The Role of Tnf and Soluble Tnf Receptors (TNFR1/2) as Therapeutic Targets for Inflammation Secondary to Intracerebral Stroke and Hemorrhage DOI Open Access

Rakan Alshaibi,

Kanishka Ekanayake,

Emily Barlow

et al.

Published: April 4, 2024

Most neurodegenerative diseases, including Alzheimer's disease, ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage are associated with inflammation. Tumor necrosis factor (TNF) is a pleiotropic pro-inflammatory cytokine that regulates cerebral infarction in stroke pathology, its action influenced by the bioavailability of membrane-bound receptors, TNFR1 TNFR2, microglial activation. During initial onset these soluble variant presents prolonged excessive activation TNFR1, resulting cell death long-term neurological impairments. Therapeutic interventions for diseases have targeted TNF to limit neuroinflammation. First-generation therapeutics been demonstrated inhibit TNFR2 receptor binding, severe side effects such as infections cancer. As such, second-generation drugs, XPro1595, developed selectively impede while still allowing Early results murine TBI models demonstrate reduced glial reactivity 50%, dendritic degeneration 30%, increased plasticity 15%, improved functional outcomes 20% post-TBI. This scoping review receptors various seeks evaluate current future therapeutic strategies well highlight potential eliminate confounding variables present literature.

Language: Английский

The role of inflammation in autoimmune disease: a therapeutic target DOI Creative Commons
Yu Xiang, Mingxue Zhang,

D.Y. Jiang

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 4, 2023

Autoimmune diseases (AIDs) are immune disorders whose incidence and prevalence increasing year by year. AIDs produced the system’s misidentification of self-antigens, seemingly caused excessive function, but in fact they result reduced accuracy due to decline system which cannot clearly identify foreign invaders thus issuing false attacks, eventually leading disease. The occurrence is often accompanied emergence inflammation, inflammatory mediators (inflammatory factors, inflammasomes) play an important role pathogenesis AIDs, mediate process affecting innate cells (such as macrophages) adaptive T B cells), ultimately promote autoimmune responses, so targeting mediators/pathways one emerging treatment strategies AIDs. This review will briefly describe inflammation different give a rough introduction inhibitors hoping have reference significance for subsequent options

Language: Английский

Citations

53
Global pattern, trend, and cross-country inequality of early musculoskeletal disorders from 1990 to 2019, with projection from 2020 to 2050 DOI Creative Commons
Yingzhao Jin, Cui Guo, Mohammadreza Abbasian

et al.

Med, Journal Year: 2024, Volume and Issue: 5(8), P. 943 - 962.e6

Published: June 3, 2024

Summary

Background

This study aims to estimate the burden, trends, forecasts, and disparities of early musculoskeletal (MSK) disorders among individuals ages 15 39 years.

Methods

The global prevalence, years lived with disabilities (YLDs), disability-adjusted life (DALYs), projection, inequality were estimated for MSK diseases, including rheumatoid arthritis (RA), osteoarthritis (OA), low back pain (LBP), neck (NP), gout, other diseases (OMSKDs).

Findings

More adolescents young adults expected develop by 2050. Across five age groups, rates YLDs, DALYs RA, NP, LBP, OMSKDs sharply increased from 15–19 35–39; however, these negligible OA before 30 but notably at 30–34, rising least 6-fold 35–39. disease burden attributable high BMI gout kidney dysfunction increased, while contribution smoking LBP RA occupational ergonomic factors decreased. Between 1990 2019, slope index six disorders, relative concentration OA, decreased RA.

Conclusions

Multilevel interventions should be initiated prevent related 30–34 tightly control dysfunction.

Funding

Global Burden Disease is funded Bill Melinda Gates Foundation. project Scientific Research Fund Sichuan Academy Medical Sciences & Provincial People's Hospital (2022QN38).

Language: Английский

Citations

13
An anti–TNF–glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases DOI
Michael Mcpherson, Adrian D. Hobson,

Axel Hernandez

et al.

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(739)

Published: March 20, 2024

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration limited because severe side effects. We therefore sought to identify an approach selectively target GCs inflamed tissue. Previous work identified that anti–tumor necrosis factor (TNF) antibodies bind transmembrane TNF undergo internalization; therefore, anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload dampen immune cell activity. Consequently, we have generated anti–TNF-GRM ADC with aim inhibiting pro-inflammatory cytokine production from stimulated human cells. In acute mouse model contact hypersensitivity, murine surrogate inhibited responses minimal effect on systemic biomarkers. addition, in collagen-induced arthritis, single-dose ADC, delivered at disease onset, was able completely inhibit arthritis greater than 30 days, whereas monoclonal antibody only partially disease. treatment peak also attenuate arthritic phenotype. Clinical data (ABBV-3373) single ascending phase 1 study healthy volunteers demonstrated antibody-like pharmacokinetic profiles lack impact serum cortisol concentrations predicted therapeutic doses. These suggest may provide improved efficacy beyond alone mediated diseases while minimizing effects associated standard treatment.

