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International Journal of Molecular... Oct 2023Since the only and the milestone FDA approval of becaplermin gel (Regranex, 0.01% human recombinant PDGF-BB) as a (diabetic) wound healing therapeutic more than 25 years... (Review)
Review
Since the only and the milestone FDA approval of becaplermin gel (Regranex, 0.01% human recombinant PDGF-BB) as a (diabetic) wound healing therapeutic more than 25 years ago, no new therapeutic (excluding physical therapies, devices, dressings, anti-microbial agents, or other preventive treatments) for any type of wound healing has advanced to clinical applications. During the same period of time, the FDA has approved additional 250 new drugs for various human tumors, which were famously described as "wounds that do not heal". Two similar pathological conditions have experienced such a dramatic difference in therapeutics. More surprisingly, few in the wound healing community seem to be alarmed by this mysterious deficit. As it is often said, "damaging is far easier than re-building". In contrast to the primary duty of a cancer drug to damage a single molecule of the signaling network, a wound healing drug must be able to re-build the multi-level damages in the wound. No known single molecule alone is capable of repairing multi-cell-type and multi-pathway damages all at once. We argue that the previous single molecule-based strategy for developing wound healing therapeutics is profoundly flawed in theory. The future success of effective wound healing therapeutics requires a fundamental change in the paradigm.
Topics: Humans; Proto-Oncogene Proteins c-sis; Wound Healing; Becaplermin; Bandages
PubMed: 37894789
DOI: 10.3390/ijms242015109 -
The Journal of Clinical Investigation Oct 2021Cardiovascular disease (CVD) and osteoporosis often occur together, suggesting an association between CVD and bone loss. Similarly, the correlation of bone loss,...
Cardiovascular disease (CVD) and osteoporosis often occur together, suggesting an association between CVD and bone loss. Similarly, the correlation of bone loss, atherosclerosis, and aortic calcification, especially in patients with chronic kidney disease, exemplifies a bone-vessel connection. In this issue of the JCI, Santhanam et al. investigated the role of the angiogenesis factor platelet-derived growth factor-BB (PDGF-BB) in vascular stiffening. Serum levels of bone-derived PDGF-BB differed between young and aged mice, and in mice fed a high-fat diet (HFD) compared with those fed normal chow. Experiments with genetic models led the authors to conclude that bone-derived PDGF-BB mediates the hallmark arterial stiffening of aging and metabolic stress. Notably, excessive preosteoclast-derived PDGF-BB production during aging inhibited osteoblastic bone formation and increased circulating PDGF-BB, which in turn, accelerated vascular stiffness. These findings suggest that modifying circulating PDGF-BB levels may benefit patients with CVD, osteoporosis, and other age-related diseases.
Topics: Aging; Animals; Becaplermin; Bone and Bones; Humans; Mice; Osteogenesis; Proto-Oncogene Proteins c-sis
PubMed: 34651590
DOI: 10.1172/JCI153644 -
The Journal of Clinical Investigation Nov 2023Glioblastoma (GBM) tumor-associated macrophages (TAMs) provide a major immune cell population contributing to growth and immunosuppression via the production of...
Glioblastoma (GBM) tumor-associated macrophages (TAMs) provide a major immune cell population contributing to growth and immunosuppression via the production of proinflammatory factors, including IL-1. In this issue of the JCI, Chen, Giotti, and colleagues investigated loss of ll1b in the immune tumor microenvironment (TME) in GBM models driven by PDGFB expression and Nf1 knockdown. Survival was only improved in PDGFB-driven GBM models, suggesting that tumor cell genotype influenced the immune TME. IL-1β in the TME increased PDGFB-driven GBM growth by increasing tumor-derived NF-κB, expression of monocyte chemoattractants, and increased infiltration of bone marrow-derived myeloid cells (BMDMs). In contrast, no requirement for IL-1β was evident in Nf1-silenced tumors due to high basal levels of NF-κB and monocyte chemoattractants and increased infiltration of BMDM and TAMs. Notably, treatment of mice bearing PDGFB-driven GBM with anti-IL-1β or an IL1R1 antagonist extended survival. These findings suggest that effective clinical immunotherapy may require differential targeting strategies.
