Biologics : Targets & Therapy最新文献

Statins have provided the first line treatment for hypercholesterolemia for over two decades with the addition of ezetimibe if low-density lipoprotein (LDL) cholesterol targets are not achieved with statins alone. However, treatment with statins and other oral small molecules is often insufficient to attain the target levels of LDL cholesterol. This review describes the monoclonal antibodies (mAbs) that have been produced to overcome the residual cardiovascular risk related to uncontrolled LDL cholesterol. In recent years the mAbs, alirocumab and evolocumab, targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have become established worldwide as an additional treatment for patients not achieving LDL cholesterol goals on statins and ezetimibe, or sometimes as an alternative treatment in those with statin intolerance. They have been shown to be safe and effective in reducing cardiovascular events in patients at high cardiovascular risk. More recently, four new mAbs targeting PCSK9 have been developed and approved in China. Some of these mAbs offer the benefit of less frequent subcutaneous dosing and some are humanized mAbs and it remains to be seen whether their efficacy will be retained with long term use. New drug targets were identified to potentially reduce elevated triglyceride levels and the mAb angiopoietin-like 3 (ANGPTL3) inhibitor, evinacumab, was found to be effective in reducing LDL cholesterol in patients with homozygous familial hypercholesterolemia (FH) and has been approved for that indication. SHR-1918 is another mAb targeting ANGPTL3 being developed in China which may also be effective to treat homozygous FH. These drugs are expensive and may not be suitable for a wider indication and there are antisense oligonucleotides and small interfering RNA treatments in development which may prove more cost effective. Another mAb at an early stage of development is MAR001 targeting angiopoietin-like 4 (ANGPTL4). The role for this remains to be established.

The TRAIL-DR5 signaling axis exhibits a pronounced "double-edged sword" nature in cardiovascular diseases, embodying both deleterious and protective roles. On one hand, it contributes to pathology by promoting cardiomyocyte apoptosis and enhancing inflammatory responses, thereby driving the progression of conditions such as myocardial ischemia-reperfusion injury, atherosclerotic plaque destabilization, and heart failure. On the other hand, under specific contexts, TRAIL-DR5 signaling can exert protective effects through mechanisms including the regulation of angiogenesis, suppression of inflammation, and facilitation of tissue repair. This functional dichotomy likely stems from cell-type specificity, dynamic microenvironmental changes, and crosstalk with other signaling pathways-such as NF-κB, MAPK, and autophagy-related processes. This review systematically examines the molecular mechanisms underlying TRAIL-DR5 signaling and its multifaceted involvement in acute myocardial infarction, heart failure, atherosclerosis, and atrial fibrillation. Furthermore, it explores targeted therapeutic strategies, including: DR5 agonists (such as monoclonal antibodies and small molecule compounds) for selective clearance of pathological cells; inhibitors (for instance, soluble DR5-Fc fusion proteins and siRNAs) to block deleterious signaling; and combination therapies (eg, with kinase inhibitors) to achieve synergistic efficacy. We propose that future investigations should prioritize the development of highly specific biomarkers, the refinement of targeted delivery systems, and a deeper mechanistic understanding of cellular and disease-stage heterogeneity. Such advances will be essential to propel the field from broad-spectrum treatments toward precision interventions, offering innovative solutions for complex cardiovascular disorders.

Purpose: Irisin, an exercise-induced myokine, promotes the browning of white adipose tissue. Over a decade of research has expanded its functions to include the amelioration of metabolic disorders and protection of neural, skeletal, muscular, cardiac, and renal systems. Exogenous administration of irisin has been demonstrated to mimic the beneficial effects of exercise, showing therapeutic potential for a range of conditions including obesity, diabetes, Alzheimer's disease, osteoporosis, sarcopenia, myocardial ischemia, and chronic kidney disease. Irisin emerges as a promising circulating biomarker for assessing health status. By offering a quantitative, data-driven perspective from macro to micro scales, bibliometrics serves as a crucial decision-support tool for irisin research. It facilitates the mapping of the intellectual landscape, pinpoints knowledge gaps and underinvestigated niches, and tracks the temporal evolution of research fronts, thereby guiding future investigative priorities.

Patients and methods: Publications were retrieved from the Web of Science Core Collection (WoSCC) using the search strategy "Topic = irisin", covering the period from its discovery in 2012 to 2024. After applying language (English-only) and type (article/review) filters, VOSviewer, CiteSpace and R package "bibliometrix" was used to conduct the bibliometric analysis.

