scholarly journals CD31 as a Therapeutic Target in Atherosclerosis

2020 ◽  
Vol 126 (9) ◽  
pp. 1178-1189 ◽  
Author(s):  
Giuseppina Caligiuri
Keyword(s):  
Therapeutic Target ◽  
Therapeutic Potential ◽  
Laboratory Animals ◽  
Adhesive Properties ◽  
Blood Leukocytes ◽  
Clinical Observations ◽  
Therapeutic Molecules ◽  
Coronary Syndromes ◽  
Therapeutic Perspective ◽  
Cd31 Expression

The potential of CD31 as a therapeutic target in atherosclerosis has been considered ever since its cloning in the 1990s, but the exact role played by this molecule in the biologic events underlying atherosclerosis has remained controversial, resulting in the stalling of any therapeutic perspective. Due to the supposed cell adhesive properties of CD31, specific monoclonal antibodies and recombinant proteins were regarded as blocking agents because their use prevented the arrival of leukocytes at sites of acute inflammation. However, the observed effect of those compounds likely resulted from the engagement of the immunomodulatory function of CD31 signaling. This was acknowledged only later though, upon the discovery of CD31’s 2 intracytoplasmic tyrosine residues called immunoreceptor tyrosine inhibitory motifs. A growing body of evidence currently points at a therapeutic potential for CD31 agonists in atherothrombosis. Clinical observations show that CD31 expression is altered at the surface of leukocytes infiltrating unhealed atherothrombotic lesions and that the physiological immunomodulatory functions of CD31 are lost at the surface of blood leukocytes in patients with acute coronary syndromes. On the contrary, translational studies using candidate therapeutic molecules in laboratory animals have provided encouraging results: synthetic peptides administered to atherosclerotic mice as systemic drugs in the acute phases of atherosclerotic complications favor the healing of wounded arteries, whereas the immobilization of CD31 agonist peptides onto coronary stents implanted in farm pigs favors their peaceful integration within the coronary arterial wall.

scholarly journals Mutational and biophysical robustness in a pre-stabilized monobody

2020 ◽  
Author(s):  
Peter G. Chandler ◽  
Li Lynn Tan ◽  
Benjamin T. Porebski ◽  
James S. Green ◽  
Blake T. Riley ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Therapeutic Potential ◽  
Binding Activity ◽  
Protein Domain ◽  
Long Term Stability ◽  
Accelerated Stability ◽  
Fibronectin Type Iii ◽  
The Stability ◽  
Complex Architecture ◽  
Shelf Stable

AbstractThe fibronectin type III (FN3) monobody domain is a promising non-antibody scaffold which features a less complex architecture than an antibody while maintaining analogous binding loops. We previously developed FN3Con, a hyper-stable monobody derivative with diagnostic and therapeutic potential. Pre-stabilization of the scaffold mitigates the stability-function trade-off commonly associated with evolving a protein domain towards biological activity. Here, we aimed to examine if the FN3Con monobody could take on antibody-like binding to therapeutic targets, while retaining its extreme stability. We targeted the first of the Adnectin derivative of monobodies to reach clinical trials, which was engineered by directed evolution for binding to the therapeutic target VEGFR2; however, this function was gained at the expense of large losses in thermostability and increased oligomerisation. In order to mitigate these losses, we grafted the binding loops from Adnectin-anti-VEGFR2 (CT-322) onto the pre-stabilized FN3Con scaffold to produce a domain that successfully bound with high affinity to the therapeutic target VEGFR2. This FN3Con-anti-VEGFR2 construct also maintains high thermostability, including remarkable long-term stability, retaining binding activity after 2 years of storage at 36 °C. Further investigations into buffer excipients doubled the presence of monomeric monobody in accelerated stability trials. These data suggest that loop grafting onto a pre-stabilized scaffold is a viable strategy for the development of monobody domains with desirable biophysical characteristics, and is therefore well-suited to applications such as the evolution of multiple paratopes or shelf-stable diagnostics and therapeutics.

scholarly journals Insulin-Like Growth Factor-1: A Promising Therapeutic Target for Peripheral Nerve Injury