Topics: Animals; Mice; Becaplermin; Brain Neoplasms; Chemotactic Factors; Cytokines; Glioblastoma; Macrophages; NF-kappa B; Proto-Oncogene Proteins c-sis; Tumor Microenvironment
PubMed: 37966120
DOI: 10.1172/JCI175127 -
Signal Transduction and Targeted Therapy Jul 2022Recent studies have suggested that transplant of hiPS-CMs is a promising approach for treating heart failure. However, the optimally clinical benefits have been hampered...
Recent studies have suggested that transplant of hiPS-CMs is a promising approach for treating heart failure. However, the optimally clinical benefits have been hampered by the immature nature of the hiPS-CMs, and the hiPS-CMs-secreted proteins contributing to the repair of cardiomyocytes remain largely unidentified. Here, we established a saponin compound optimally induced system to generate hiPS-CMs with stable functional attributes in vitro and transplanted in heart failure mice. Our study showed enhanced therapeutic effects of optimally induced hiPS-CMs by attenuating cardiac remodeling and dysfunction, these beneficial effects were concomitant with reduced cardiomyocytes death and increased angiogenesis. Moreover, the optimally induced hiPS-CMs could gathering to the injured heart and secret an abundant PDGF-BB. The reparative effect of the optimally induced hiPS-CMs in the hypoxia-injured HCMs was mimicked by PDGF-BB but inhibited by PDGF-BB neutralizing antibody, which was accompanied by the changed expression of p-PI3K and p-Akt proteins. It is highly possible that the PI3K/Akt pathway is regulated by the PDGF-BB secreted from the compound induced hiPS-CMs to achieve a longer lasting myocardial repair effect compared with the standard induced hiPS-CMs. Taken together, our data strongly implicate that the compound induced hiPS-CMs promote the recovery of injured hearts via paracrine action. In this process, the paracrine factor PDGF-BB derived from the compound induced hiPS-CMs reduces isoproterenol-induced adverse cardiac remodeling, which is associated with improved cardiac function, and these effects are mediated by the PI3K/Akt pathway, suggesting that the optimally induced hiPS-CMs may serve as a new promising cell therapy for clinical applications.
Topics: Animals; Becaplermin; Heart Failure; Humans; Induced Pluripotent Stem Cells; Mice; Myocytes, Cardiac; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Ventricular Remodeling
PubMed: 35902567
DOI: 10.1038/s41392-022-01045-4 -
Cancer Letters Oct 2008Lycopene (psi,psi-carotene) is the most abundant carotenoid in tomatoes and is the red pigment of not only tomatoes but also rosehips, watermelon, papaya, pink... (Review)
Review
Lycopene (psi,psi-carotene) is the most abundant carotenoid in tomatoes and is the red pigment of not only tomatoes but also rosehips, watermelon, papaya, pink grapefruit, and guava. Unlike beta-carotene, lycopene lacks a beta-ionone ring and therefore has no pro-vitamin A activity. However, the 11 conjugated and two non-conjugated double bonds in lycopene make it highly reactive towards oxygen and free radicals, and this anti-oxidant activity probably contributes to its efficacy as a chemoprevention agent. The reactivity of lycopene also explains why it isomerizes rapidly in blood and tissues from the biosynthetic all-trans form to a mixture of cis-isomers. Prospective and retrospective epidemiological studies indicating an inverse relationship between lycopene intake and prostate cancer risk have been supported by in vitro and in vivo experiments showing that oral lycopene is bioavailable, accumulates in prostate tissue and is localized to the nucleus of prostate epithelial cells. In addition to antioxidant activity, in vitro experiments indicate other mechanisms of chemoprevention by lycopene including induction of apoptosis and antiproliferation in cancer cells, anti-metastatic activity, and the upregulation of the antioxidant response element leading to the synthesis of cytoprotective enzymes. Lycopene is a substrate for carotene-9',10'-monooxygenase (CMO2) and can be converted to apo-10'-carotenal. Although Phase I and II studies have been published that establish the safety of lycopene supplementation, carefully designed and adequately powered clinical studies of lycopene are still needed to confirm its efficacy as a chemoprevention agent.
Topics: Animals; Anticarcinogenic Agents; Antioxidants; Apoptosis; Becaplermin; Biological Availability; Carotenoids; Cell Cycle; Clinical Trials as Topic; Humans; Lycopene; Neoplasm Invasiveness; Neoplasms; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Response Elements
PubMed: 18585855
DOI: 10.1016/j.canlet.2008.05.016 -
Journal of Cerebral Blood Flow and... May 2023Pericytes are the mural cells of the microvascular network that are in close contact with underlying endothelial cells. Endothelial-secreted PDGFB leads to recruitment...
