Reduction of chronic allograft nephropathy by inhibition of extracellular signal-regulated kinase 1 and 2 signaling

2008 ◽  
Vol 295 (3) ◽  
pp. F672-F679 ◽  
Author(s):  
Shuang Wang ◽  
Jifu Jiang ◽  
Qiunong Guan ◽  
Hao Wang ◽  
Christopher Y. C. Nguan ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Mek Inhibitor ◽  
Treated Group ◽  
Chronic Allograft Nephropathy ◽  
Beneficial Effects ◽  
Extracellular Signal ◽  
Vehicle Treated Group

Chronic allograft nephropathy (CAN), the most common cause of late kidney allograft failure, is not effectively prevented by immunosuppressive regimens. Activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) via MEK mediates actions of various growth factors, including transforming growth factor (TGF)-β1, which plays a key role in CAN. Hence, we tested the therapeutic potential of MEK-ERK1/2 signaling disruption to prevent CAN. Kidneys from C57BL/6J (H-2b) mice were transplanted to bilaterally nephrectomized BALB/c (H-2d) mice. At 14 days after transplantation, the recipients were subjected to 28 days of treatment with the MEK inhibitor CI-1040. All six CI-1040-treated allografts survived, while two of seven grafts in the vehicle-treated group were lost. At the end of the experiment, the function and structure of grafts in the CI-1040-treated group were significantly preserved, as indicated by lower levels of serum creatinine or blood urea nitrogen than in the vehicle-treated group [30 ± 6 vs. 94 ± 39 μM creatinine ( P = 0.0015) and 22 ± 8 vs. 56 ± 25 mM BUN ( P = 0.0054)] and reduced CAN in the CI-1040-treated group compared with vehicle controls (CAN score = 4.2 vs. 10.3, P = 0.0119). The beneficial effects induced by CI-1040 were associated with reduction of ERK1/2 phosphorylation and TGFβ1 levels in grafts. Also, CI-1040 potently suppressed not only TGFβ biosynthesis in kidney cell cultures but also antiallograft immune responses in vitro and in vivo. Our data suggest that interference of MEK-ERK1/2 signaling with a pharmacological agent (e.g., CI-1040) has therapeutic potential to prevent CAN in kidney transplantation.

scholarly journals Targeting necroptosis as therapeutic potential in chronic myocardial infarction

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Chanon Piamsiri ◽  
Chayodom Maneechote ◽  
Natthaphat Siri-Angkul ◽  
Siriporn C. Chattipakorn ◽  
Nipon Chattipakorn
Keyword(s):  
Myocardial Infarction ◽  
Therapeutic Potential ◽  
Coronary Perfusion ◽  
Beneficial Effects ◽  
Cell Death Pathways ◽  
Threatening Condition ◽  
Underlying Mechanisms ◽  
Novel Therapeutic Strategies

AbstractCardiovascular diseases (CVDs) are considered the predominant cause of morbidity and mortality globally. Of these, myocardial infarction (MI) is the most common cause of CVD mortality. MI is a life-threatening condition which occurs when coronary perfusion is interrupted leading to cardiomyocyte death. Subsequent to MI, consequences include adverse cardiac remodeling and cardiac dysfunction mainly contribute to the development of heart failure (HF). It has been shown that loss of functional cardiomyocytes in MI-induced HF are associated with several cell death pathways, in particular necroptosis. Although the entire mechanism underlying necroptosis in MI progression is still not widely recognized, some recent studies have reported beneficial effects of necroptosis inhibitors on cell viability and cardiac function in chronic MI models. Therefore, extensive investigation into the necroptosis signaling pathway is indicated for further study. This article comprehensively reviews the context of the underlying mechanisms of necroptosis in chronic MI-induced HF in in vitro, in vivo and clinical studies. These findings could inform ways of developing novel therapeutic strategies to improve the clinical outcomes in MI patients from this point forward.

scholarly journals ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment

2021 ◽  
Vol 7 (23) ◽  
pp. eabg2697
Author(s):  
Jiye Liu ◽  
Teru Hideshima ◽  
Lijie Xing ◽  
Su Wang ◽  
Wenrong Zhou ◽  
...  
Keyword(s):  
Patient Outcome ◽  
Bone Marrow ◽  
Nuclear Factor Κb ◽  
Mek Inhibitor ◽  
Erk Signaling ◽  
Immunomodulatory Drugs ◽  
Pathway Activation ◽  
Extracellular Signal

Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here, we identify that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) knockdown (KD)/knockout (KO) in MM cells mediates IMiD resistance via activation of noncanonical nuclear factor κB (NF-κB) and extracellular signal–regulated kinase (ERK) signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF-α induces proteasomal degradation of TRAF2, noncanonical NF-κB, and downstream ERK signaling in MM cells, whereas interleukin-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells both in vitro and in vivo. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance in the BM microenvironment and improve patient outcome in MM.