2021 ◽  
Vol 9 ◽  
Author(s):  
Benjamin R. Slavin ◽  
Karim A. Sarhane ◽  
Nicholas von Guionneau ◽  
Phillip J. Hanwright ◽  
Chenhu Qiu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Peripheral Nerve ◽  
Therapeutic Target ◽  
Surgical Repair ◽  
Therapeutic Potential ◽  
Regenerative Process ◽  
Insulin Like Growth Factor ◽  
Peripheral Nerve Injuries ◽  
Promising Therapeutic Target ◽  
Apoptotic Effects

Patients who sustain peripheral nerve injuries (PNIs) are often left with debilitating sensory and motor loss. Presently, there is a lack of clinically available therapeutics that can be given as an adjunct to surgical repair to enhance the regenerative process. Insulin-like growth factor-1 (IGF-1) represents a promising therapeutic target to meet this need, given its well-described trophic and anti-apoptotic effects on neurons, Schwann cells (SCs), and myocytes. Here, we review the literature regarding the therapeutic potential of IGF-1 in PNI. We appraised the literature for the various approaches of IGF-1 administration with the aim of identifying which are the most promising in offering a pathway toward clinical application. We also sought to determine the optimal reported dosage ranges for the various delivery approaches that have been investigated.

Changes in nucleoid DNA structure and adhesive properties of blood leukocytes in animals soon after irradiation

1992 ◽  
Vol 114 (3) ◽  
pp. 1351-1354
Author(s):  
S. D. Ivanov ◽  
L. V. Nikolaevskaya ◽  
B. A. Fedorov ◽  
A. B. Chukhlovin
Keyword(s):  
Dna Structure ◽  
Adhesive Properties ◽  
Blood Leukocytes

scholarly journals Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitis

2021 ◽  
Author(s):  
Fumika Honda ◽  
Hiroto Tsuboi ◽  
Yuko Ono ◽  
Saori Abe ◽  
Hiroyuki Takahashi ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Therapeutic Target ◽  
Therapeutic Potential ◽  
Inflammatory Cells ◽  
Therapeutic Effects ◽  
Fibrosis Score ◽  
Immunoglobulin G4 ◽  
Recombinant Mouse ◽  
Nih 3T3

Abstract Background Our previous studies reveal that CCL18-CCR8 chemokine axis is upregulated in patients of immunoglobulin G4-related disease (IgG4-RD), suggest that the CCL18–CCR8 axis is implicated in the etiology of IgG4-RD. Although, whether this axis has a potential as a therapeutic target remains unclear. Our purpose was to clarify the pathogenic roles and therapeutic potential of the murine CCL8 (analogue of human CCL18)–CCR8 axis by using an animal model of IgG4-RD (LAT Y136F knockin mice; LAT mice).Methods We compared the infiltration of inflammatory cells and the fibrosis of the salivary glands of 6-week-old LAT mice and littermate mice. The expressions of Ccl8 and Ccr8 were also compared. Next, we investigated the therapeutic effects of intravenous administration of anti-CCL8 neutralizing antibody in LAT mice against inflammation and fibrosis of the salivary glands. We also investigated the effects of stimulation with recombinant mouse CCL8 on the collagen production in a mouse fibroblast cell line (NIH/3T3) in vitro.Results When compared with the littermates, the LAT mice showed apparent infiltration of inflammatory cells, and fibrosis in the salivary glands. The focus and fibrosis score in the salivary glands were significantly higher in the LAT mice than in the littermates. The expression levels of Ccl8 in the spleen and of Ccr8 in the salivary glands were significantly higher in the LAT mice than in the littermates. Anti-CCL8 antibody significantly improved the focus and fibrosis score in the salivary glands of the LAT mice. In vitro, stimulation with recombinant mouse CCL8 significantly increased the expression of collagen and ERK1/2 phosphorylation in NIH/3T3.Conclusion We clarified the overexpression and therapeutic potential of the mouse CCL8–CCR8 axis in LAT mice, which could play a crucial role in fibrosis via ERK1/2 phosphorylation, as well as the chemotaxis of inflammatory cells. The human CCL18–CCR8 axis might be a novel therapeutic target for IgG4-RD.

scholarly journals Nanocurcumin-Loaded UCNPs for Cancer Theranostics: Physicochemical Properties, In Vitro Toxicity, and In Vivo Imaging Studies