Pericytes are the mural cells of the microvascular network that are in close contact with underlying endothelial cells. Endothelial-secreted PDGFB leads to recruitment of pericytes to the vessel wall, but this is disrupted in mice when the PDGFB retention motif is deleted. This results in severely reduced pericyte coverage on blood vessels. In this study, we investigated vascular abnormalities and hemodynamics in mice throughout the cerebrovascular network and in different cortical layers by two-photon microscopy. We confirmed that mice are severely deficient in pericytes throughout the vascular network, with enlarged brain blood vessels and a reduced number of vessel branches. Red blood cell velocity, linear density, and tube hematocrit were reduced in mice, which may impair oxygen delivery to the tissue. We also measured intravascular PO and found that concentrations were higher in cortical Layer 2/3 in mice, indicative of reduced blood oxygen extraction. Finally, we found that mice had a reduced capacity for vasodilation in response to an acetazolamide challenge during functional MRI imaging. Taken together, these results suggest that severe pericyte deficiency can lead to vascular abnormalities and altered cerebral blood flow, reminiscent of pathologies such as arteriovenous malformations.
Topics: Mice; Animals; Proto-Oncogene Proteins c-sis; Pericytes; Endothelial Cells; Disease Models, Animal; Becaplermin; Hemodynamics; Oxygen
PubMed: 36545806
DOI: 10.1177/0271678X221147366 -
Clinical Cancer Research : An Official... Oct 2022Biliary tract cancers (BTC) are aggressive malignancies refractory to chemotherapy and immunotherapy. MEK inhibition (MEKi)-based regimens may have utility in this...
PURPOSE
Biliary tract cancers (BTC) are aggressive malignancies refractory to chemotherapy and immunotherapy. MEK inhibition (MEKi)-based regimens may have utility in this disease when combined with PD-L1 blockade. We hypothesize that dual MEK/PD-L1 inhibition alters circulating soluble and cellular immune mediators to improve clinical outcomes in patients with advanced BTC.
EXPERIMENTAL DESIGN
We examined immune features in peripheral blood from 77 patients with advanced BTC enrolled in a phase II clinical trial investigating atezolizumab with or without cobimetinib. Plasma and peripheral blood mononuclear cells (PBMC) were isolated from whole blood to evaluate soluble factors and immune cell populations. Baseline blood samples were additionally compared with healthy donors to identify immune signatures unique to BTC.
RESULTS
At baseline, the soluble factors platelet-derived growth factor B (PDGF)-BB, placental growth factor (PlGF)-1, IL5, and IL17A were elevated in patients with BTC compared with healthy adult donors, and higher baseline frequencies of CD8+BTLA+ T cells correlated with better overall survival (OS) in this trial. There were also significant treatment-related alterations in several factors, including decreased PDGF-BB following combination treatment, that correlated with improved OS and progression-free survival (PFS). Higher baseline levels of IL23 and RANTES corresponded to improved clinical outcomes following combination treatment. Dual MEK/PD-L1 inhibition increased populations of CD4+TIM3+ and decreased CD8+VISTA+ T cells, correlating with worse OS and better PFS, respectively.
CONCLUSIONS
This work represents a comprehensive analysis of peripheral immune features in patients with BTC and systemic responses to dual MEK/PD-L1 inhibition. These data support further investigation to understand how MEKi combines with immunotherapeutic approaches to improve clinical outcomes for patients with advanced BTC.
Topics: Adult; B7-H1 Antigen; Becaplermin; Bile Duct Neoplasms; Biliary Tract Neoplasms; Chemokine CCL5; Cytokines; Female; Hepatitis A Virus Cellular Receptor 2; Humans; Interleukin-5; Leukocytes, Mononuclear; Lymphocytes; Mitogen-Activated Protein Kinase Kinases; Placenta Growth Factor; Proto-Oncogene Proteins c-sis
PubMed: 35833954
DOI: 10.1158/1078-0432.CCR-22-1123 -
International Journal of Molecular... Jan 2024Cutaneous wound healing consists of four stages: hemostasis, inflammation, proliferation/repair, and remodeling. While healthy wounds normally heal in four to six weeks,... (Review)
Review
Cutaneous wound healing consists of four stages: hemostasis, inflammation, proliferation/repair, and remodeling. While healthy wounds normally heal in four to six weeks, a variety of underlying medical conditions can impair the progression through the stages of wound healing, resulting in the development of chronic, non-healing wounds. Great progress has been made in developing wound dressings and improving surgical techniques, yet challenges remain in finding effective therapeutics that directly promote healing. This review examines the current understanding of the pro-healing effects of targeted pharmaceuticals, re-purposed drugs, natural products, and cell-based therapies on the various cell types present in normal and chronic wounds. Overall, despite several promising studies, there remains only one therapeutic approved by the United States Food and Drug Administration (FDA), Becaplermin, shown to significantly improve wound closure in the clinic. This highlights the need for new approaches aimed at understanding and targeting the underlying mechanisms impeding wound closure and moving the field from the management of chronic wounds towards resolving wounds.
