crucial molecule in regulating body weight, exerting a preventive effect on HFD-induced obesity. This study offers new perspectives on the influence of host-gut microbial xanthine co-metabolism on HFD-fed mice and emphasizes the promising role of xanthine in promoting weight loss</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Defects of parvalbumin-positive interneurons are implicated in psychiatric disorders","authors":"","doi":"10.1016/j.bcp.2024.116599","DOIUrl":"10.1016/j.bcp.2024.116599","url":null,"abstract":"<div><div>Psychiatric disorders are a common cause of severe long-term disability and socioeconomic burden worldwide. Although our understanding of these disorders has advanced substantially over the last few years, little has changed the standards of care for these illnesses. Fast-spiking parvalbumin-positive interneurons (PVIs), a subpopulation of gamma-aminobutyric acid (GABA)ergic interneurons, are widely distributed in the hippocampus and have been reported to play an important role in various mental disorders. However, the mechanisms underlying the regulation of the molecular networks relevant to depression and schizophrenia (SCZ) are unknown. Here, we discuss the functions of PVIs in psychiatric disorders, including depression and SCZ. After reviewing several studies, we concluded that dysfunction in PVIs could cause depression-like behavior, as well as cognitive categories in SCZ, which might be mediated in large part by greater synaptic variability. In summary, this scientific review aims to discuss the current knowledge regarding the function of PVIs in depression and SCZ. Moreover, we highlight the importance of neurogenesis and synaptic plasticity in the pathogenesis of depression and SCZ, which seem to be mediated by PVIs activity. These findings provide a better understanding of the role of PVIs in psychiatric disorders.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}