Nanomaterials ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2234
Author(s):  
Anbharasi Lakshmanan ◽  
Roman A. Akasov ◽  
Natalya V. Sholina ◽  
Polina A. Demina ◽  
Alla N. Generalova ◽  
...  
Keyword(s):  
Near Infrared ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Laboratory Animals ◽  
In Vitro Toxicity ◽  
Upconversion Nanoparticles ◽  
Lewis Lung Cancer ◽  
Spectral Bands

Formulation of promising anticancer herbal drug curcumin as a nanoscale-sized curcumin (nanocurcumin) improved its delivery to cells and organisms both in vitro and in vivo. We report on coupling nanocurcumin with upconversion nanoparticles (UCNPs) using Poly (lactic-co-glycolic Acid) (PLGA) to endow visualisation in the near-infrared transparency window. Nanocurcumin was prepared by solvent-antisolvent method. NaYF4:Yb,Er (UCNP1) and NaYF4:Yb,Tm (UCNP2) nanoparticles were synthesised by reverse microemulsion method and then functionalized it with PLGA to form UCNP-PLGA nanocarrier followed up by loading with the solvent-antisolvent process synthesized herbal nanocurcumin. The UCNP samples were extensively characterised with XRD, Raman, FTIR, DSC, TGA, UV-VIS-NIR spectrophotometer, Upconversion spectrofluorometer, HRSEM, EDAX and Zeta Potential analyses. UCNP1-PLGA-nanocurcumin exhibited emission at 520, 540, 660 nm and UCNP2-PLGA-nanocurmin showed emission at 480 and 800 nm spectral bands. UCNP-PLGA-nanocurcumin incubated with rat glioblastoma cells demonstrated moderate cytotoxicity, 60–80% cell viability at 0.12–0.02 mg/mL marginally suitable for therapeutic applications. The cytotoxicity of UCNPs evaluated in tumour spheroids models confirmed UCNP-PLGA-nanocurcumin therapeutic potential. As-synthesised curcumin-loaded nanocomplexes were administered in tumour-bearing laboratory animals (Lewis lung cancer model) and showed adequate contrast to enable in vivo and ex vivo study of UCNP-PLGA-nanocurcumin bio distribution in organs, with dominant distribution in the liver and lungs. Our studies demonstrate promise of nanocurcumin-loaded upconversion nanoparticles for theranostics applications.

Vitamin D/VDR in acute kidney injury: a potential therapeutic target

2020 ◽  
Vol 27 ◽  
Author(s):  
Siqing Jiang ◽  
Lihua Huang ◽  
Wei Zhang ◽  
Hao Zhang
Keyword(s):  
Vitamin D ◽  
Acute Kidney Injury ◽  
Therapeutic Target ◽  
Poor Prognosis ◽  
Therapeutic Potential ◽  
Kidney Injury ◽  
Potential Therapeutic Target ◽  
Promising Therapeutic Target ◽  
Incidence And Mortality

: Despite many strategies and parameters used in clinical practice, the incidence and mortality of acute kidney injury (AKI) are still high with poor prognosis. With the development of molecular biology, the role of vitamin D and vitamin D receptor (VDR) in AKI is drawing increasing attention. Accumulated researches have suggested that Vitamin D deficiency is a risk factor of both clinical and experimental AKI, and vitamin D/VDR could be a promising therapeutic target against AKI. However, more qualitative clinical researches are needed to provide stronger evidence for clinical application of vitamin D and VDR agonists in the future. Issues like the route and dosage of administration also await more attention. The present review aims to summarize the current works on the role of vitamin D/VDR in AKI and try to provide some new insight of its therapeutic potential.

p-Benzoquinone as a Privileged Scaffold of Pharmacological Significance: A Review

2020 ◽  
Vol 20 (16) ◽  
pp. 1586-1609
Author(s):  
Pragati Silakari ◽  
Priyanka ◽  
Poonam Piplani
Keyword(s):  
Therapeutic Potential ◽  
Biologically Active ◽  
Structural Motif ◽  
Therapeutic Implications ◽  
Pharmacological Significance ◽  
Therapeutic Molecules ◽  
Varied Range ◽  
Privileged Scaffold ◽  
Pharmacological Potential ◽  
Chemical Groups