Uncaria tomentosa (Willd. ex Schult.): focus on nutraceutical aspects

2021 ◽  
Vol 17 ◽  
Author(s):  
Amirhossein Nazhand ◽  
Alessandra Durazzo ◽  
Massimo Lucarini ◽  
Amelia M. Silva ◽  
Selma B. Souto ◽  
...  
Keyword(s):  
Medicinal Plants ◽  
Therapeutic Potential ◽  
Production Costs ◽  
Industrialized Countries ◽  
Uncaria Tomentosa ◽  
Beneficial Effects ◽  
Microbial Infections ◽  
Health Promoting

: Medicinal plants have been globally exploiting as an alternative to chemical drugs in the treatment of several diseases due to low unwanted side effects, environmentally friendly nature and low production costs, therefore, it is important to analyze the therapeutic properties of various medicinal plants to understand their potential bioactivity. Uncaria tomentosa is one of these medicinal plants with many health-promoting effects. Although the geographical resources of cat's claw go back to the remote tropics of the Amazon, industrialized countries use the plant extensively in trade. Various parts of the plants such as flowers, leaves, Stem, hook, and seed are mainly used medicinally to treat inflammation, asthma, allergies, skin impurities, microbial infections, neurodegenerative diseases, cancer, cirrhosis, gastrointestinal disorders, arthritis, heart disease, rheumatism, and fever. The end point of this review article is to prospectively scrutinize in vitro and in vivo the therapeutic potential of this plant, especially in terms of its nutritional applications and health beneficial effects.

scholarly journals Pharmacological and Therapeutic Potential of Myristicin: A Literature Review

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5914
Author(s):  
Elisa Frederico Seneme ◽  
Daiane Carla dos Santos ◽  
Evelyn Marcela Rodrigues Silva ◽  
Yollanda Edwirges Moreira Franco ◽  
Giovanna Barbarini Longato
Keyword(s):  
Literature Review ◽  
Therapeutic Potential ◽  
Review Article ◽  
In Vivo Studies ◽  
Exclusion Criteria ◽  
Asian Continent ◽  
Natural Origin ◽  
Beneficial Effects

Natural products have been used by humanity for many centuries to treat various illnesses and with the advancement of technology, it became possible to isolate the substances responsible for the beneficial effects of these products, as well as to understand their mechanisms. In this context, myristicin, a substance of natural origin, has shown several promising activities in a large number of in vitro and in vivo studies carried out. This molecule is found in plants such as nutmeg, parsley, carrots, peppers, and several species endemic to the Asian continent. The purpose of this review article is to discuss data published in the last 10 years at Pubmed, Lilacs and Scielo databases, reporting beneficial effects, toxicity and promising data of myristicin for its future use in medicine. From 94 articles found in the literature, 68 were included. Exclusion criteria took into account articles whose tested extracts did not have myristicin as one of the major compounds.

scholarly journals Growth Hormone-Releasing Hormone in Lung Physiology and Pulmonary Disease

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2331
Author(s):  
Chongxu Zhang ◽  
Tengjiao Cui ◽  
Renzhi Cai ◽  
Medhi Wangpaichitr ◽  
Mehdi Mirsaeidi ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Lung Physiology ◽  
Extracellular Signal ◽  
P21 Activated Kinase

Growth hormone-releasing hormone (GHRH) is secreted primarily from the hypothalamus, but other tissues, including the lungs, produce it locally. GHRH stimulates the release and secretion of growth hormone (GH) by the pituitary and regulates the production of GH and hepatic insulin-like growth factor-1 (IGF-1). Pituitary-type GHRH-receptors (GHRH-R) are expressed in human lungs, indicating that GHRH or GH could participate in lung development, growth, and repair. GHRH-R antagonists (i.e., synthetic peptides), which we have tested in various models, exert growth-inhibitory effects in lung cancer cells in vitro and in vivo in addition to having anti-inflammatory, anti-oxidative, and pro-apoptotic effects. One antagonist of the GHRH-R used in recent studies reviewed here, MIA-602, lessens both inflammation and fibrosis in a mouse model of bleomycin lung injury. GHRH and its peptide agonists regulate the proliferation of fibroblasts through the modulation of extracellular signal-regulated kinase (ERK) and Akt pathways. In addition to downregulating GH and IGF-1, GHRH-R antagonist MIA-602 inhibits signaling pathways relevant to inflammation, including p21-activated kinase 1-signal transducer and activator of transcription 3/nuclear factor-kappa B (PAK1-STAT3/NF-κB and ERK). MIA-602 induces fibroblast apoptosis in a dose-dependent manner, which is an effect that is likely important in antifibrotic actions. Taken together, the novel data reviewed here show that GHRH is an important peptide that participates in lung homeostasis, inflammation, wound healing, and cancer; and GHRH-R antagonists may have therapeutic potential in lung diseases.