Language: Английский

Citations

9
Glucocorticoid receptor signaling: intricacies and therapeutic opportunities DOI Creative Commons
Dorien Clarisse, Laura Van Moortel, Chloé Van Leene

et al.

Trends in Biochemical Sciences, Journal Year: 2024, Volume and Issue: 49(5), P. 431 - 444

Published: Feb. 29, 2024

The glucocorticoid receptor (GR) is a major nuclear (NR) drug target for the treatment of inflammatory disorders and several cancers. Despite effectiveness GR ligands, their systemic action triggers plethora side effects, limiting long-term use. Here, we discuss new concepts insights into mechanisms to assist in identification routes toward enhanced therapeutic benefits. We zoom on communication between different domains how this influenced by ligands. detail findings interaction chromatin, highlight condensate formation coregulator confinement can perturb transcriptional responses. Last, potential novel ligands exploitation crosstalk with other NRs.

Language: Английский

Citations

8
Nanotechnology-empowered combination therapy for rheumatoid arthritis: principles, strategies, and challenges DOI Creative Commons

Shujing Ren,

Yuhang Xu,

Xingpeng Dong

et al.

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: July 22, 2024

Abstract Rheumatoid arthritis (RA) is an autoimmune disease with multifactorial etiology and intricate pathogenesis. In RA, repeated monotherapy frequently associated inadequate efficacy, drug resistance, severe side effects. Therefore, a shift has occurred in clinical practice toward combination therapy. However, conventional therapy encounters several hindrances, including low selectivity to arthritic joints, short half-lives, varying pharmacokinetics among coupled drugs. Emerging nanotechnology offers incomparable opportunity for developing advanced against RA. First, it allows co-delivering multiple drugs augmented physicochemical properties, targeted delivery capabilities, controlled release profiles. Second, enables therapeutic nanomaterials development, thereby expanding regimens include multifunctional nanomedicines. Lastly, facilitates the construction of all-in-one nanoplatforms assembled modalities, such as phototherapy, sonodynamic therapy, imaging. Thus, promising solution current bottleneck both RA treatment diagnosis. This review summarizes rationale, advantages, recent advances nano-empowered It also discusses safety considerations, drug–drug interactions, potential translation. Additionally, provides design tips outlook on future developments The objective this achieve comprehensive understanding mechanisms underlying unlock maximum nanotechnology, facilitating smooth transition research findings from laboratory practice.

Language: Английский

Citations

8
Precision Medicine in Rheumatic Diseases: Unlocking the Potential of Antibody-Drug Conjugates DOI Open Access
Zhiwen Huang, Zachary Braunstein, Jun Chen

et al.

Pharmacological Reviews, Journal Year: 2024, Volume and Issue: 76(4), P. 579 - 598

Published: April 15, 2024

In the era of precision medicine, Antibody-Drug Conjugates (ADCs) have emerged as a cutting-edge therapeutic strategy. These innovative compounds combine monoclonal antibodies with potent cell-killing or immune-modulating abilities attached drug payloads. This unique strategy not only reduces off-target toxicity but also enhances effectiveness drugs. Beyond their well-established role in oncology, ADCs are now showing promising potential addressing unmet needs therapeutics rheumatic diseases. Rheumatic diseases, diverse group chronic autoimmune diseases varying etiologies, clinical presentations, and prognoses, often demand prolonged pharmacological interventions, creating pressing need for novel, efficient low-risk treatment options. ADCs, ability to precisely target immune components, novel this context. review will provide an overview core components mechanisms behind summary latest trials if well discussion on challenges future prospects faced by development next-generation ADCs. Significance Statement There is lack targeted Antibody-drug conjugates, class drugs, disease. While there limited literature summarizing progress antibody-drug conjugates field disease, updating advancements area provides insights into anti-rheumatic

Language: Английский

Citations

6
Antibody-Drug Conjugates: Functional Principles and Applications in Oncology and Beyond DOI Creative Commons
Charalampos Theocharopoulos, Panagiotis-Petros Lialios, Michael Samarkos

et al.