Topics: Humans; Wound Healing; Prodrugs; Bandages; Becaplermin; Inflammation
PubMed: 38279304
DOI: 10.3390/ijms25021304 -
Dermatologic Therapy 2016Large difficult to heal ulcers of various etiologies carry a high morbidity and mortality rate. Becaplermin is a recombinant platelet-derived growth factor approved for...
Large difficult to heal ulcers of various etiologies carry a high morbidity and mortality rate. Becaplermin is a recombinant platelet-derived growth factor approved for treatment of diabetic ulcers. In this two-case series, we report the use of becaplermin in the treatment of ulcers due to (i) calciphylaxis, an often fatal condition resulting from systemic calcification and thrombosis of vessels and (ii) pyoderma gangrenosum (PG), a neutrophilic dermatosis. We also report that topical collagenase worsened PG ulcers, consistent with pathergy. Becaplermin can be used to help treat ulcers resulting from calciphylaxis and PG. These encouraging results lend support for the utilization of becaplermin in the treatment of nondiabetic chronic ulcers of various etiologies.
Topics: Adult; Aged; Angiogenesis Inducing Agents; Becaplermin; Calciphylaxis; Humans; Male; Proto-Oncogene Proteins c-sis; Pyoderma Gangrenosum; Skin Ulcer; Treatment Outcome
PubMed: 26556220
DOI: 10.1111/dth.12318 -
Clinical and Experimental Hypertension... Dec 2023Neointimal hyperplasia is the primary mechanism underlying atherosclerosis and restenosis after percutaneous coronary intervention. Ketogenic diet (KD) exerts beneficial...
OBJECTIVE
Neointimal hyperplasia is the primary mechanism underlying atherosclerosis and restenosis after percutaneous coronary intervention. Ketogenic diet (KD) exerts beneficial effects in various diseases, but whether it could serve as non-drug therapy for neointimal hyperplasia remains unknown. This study aimed to investigate the effect of KD on neointimal hyperplasia and the potential mechanisms.
METHODS AND RESULTS
Carotid artery balloon-injury model was employed in adult Sprague-Dawley rats to induce neointimal hyperplasia. Then, animals were subjected to either standard rodent chow or KD. For in-vitro experiment, impacts of β-hydroxybutyrate (β-HB), the main mediator of KD effects, on platelet-derived growth factor BB (PDGF-BB) induced vascular smooth muscle cell (VSMC) migration and proliferation were determined. Balloon injury induced event intimal hyperplasia and upregulation of protein expression of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA), and these changes were significantly ameliorated by KD. In addition, β-HB could markedly inhibit PDGF-BB induced VMSC migration and proliferation, as well as inhibiting expressions of PCNA and α-SMC. Furthermore, KD inhibited balloon-injury induced oxidative stress in carotid artery, indicated by reduced ROS level, malondialdehyde (MDA) and myeloperoxidase (MPO) activities, and increased superoxide dismutase (SOD) activity. We also found balloon-injury induced inflammation in carotid artery was suppressed by KD, indicated by decreased expressions of proinflammatory cytokines IL-1β and TNF-α, and increased expression of anti-inflammatory cytokine IL-10.
CONCLUSION
KD attenuates neointimal hyperplasia through suppressing oxidative stress and inflammation to inhibit VSMC proliferation and migration. KD may represent a promising non-drug therapy for neointimal hyperplasia associated diseases.
Topics: Rats; Animals; Hyperplasia; Rats, Sprague-Dawley; Becaplermin; Proliferating Cell Nuclear Antigen; Diet, Ketogenic; Neointima; Carotid Artery Injuries; Oxidative Stress; Inflammation; Cell Proliferation; Cell Movement; Cells, Cultured
PubMed: 37395230
DOI: 10.1080/10641963.2023.2229538