Mechanism of chronic aristolochic acid nephropathy: role of Smad3

2010 ◽  
Vol 298 (4) ◽  
pp. F1006-F1017 ◽  
Author(s):  
Li Zhou ◽  
Ping Fu ◽  
Xiao Ru Huang ◽  
Fei Liu ◽  
Arthur C. K. Chung ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Aristolochic Acid ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Chronic Administration ◽  
Mesenchymal Transition ◽  
Aristolochic Acid Nephropathy

Aristolochic acid nephropathy (AAN) has become a worldwide disease and is the most severe complication related to the use of traditional Chinese medicine. However, the pathogenic mechanisms of AAN remain unclear and therapies are limited. The present study tested the hypothesis that transforming growth factor (TGF)-β/Smad3 may be a key pathway leading to chronic AAN. This was examined in vivo in Smad3 wild-type/knockout (WT/KO) mice and in vitro in tubular epithelial cells with knockdown of Smad2 or Smad3. Results revealed that chronic administration of aristolochic acid (AA) resulted in a severe AAN characterized by progressive renal dysfunction and tubulointerstitial fibrosis including epithelial-mesenchymal transition (EMT) in Smad3 WT mice, but not in Smad3 KO mice, suggesting a critical role for Smad3 in the development of AAN. This was further tested in vitro. We found that AA was able to activate Smad signaling to mediate EMT and renal fibrosis via both TGF-β-dependent and JNK/MAP kinase-dependent mechanisms because blockade of JNK and specific knockdown of Smad3, but not Smad2, were able to attenuate AA-stimulated collagen matrix expression and EMT. In conclusion, TGF-β/Smad3 may be an essential mediator for chronic AAN. Results from this study indicate that specific blockade of the TGF-β/Smad3 signaling pathway may have therapeutic potential for chronic AAN.

scholarly journals Effect of Peptide Receptor Radionuclide Therapy in Combination with Temozolomide against Tumor Angiogenesis in a Glioblastoma Model

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5029
Author(s):  
Sang Hee Lee ◽  
Ji Young Choi ◽  
Jae Ho Jung ◽  
In Ho Song ◽  
Hyun Soo Park ◽  
...  
Keyword(s):  
Tumor Angiogenesis ◽  
Radionuclide Therapy ◽  
Tumor Volume ◽  
Therapeutic Potential ◽  
Combined Therapy ◽  
Peptide Receptor Radionuclide Therapy ◽  
Treated Group ◽  
Peptide Receptor ◽  
Vehicle Treated Group

Cell adhesion receptor integrin avb3 is a promising biomarker for developing tumor-angiogenesis targeted theranostics. In this study, we aimed to examine the therapeutic potential of peptide receptor radionuclide therapy (PRRT) with 188Re-IDA-D-[c(RGDfK)]2 (11.1 MBq). The results showed that the tumor volume was significantly decreased by 81% compared with the vehicle-treated group in U87-MG xenografts. The quantitative in vivo anti-angiogenic responses of PRRT were obtained using 99mTc-IDA-D-[c(RGDfK)]2 SPECT and corresponded to the measured tumor volume. PRRT combined with temozolomide (TMZ) resulted in a 93% reduction in tumor volume, which was markedly greater than that of each agent used individually. In addition, histopathological characterization showed that PRRT combined with TMZ was superior to PRRT or TMZ alone, even when TMZ was used at half dose. Overall, our results indicated that integrin-targeted PRRT and TMZ combined therapy might be a new medical tool for the effective treatment of glioblastoma.

scholarly journals Antioxidant Effects of Protocatechuic Acid and Protocatechuic Aldehyde: Old Wine in a New Bottle

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Shijun Zhang ◽  
Zhibo Gai ◽  
Ting Gui ◽  
Juanli Chen ◽  
Qingfa Chen ◽  
...  
Keyword(s):  
Phenolic Compounds ◽  
Protocatechuic Acid ◽  
Therapeutic Potential ◽  
Antioxidant Property ◽  
Biological Properties ◽  
Structural Variations ◽  
Beneficial Effects ◽  
Protocatechuic Aldehyde