Vaccines, Journal Year: 2021, Volume and Issue: 9(10), P. 1111 - 1111

Published: Sept. 29, 2021

In the era of precision medicine, antibody-based therapeutics are rapidly enriched with emerging advances and new proof-of-concept formats. this context, antibody-drug conjugates (ADCs) have evolved to merge high selectivity specificity monoclonal antibodies (mAbs) cytotoxic potency attached payloads. So far, ten ADCs been approved by FDA for oncological indications many others currently being tested in clinical preclinical level. This paper summarizes essential components ADCs, from their functional principles structure up limitations resistance mechanisms, focusing on all latest bioengineering breakthroughs such as bispecific mAbs, dual-drug platforms well novel linkers conjugation chemistries. continuation our recent review anticancer implication ADC's technology, further insights regarding potential usage outside spectrum also presented. Better understanding immunoconjugates could maximize efficacy optimize safety, extending use everyday practice.

Language: Английский

Citations

38
Discovery of ABBV-154, an anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody-Drug Conjugate (iADC) DOI
Adrian D. Hobson, Jianwen Xu,

Dennie S. Welch

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(17), P. 12544 - 12558

Published: Sept. 1, 2023

Stable attachment of drug-linkers to the antibody is a critical requirement, and for maleimide conjugation cysteine, it achieved by ring hydrolysis succinimide ring. During ADC profiling in our in-house property screening funnel, we discovered that open form equilibrium with closed succinimide. Bromoacetamide (BrAc) was identified as optimal replacement, affords stable drug-linker while completely removing undesired open-closed equilibrium. Additionally, BrAc also offers multiple benefits over maleimide, especially respect homogeneity structure. In combination short, hydrophilic linker phosphate prodrug on payload, this afforded (ABBV-154) desired properties enable long-term stability facilitate subcutaneous self-administration.

Language: Английский

Citations

15
The medicinal chemistry evolution of antibody–drug conjugates DOI
Adrian D. Hobson

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 15(3), P. 809 - 831

Published: Jan. 1, 2024

Antibody-drug conjugates (ADCs) comprise 3 components of wildly differing sizes: antibody (150 000 Da), linker (typically <500 Da) and payload Da). While the drug-linker makes up only a small percent ADC it has disproportionately massive impact on all aspects ADC. Replacing maleimide with bromoacetamide (BrAc) affords stable attachment to cysteine, supports total flexibility for design more homogenous Optimisation protease cleavable dipeptide reduces aggregation, facilitates moderation physicochemical properties enables long-term stability facilitate subcutaneous self-administration. Payloads are designed specifically afford optimal Structural information SAR guide improve both potency selectivity molecule target improving therapeutic index resulting ADCs. Minimising solvent exposed hydrophobic surface area improves drug-like ADC, realisation that heteroatom can be than just site as also drive adoption prodrug strategy at project initiation key areas medicinal chemistry drives. For an symbiotic relationship three structurally disparate requires they function in unison huge role ensure this happens.

Language: Английский

Citations

5
Natural Products and Traditional Herbal Medicines as Managerial Therapies to Combat Rheumatoid Arthritis DOI
Neha Ghosh,

Shivam Pathak,

Malsawmdawngkimi

et al.

Deleted Journal, Journal Year: 2024, Volume and Issue: 22(1)

Published: March 8, 2024

Rheumatoid arthritis (RA) is a complex and challenging autoimmune disease characterized by chronic inflammation of the joints, discomfort, stiffness, functional impairment, systemic complications that affect millions people around world. Despite advances in medication, controlling RA remains difficult due to its complicated pathophysiology numerous clinical symptoms. Synthetic medications, while effective, frequently cause considerable adverse effects, necessitating investigation alternate therapeutic options. This study attempts provide complete overview synthetic medications natural items used treat RA. It specifically investigates pathophysiological mechanisms underpin efficacy safety profiles pharmaceuticals. such as disease-modifying antirheumatic drugs (DMARDs), biologics remain important treatments for RA, albeit with hazards. So explore safer more effective therapy treatment need exploit possible benefits antioxidants, plant secondary metabolites, traditional herbal remedies arises. By encompassing spectrum insights, from molecular level holistic practices, this review aims understanding role products medicines managerial landscape Furthermore, it effect nutrition regulating development Integrative techniques use present intriguing adjuvant therapy, delivering anti-inflammatory, analgesic, immunomodulatory effects potentially fewer side effects. Understanding interaction products, well nutrition, can help enhance regimens, improve patient outcomes, reduce treatment-related problems. valuable resource doctors, researchers, patients looking evidence-based methods care. The synthesis knowledge contributes ongoing pursuit enhanced strategies, fostering improved outcomes quality life individuals grappling rheumatoid arthritis.

Language: Английский

Citations

4