Quinones are a huge class of compounds with affluent and captivating chemistry. p-Benzoquinone (p-BNZ) or 1,4-Benzoquinone is the key structural motif of numerous biologically active synthetic and natural compounds. This draws interest in its biological exploration to assess prospective therapeutic implications. It possesses immense therapeutic potential depending on different substitutions. This moiety has a marvelous potential to regulate a varied range of different cellular pathways which can be investigated for various selective activities. p-Benzoquinones have been a requisite core for the development of novel therapeutic molecules with minimum side effects. In this review, various synthetic, pharmacological approaches and structure-activity relationship studies focusing on the chemical groups responsible for evoking the pharmacological potential of p-benzoquinone derivatives have been emphasized. Additionally, the compilation highlights the chemical, pharmaceutical and medicinal aspects of synthetic and natural benzoquinone derivatives. The natural occurrences of p-benzoquinone derivatives with different pharmacological significance have also been reported in this review.

Neuroprotective Potential of Caffeic Acid Phenethyl Ester (CAPE) in CNS Disorders: Mechanistic and Therapeutic Insights

2021 ◽  
Vol 19 ◽  
Author(s):  
Namrata Pramod Kulkarni ◽  
Bhupesh Vaidya ◽  
Acharan Narula ◽  
Shyam Sunder Sharma
Keyword(s):  
Caffeic Acid ◽  
Neurological Disorders ◽  
Therapeutic Potential ◽  
Caffeic Acid Phenethyl Ester ◽  
Depression And Anxiety ◽  
Age Related ◽  
Anti Cancer ◽  
Therapeutic Molecules ◽  
Conifer Trees ◽  
Lateral Sclerosis

: Neurological disorders like Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, amyotrophic lateral sclerosis, Huntington’s disease (HD), epilepsy, traumatic brain injury (TBI), depression and anxiety are responsible for thousands of deaths worldwide every year. With the increase in life expectancy, there has been a rise in the prevalence of these disorders. Age is one of the major risk factors for these neurological disorders and with the aged population is set to rise to 1.25 billion by 2050. There is a growing concern to look for new therapeutic molecules to treat age-related diseases. Caffeic acid phenethyl ester (CAPE) is a molecule obtained from a number of botanical sources such as the bark of conifer trees as well as propolis which is extracted from beehives. Though CAPE remains relatively unexplored in human trials, it possesses antioxidant, anti-inflammatory, antimitogenic and anti-cancer activities as shown by preclinical studies. Apart from this, it also exhibits tremendous potential for the treatment of neurological disorders through modulation of multiple molecular pathways and attenuation of behavioural deficits. In the present article, we have reviewed the therapeutic potential of CAPE and its mechanisms in the treatment of neurological disorders.

Contribution of Stemness-linked Transcription Regulators to the Progression of Breast Cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
David Segura-Bautista ◽  
Guadalupe Maya-Nunez ◽  
Arturo Aguilar-Rojas ◽  
Maira Huerta-Reyes ◽  
Marco Allan Pérez-Solis
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Immunological Response ◽  
Malignant Cells ◽  
Mesenchymal Transition ◽  
Underlying Causes ◽  
Transcription Regulators ◽  
Therapeutic Perspective

: Although there are currently several factors that allow measuring the risk of having breast cancer or predicting its progression, the underlying causes of this malignancy have remained unknown. Several molecular studies have described some mechanisms involved in the progress of breast cancer. These have helped in identifying new targets with therapeutic potential. However, despite the therapeutic strategies implemented from the advances achieved in breast cancer research, a large percentage of patients with breast cancer die due to the spread of malignant cells to other tissues or organs, such as bones and lungs. Therefore, determining the processes that promote the migration of malignant cells remains one of the greatest challenges for oncological research. Several research groups have reported evidence on how the dedifferentiation of tumor cells leads to the acquisition of stemness characteristics, such as invasion, metastasis, the capability to evade the immunological response, and resistance to several cytotoxic drugs. These phenotypic changes have been associated with a complex reprogramming of gene expression in tumor cells during the Epithelial-Mesenchymal Transition (EMT). Considering the determining role that the transcriptional regulation plays in the expression of the specific characteristics and attributes of breast cancer during ETM, in the present work, we reviewed and analyzed several transcriptional mechanisms that support the mesenchymal phenotype. In the same way, we established the importance of transcription factors with a therapeutic perspective in the progress of breast cancer.

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