Phenolic compounds are naturally present as secondary metabolites in plant-based sources such as fruits, vegetables, and spices. They have received considerable attention for their antioxidant, anti-inflammatory, and anti-carcinogenic properties for protection against many chronic disorders such as neurodegenerative diseases, diabetes, cardiovascular diseases, and cancer. They are categorized into various groups based on their chemical structure and include phenolic acids, flavonoids, curcumins, tannins, and quinolones. Their structural variations contribute to their specific beneficial effects on human health. The antioxidant property of phenolic compounds protects against oxidative stress by up-regulation of endogenous antioxidants, scavenging free radicals, and anti-apoptotic activity. Protocatechuic acid (PCA; 3,4-dihydroxy benzoic acid) and protocatechuic aldehyde (PAL; 3,4-dihydroxybenzaldehyde) are naturally occurring polyphenols found in vegetables, fruits, and herbs. PCA and PAL are the primary metabolites of anthocyanins and proanthocyanidins, which have been shown to possess pharmacological actions including antioxidant activity in vitro and in vivo. This review aims to explore the therapeutic potential of PCA and PAL by comprehensively summarizing their pharmacological properties reported to date, with an emphasis on their mechanisms of action and biological properties.

scholarly journals Exploration of Anti-Diabetic, Anti-Diarrheal, Gastrointestinal Motility and Acute Toxicity of Different Extracts of Citrus Assamensis Leaf

2018 ◽  
Vol 42 (2) ◽  
pp. 111-120
Author(s):  
Mohammad Shahriar ◽  
Mohiuddin Ahmed Bhuiyan ◽  
Md Sohel Rana
Keyword(s):  
Acute Toxicity ◽  
Gastrointestinal Motility ◽  
Treated Group ◽  
Chloroform Extract ◽  
Leaf Extracts ◽  
Ethanol Extracts ◽  
Academy Of Sciences ◽  
Vehicle Treated Group

Citrus assamensis (Family: Rutaceae), commonly known as Satkara, is a pharmacologically diverse medicinal plant. In the present study, the leaf extracts of C. assamensis were subjected to evaluate in vitro anti-diabetic as well as in vivo anti-diarrheal, gastrointestinal motility and acute toxicity activity on Swiss albino mice by using standard protocol. Ethanol and chloroform extracts showed significant inhibitory potentials (**p<0.01) against in vitro α-amylase enzyme at the concentration of 80μg/mL. Significant (*p<0.05, **p<0.01, ***p<0.001) reduction in the number of wet feces and percentage inhibition of diarrheal activity over three hours was observed with all the test doses of the extract compared with the vehicle treated group. Both doses of methanol and ethanol extracts (*p<0.05) and chloroform extract at doses of 100 mg/kg significantly reduced the number of wet feces compared to the control. None of the extracts showed any significant in vivo acute toxicity effect on mice. Journal of Bangladesh Academy of Sciences, Vol. 42, No. 2, 111-120, 2018

Blocking p38 signalling inhibits chondrogenesis in vitro but not ankylosis in a model of ankylosing spondylitis in vivo

2011 ◽  
Vol 71 (5) ◽  
pp. 722-728 ◽  
Author(s):  
Kirsten Braem ◽  
Frank P Luyten ◽  
Rik J U Lories
Keyword(s):  
Proinflammatory Cytokines ◽  
Chondrogenic Differentiation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Inhibitory Effect ◽  
Mitogen Activated Protein Kinase ◽  
Alternative Activation ◽  
Beneficial Effects

ObjectivesTo investigate p38 mitogen activated protein kinase (MAPK) signalling in an in vitro model of bone morphogenetic protein (BMP) and transforming growth factor β (TGFβ)-induced chondrogenesis and in vivo, with specific attention to its potential role in ankylosing enthesitis.MethodsHuman periosteum-derived cells (hPDCs) were cultured in pellets and stimulated with BMP2 or TGFβ1 in the presence or absence of a p38 inhibitor SB203580 or proinflammatory cytokines. Chondrogenic differentiation was evaluated using quantitative PCR. Male DBA/1 mice from different litters were caged together at the age of 8 weeks and treated with SB203580 in both a preventive and therapeutic strategy. The mice were evaluated for prospective signs of arthritis and the toe joints were analysed histologically to assess disease severity.Resultsp38 inhibition by SB203580 and proinflammatory cytokines downregulated chondrogenic markers in pellet cultures stimulated by BMP2 or TGFβ1. In contrast, the in vivo experiments resulted in an increased clinical incidence of arthritis and pathology severity score, reflecting progression towards ankylosis in mice given SB203580.ConclusionInhibition of p38 inhibited chondrogenic differentiation of progenitor cells, showing that not only the SMAD signalling pathways and also alternative activation of MAPKs including p38 contribute to chondrogenesis. Such an inhibitory effect is not found in an in vivo model of joint ankylosis and spondyloarthritis. Increased incidence and severity of disease in preventive experiments and shifts in disease stages in a therapeutic experimental set-up suggest that specific inhibition of p38 may have deleterious rather than beneficial effects.

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