Results: This bibliometric analysis was conducted on a total of 2412 articles sourced from 78 countries. China emerged as the leading contributor, ranking first among the corresponding authors' countries. The primary research institutions identified were the Egyptian Knowledge Bank, Firat University, and Harvard University. The most locally cited authors were Mantzoros CS and Spiegelman BM, while Aydin S was recognized as the most relevant author. The most frequently occurring keywords included "exercise", "obesity", and "FNDC5". The latest trend topics identified were "neuroinflammation", "ferroptosis", "chronic kidney disease", and "cognition".

Conclusion: This bibliometric study delineates irisin's emerging clinical translational prospects, thereby providing evidence-based guidance for prioritizing research on irisin's therapeutic targeting and biomarker validation across multidisciplinary clinical contexts.

Lupus erythematosus panniculitis (LEP) is a rare and serious skin lesion associated with systemic lupus erythematosus (SLE). In the past, the management of LEP has followed the treatment guidelines for SLE, which is based on the administration of high doses of hormones together with immunosuppressants, with no treatment plans specific for LEP. However, the long-term use of high hormone doses and immunosuppressants can exacerbate skin breakage and calcification. Telitacicep is an approved biological agent demonstrating significant therapeutic efficacy in immune system disorders. We report a case of lupus erythematosus panniculitis in which the patient's clinical symptoms and laboratory test results improved after treatment with a combination of steroids, cyclophosphamide, and the biologic agent Telitacicept. The condition was significantly controlled and alleviated. This report highlights the successful application of Telitacicept in the treatment of lupus panniculitis, providing valuable insights for future management of this condition.

Hidradenitis suppurativa (HS), a chronic inflammatory disorder affecting approximately 1% of the global population, remains challenging to treat due to the limited efficacy of single biologics (TNFa/IL-17/IL-36 inhibitors) against draining tunnels (dTs). A man with refractory HS (Hurley stage III) was treated with recibokibart (anti-IL36R antibody) and secukinumab (anti-IL17A antibody). Disease severity was assessed using previously validated clinical outcome measures and ultrasonography. Rapid clinical improvement was observed in this patient. HiSCR50 was achieved at week 2, and HiSCR100 (complete resolution of inflammatory nodules and abscesses without new dTs) by week 10. The pain score decreased from 8 to 2, and the exudation resolved. The size of the tunnels in the four intertrigonal areas was significantly reduced, as assessed by ultrasound. This case highlights the synergistic potential of dual IL-17/IL-36 blockade, particularly for dTs, and offers a novel therapeutic strategy for treating severe HS.

Migrasomes, vesicle-like organelles observed during cell migration, have emerged as a significant focus in cell biology. These organelles play a pivotal role in intercellular communication, signal transduction, and tissue development through the release of signalling molecules. Evidence indicates that the pathogenesis and progression of various diseases are closely associated with aberrant cell migration, impaired intercellular communication, and disrupted signalling pathways. Notably, migrasomes can facilitate the invasion and metastasis of tumor cells: they carry metastasis-promoting signals and help form an immunosuppressive microenvironment. Additionally, migrasomes mediate viral spread. Migrasomes derived from macrophages can accelerate the progression of cardiovascular and cerebrovascular diseases by promoting neuroinflammation and neuronal damage. Meanwhile, migrasomes derived from podocytes serve as biomarkers for early kidney injury. Thus, elucidating the role of migrasomes in pathological processes and defining their specific functions holds great promise for developing novel therapeutic strategies for diseases. This review synthesizes current advances in migrasome biology, highlighting their potential as diagnostic biomarkers and therapeutic targets for conditions such as cancer, viral infections, and renal disorders.

Osteoarthritis (OA) is a prevalent chronic disease, characterized by progressive joint degeneration and primarily affects older adults. OA leads to reduced functional abilities, a lower quality of life, and an increased mortality rate. Currently, effective treatment options for OA are lacking. Non-coding RNAs (ncRNAs) are functional RNAs transcribed from DNA but not translated into proteins. Among ncRNAs, small interfering RNAs (siRNAs), transfer RNAs (tRNAs), and ribosomal RNAs (rRNAs) have become significant in the field, which is intricately linked to the progression of OA and perform significant regulatory functions in transcription, post-transcription, and post-translation, making them potential biological targets for the prevention, diagnosis, and treatment of OA. This review summarizes the general functions of siRNAs, tRNAs, and rRNAs and their application in OA. The primary focus has been on regulating cartilage degradation. Other participations include regulating synovium, protecting anterior cruciate ligament cells, and diagnosis. No clinical trials were found as challenges such as effective delivery systems, immune responses, long-term effects, and interactions between therapies need to be demonstrated first.

