Designing novel therapeutic strategies against tumor stroma and fibrosis

Statins are currently the major therapeutic strategies to lower low-density lipoprotein cholesterol (LDL-C) levels. However, a number of hypercholesterolemia patients still have a residual cardiovascular disease (CVD) risk despite taking the maximum-tolerated dose of statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein receptor (LDLR), inducing its degradation in the lysosome and inhibiting LDLR recirculating to the cell membranes. The gain-offunction mutations in PCSK9 elevate the LDL-C levels in plasma. Therefore, PCSK9 inhibitors become novel therapeutic approaches in the treatment of hypercholesterolemia. Several PCSK9 inhibitors have been under investigation, and much progress has been made in clinical trials, especially for monoclonal antibodies (MoAbs). Two MoAbs, evolocumab and alirocumab, are now in clinical use. In this review, we summarize the development of PCSK9 inhibitors, including antisense oligonucleotides (ASOs), small interfering RNA (siRNA), small molecule inhibitor, MoAbs, mimetic peptides and adnectins, and the related safety issues.

Download Full-text

The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases

Biology ◽

10.3390/biology9120485 ◽

2020 ◽

Vol 9 (12) ◽

pp. 485

Author(s):

Lorenzo Cuollo ◽

Fabrizio Antonangeli ◽

Angela Santoni ◽

Alessandra Soriani

Keyword(s):

Cancer Therapy ◽

Molecular Mechanisms ◽

Therapeutic Strategies ◽

Senescent Cell ◽

Pharmacological Intervention ◽

Tissue Microenvironment ◽

Age Related ◽

Secretory Phenotype ◽

Novel Therapeutic Strategies ◽

Novel Therapeutic

Cellular senescence represents a robust tumor-protecting mechanism that halts the proliferation of stressed or premalignant cells. However, this state of stable proliferative arrest is accompanied by the Senescence-Associated Secretory Phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment and contributes to age-related conditions, including, paradoxically, cancer. Novel therapeutic strategies aim at eliminating senescent cells with the use of senolytics or abolishing the SASP without killing the senescent cell with the use of the so-called “senomorphics”. In addition, recent works demonstrate the possibility of modifying the composition of the secretome by genetic or pharmacological intervention. The purpose is not to renounce the potent immunostimulatory nature of SASP, but rather learning to modulate it for combating cancer and other age-related diseases. This review describes the main molecular mechanisms regulating the SASP and reports the evidence of the feasibility of abrogating or modulating the SASP, discussing the possible implications of both strategies.

Download Full-text

Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2021.111708 ◽

2021 ◽

Vol 139 ◽

pp. 111708

Author(s):

Pushkar Singh Rawat ◽

Aiswarya Jaiswal ◽

Amit Khurana ◽

Jasvinder Singh Bhatti ◽

Umashanker Navik

Keyword(s):

Molecular Mechanism ◽

Therapeutic Strategies ◽

Effective Management ◽

Novel Therapeutic Strategies ◽

Novel Therapeutic

Download Full-text

Short-Term Reproducibility of MUC5AC Measurement in Human Tear Fluid

Diagnostics ◽

10.3390/diagnostics11010057 ◽

2021 ◽

Vol 11 (1) ◽

pp. 57

Author(s):

Ashley M. Woodward ◽

Michelle Senchyna ◽

Pablo Argüeso

Keyword(s):

Statistical Difference ◽

Tear Film ◽

Therapeutic Strategies ◽

Individual Variability ◽

Tear Fluid ◽

Individual Data ◽

Short Term ◽

Coefficients Of Variation ◽

Novel Therapeutic Strategies ◽

Novel Therapeutic

The assessment of tear fluid components is a common and valuable approach to understanding ocular surface disease and testing the efficacy of novel therapeutic strategies. However, the interpretation and utility of the findings can be limited by changes in the composition of the tear film, particularly in studies requiring repetitive patient sampling. Here, tear samples were collected twice within a one-hour interval to evaluate the short-term reproducibility of an immunoassay aimed to measure the amount of MUC5AC mucin. We found no statistical difference in total protein or MUC5AC content between the two consecutive collections of tear fluid, although the inter-individual variability in each group was high, with coefficients of variation exceeding 30% and 50%, respectively. Scatterplots showed a significant correlation in both protein and MUC5AC following collection within a one-hour interval. These data indicate that, regardless of the high inter-individual variability, repeated collection of tear fluid within an hour interval produces reproducible intra-individual data in terms of MUC5AC mucin content, and suggest that the normal mucin composition of the tear fluid can be re-established within an hour of the initial collection.

Download Full-text