Purpose: Pancreatic cancer is one of the most lethal malignancies, with a five-year survival rate rarely exceeding 10%. Due to its asymptomatic onset, it is frequently diagnosed at an advanced and often inoperable stage. This review assesses current strategies for early detection, including genomic testing, advanced imaging technologies, and biomarker-based platforms, with a focus on their clinical utility and integration into surveillance protocols.

Methods: This narrative review synthesizes findings from published literature on germline genetic testing (GGT), imaging modalities such as endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI), and the latest advancements in biomarker discovery and molecular diagnostics for early pancreatic cancer detection. International guidelines and emerging evidence were assessed to explore their clinical implementation and challenges.

Results: Although EUS and MRI show promise for detecting early pancreatic lesions, both require specialized expertise and are limited by accessibility and cost. Emerging blood-based biomarkers and molecular platforms, however, may offer a more scalable, non-invasive alternative for detecting pancreatic cancer at earlier, treatable stages.

Conclusion: Early detection of pancreatic cancer is pivotal to improving survival outcomes. While imaging techniques and genetic screening have enhanced risk stratification and early diagnosis in high-risk populations, novel biomarker and molecular testing platforms offer an accessible and scalable solution. Future efforts should focus on validating these assays in large-scale prospective cohorts and integrating them into screening protocols, particularly for individuals with genetic susceptibility.

Objective: We aim to evaluate the malignancy risk between Janus kinase inhibitors (JAKi) users and tumor necrosis factor inhibitors (TNFi) users in rheumatoid arthritis (RA) patients, using a large real-world electronic health record database (TriNetX).

Methods: In this retrospective cohort study, we identified adult RA patients initiating JAKi or TNFi therapy between January 1, 2018, and December 31, 2022, within the TriNetX global federated network. The hazard ratio (HR) and confidence intervals (CI) of incident-specific cancers, overall cancer incidence, and all-cause mortality, were calculated between the propensity score matched JAKi and TNFi cohorts. The probability of the outcome of interest was estimated using the Kaplan-Meier analysis.

Results: After propensity score matching, there were 4045 each in JAKi or TNFi user cohorts. The mean (standard deviation) age was 57.7 (13.3) and 57.6 (13.9) years, 81.4% and 80.8% were female, and median (interquartile range) follow-up time 3.69 (2.61) years vs 3.69 (2.68) years, in the JAKi and the TNFi cohorts, respectively. No significant differences were observed in risks of overall cancer incidence and all-cause mortality between the two cohorts. JAKi users had a reduced risk of incident digestive organ cancers compared with TNFi users (adjusted HR: 0.599, 95% CI: 0.439-0.817), mainly observed among females. The risks of incident respiratory and intrathoracic organs cancers were increased in JAKi users compared to TNFi users among females (adjusted HR: 2.582, 95% CI: 1.109-6.011) but not in males.

Conclusion: In a large real-world database, we did not find an increased risk of overall cancer incidence in JAKi compared to TNFi users among RA patients. JAKi users had a lower risk of incident digestive organs cancers, and a higher risk of respiratory cancer in females, when compared with TNFi users.

Purpose: Targeting the distinct genetic and protein expression profiles of keloids necessitates the identification of novel therapeutic targets. This study was aimed to elucidate the role of Bcl-2-associated athanogene 2 (BAG2) in keloid pathology and identify compounds with high-affinity to BAG2.

Patients and methods: Cell migration, and cell proliferation assays, along with flow cytometry, were used to evaluate the effects of BAG2 on keloid fibroblasts (KFs) derived from tissue samples of patients with abdominal or chest keloids. Additionally, histological examinations and Western blotting were performed to investigate BAG2's role in keloids. Surface plasmon resonance (SPR) was employed to identify compounds with high-affinity to BAG2, and the effects of these compounds on keloids was assessed.

Results: Inhibition of BAG2 significantly decreased collagen deposition, cell proliferation and migration in keloid tissues. The modulatory effect of BAG2 on these processes appears to be mediated partly by the MEK signaling pathway. Among the tested compounds, Bazedoxifene acetate and Ponesimod showed high affinity for BAG2 and demonstrated a more pronounced inhibitory effect on collagen deposition of the keloid tissues than other candidates.

Conclusion: This study revealed the pathogenic role of BAG2 in keloid and identified compounds with high-affinity to BAG2, Bazedoxifene acetate and Ponesimod. The therapeutic capabilities of these compounds demonstrated their potential to improve therapeutic strategies for localized, targeted treatment to keloids.