scholarly journals Inhibition of Rho Kinase by Fasudil Ameliorates Cognition Impairment in APP/PS1 Transgenic Mice via Modulation of Gut Microbiota and Metabolites

2021 ◽  
Vol 13 ◽  
Author(s):  
Yuqing Yan ◽  
Ye Gao ◽  
Qingli Fang ◽  
Nianping Zhang ◽  
Gajendra Kumar ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Abundance Ratio ◽  
Therapeutic Effects ◽  
Beneficial Effects ◽  
Model Of Alzheimer’S Disease ◽  
Potential Biomarker ◽  
Novel Strategy ◽  
Potential Biomarkers

Background: Fasudil, a Rho kinase inhibitor, exerts therapeutic effects in a mouse model of Alzheimer's disease (AD), a chronic neurodegenerative disease with progressive loss of memory. However, the mechanisms remain unclear. In addition, the gut microbiota and its metabolites have been implicated in AD.Methods: We examined the effect of fasudil on learning and memory using the Morris water-maze (MWM) test in APPswe/PSEN1dE9 transgenic (APP/PS1) mice (8 months old) treated (i.p.) with fasudil (25 mg/kg/day; ADF) or saline (ADNS) and in age- and gender-matched wild-type (WT) mice. Fecal metagenomics and metabolites were performed to identify novel biomarkers of AD and elucidate the mechanisms of fasudil induced beneficial effects in AD mice.Results: The MWM test showed significant improvement of spatial memory in APP/PS1 mice treated with fasudil as compared to ADNS. The metagenomic analysis revealed the abundance of the dominant phyla in all the three groups, including Bacteroidetes (23.7–44%) and Firmicutes (6.4–26.6%), and the increased relative abundance ratio of Firmicutes/Bacteroidetes in ADNS (59.1%) compared to WT (31.7%). In contrast, the Firmicutes/Bacteroidetes ratio was decreased to the WT level in ADF (32.8%). Lefse analysis of metagenomics identified s_Prevotella_sp_CAG873 as an ADF potential biomarker, while s_Helicobacter_typhlonius and s_Helicobacter_sp_MIT_03-1616 as ADNS potential biomarkers. Metabolite analysis revealed the increment of various metabolites, including glutamate, hypoxanthine, thymine, hexanoyl-CoA, and leukotriene, which were relative to ADNS or ADF microbiota potential biomarkers and mainly involved in the metabolism of nucleotide, lipids and sugars, and the inflammatory pathway.Conclusions: Memory deficit in APP/PS1 mice was correlated with the gut microbiome and metabolite status. Fasudil reversed the abnormal gut microbiota and subsequently regulated the related metabolisms to normal in the AD mice. It is believed that fasudil can be a novel strategy for the treatment of AD via remodeling of the gut microbiota and metabolites. The novel results also provide valuable references for the use of gut microbiota and metabolites as diagnostic biomarkers and/or therapeutic targets in clinical studies of AD.

scholarly journals Inhibition of Rho Kinase by Fasudil Ameliorates Cognition Impairment in APP/PS1 Transgenic Mice via Modulation of Gut Microbiota and Metabolites

2021 ◽  
Author(s):  
Yuqing Yan ◽  
Ye Gao ◽  
Qingli Fang ◽  
Nianping Zhang ◽  
Gajendra Kumar ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Morris Water Maze ◽  
Water Maze ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Morris Water Maze Test ◽  
Therapeutic Effects ◽  
Model Of Alzheimer’S Disease ◽  
Potential Biomarker ◽  
Potential Biomarkers

Abstract Background: Fasudil, a Rho kinase inhibitor, exerts therapeutic effects in the mouse model of Alzheimer’s disease (AD), a chronic neurodegenerative disease with progressive loss of memory. However, the mechanisms remain unclear. In addition, the gut microbiota and its metabolites have been implicated in AD. Methods: Here, we examined the effect of fasudil on learning and memory using the Morris water-maze (MWM) test in APPswe/PSEN1dE9 transgenic (APP/PS1) mice (8 months old) treated (i.p.) with fasudil (25 mg/kg/day; ADF) or saline (ADNS) and in age- and gender-matched wild-type (WT) mice. Fecal metagenomics and metabolites were analyzed to identify novel biomarkers of AD and to elucidate the mechanisms whereby fasudil produced beneficial effects in AD mice. Results: Morris water maze test showed significant improvement of spatial memory in APP/PS1 mice treated with fasudil as compared to ADNS. The metagenomic analysis revealed the abundance of the dominant phyla in all the three groups, including Bacteroidetes (23.7% - 44%) and Firmicutes (6.4% - 26.6%), and the increased relative abundance ratio of Firmicutes/Bacteroidetes in ADNS (59.1%) compared to WT (31.7%). In contrast, the Firmicutes/Bacteroidetes ratio was decreased to the WT level in ADF (32.8%). Lefse analysis results of metagenomics showed s_Prevotella_sp_CAG873 as an ADF potential biomarker, while s_Helicobacter_typhlonius and s_Helicobacter_sp_MIT_03-1616 as ADNS potential biomarkers. Metabolite analysis revealed the increment of various metabolites, including glutamate, hypoxanthine, thymine, hexanoyl-CoA, and leukotriene, were relative to ADNS or ADF microbiota potential biomarkers and mainly involved in the metabolism of nucleotide, lipids, sugars, and the inflammatory pathway. Conclusions: Memory deficit in APP/PS1 mice was correlated with the gut microbiome and metabolite status. Fasudil reversed the abnormal gut microbiota and subsequently regulated the related metabolisms to normal in the AD mice. It is believed that fasudil can be a novel strategy for the treatment of AD via remodeling of the gut microbiota and metabolites. The novel results also provide valuable references for the use of gut microbiota and metabolites as diagnostic biomarkers and/or therapeutic targets in clinical studies of AD.

Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9006-9006
Author(s):  
Joshua Bauml ◽  
Byoung Chul Cho ◽  
Keunchil Park ◽  
Ki Hyeong Lee ◽  
EUN KYUNG CHO ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Complete Response ◽  
Combination Regimen ◽  
Resistance Mutations ◽  
Tumor Biopsy ◽  
Potential Biomarker ◽  
Treatment Naïve ◽  
Exon 19 Deletion ◽  
Potential Biomarkers

9006 Background: Preliminary efficacy was observed with the combination of amivantamab, an EGFR-MET bispecific antibody, and lazertinib, a 3rd-generation tyrosine kinase inhibitor, in both treatment-naïve and osimertinib (osi)-relapsed patients (pts) with EGFRm NSCLC (Cho Ann Oncol 2020;31:S813). We present updated results of the combination in osi-relapsed pts, including an analysis of potential biomarkers of response. Methods: Pts with EGFR exon 19 deletion or L858R mutation NSCLC, who had progressed on osi without intervening chemotherapy, were enrolled in the combination cohort of the ongoing CHRYSALIS study (NCT02609776). With pre-treatment tumor biopsies and ctDNA collected prospectively, pts received the combination dose of 1050/1400 mg amivantamab + 240 mg lazertinib to assess safety and efficacy in the osi-relapsed population. Response was assessed by investigator per RECIST v1.1. Osi-resistance mutations or amplifications in EGFR/MET identified by next-generation sequencing (NGS) in either ctDNA or tumor biopsy (biomarker-positive [pos]), were evaluated for enriching response. Immunohistochemistry (IHC) staining for EGFR and MET expression was also explored as a potential biomarker for response. Results: Of the 45 osi-relapsed pts, 36% (95% CI, 22–51) had a confirmed response (1 complete response and 15 partial responses [PR]). At a median follow-up of 8.2 mo (1.0–11.8), 20/45 pts (44%) remain on treatment. With 11/16 pts (69%) continuing in response (2.6–9.6+ mo), median duration of response has not been reached (NR). The median progression-free survival (mPFS) was 4.9 mo (95% CI, 3.7–8.3). In total, 44/45 pts were evaluable by ctDNA and 29/45 by tumor NGS. Genetic testing identified 17 biomarker-pos pts, of whom 8 (47%) responded. Of the remaining 28 pts, 8 (29%) responded. Among these 28 pts, 18 had unknown mechanisms of osi-resistance (8 PR) and 10 had non-EGFR/MET mechanisms of resistance identified (none responded). The mPFS (95% CI) for biomarker-pos and remaining pts was 6.7 mo (3.4–NR) and 4.1 mo (1.4–9.5), respectively. Adequate tissue was available for 20 pts to perform IHC testing for EGFR and MET–9/10 (90%) IHC high (combined EGFR+MET H score>400) pts responded to treatment, while 1/10 IHC low pts responded to treatment. Conclusions: Treatment with the combination of amivantamab and lazertinib yielded responses in 36% of chemotherapy-naïve pts who progressed on osi. Among these pts, genetic EGFR and MET-based biomarkers of resistance identified a subgroup of pts more likely to respond to amivantamab and lazertinib, although additional pts lacking identified resistance markers also responded. An IHC-based approach may identify pts most likely to benefit from the combination regimen, but further investigation is warranted. Clinical trial information: NCT02609776.

scholarly journals Rosuvastatin intensifies the beneficial effects of rho-kinase inhibitor in reversal of monocrotaline-induced pulmonary hypertension

2016 ◽  
Vol 4 ◽  
pp. 898-905 ◽  
Author(s):  
Magdalena Jasińska-Stroschein ◽  
Jacek Owczarek ◽  
Urszula Sołtysiak ◽  
Daria Orszulak-Michalak
Keyword(s):  
Pulmonary Hypertension ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Beneficial Effects ◽  
Rho Kinase Inhibitor

Preventive and therapeutic effects of the selective Rho-kinase inhibitor fasudil on experimental autoimmune neuritis

2011 ◽  
Vol 306 (1-2) ◽  
pp. 115-120 ◽  
Author(s):  
Arnold Angelo M. Pineda ◽  
Motozumi Minohara ◽  
Nobutoshi Kawamura ◽  
Takuya Matsushita ◽  
Ryo Yamasaki ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Therapeutic Effects ◽  
Experimental Autoimmune Neuritis ◽  
Rho Kinase Inhibitor ◽  
Experimental Autoimmune

Rho-kinase: important new therapeutic target in cardiovascular diseases

2011 ◽  
Vol 301 (2) ◽  
pp. H287-H296 ◽  
Author(s):  
Kimio Satoh ◽  
Yoshihiro Fukumoto ◽  
Hiroaki Shimokawa
Keyword(s):  
Cardiovascular Diseases ◽  
Therapeutic Target ◽  
Kinase Inhibitor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Rho Kinase ◽  
Inflammatory Cells ◽  
Beneficial Effects ◽  
Kinase Pathway

Rho-kinase (ROCKs) belongs to the family of serine/threonine kinases and is an important downstream effector of the small GTP-binding protein RhoA. There are two isoforms of Rho-kinase, ROCK1 and ROCK2, and they have different functions with ROCK1 for circulating inflammatory cells and ROCK2 for vascular smooth muscle cells. It has been demonstrated that the RhoA/Rho-kinase pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation, and apoptosis, leading to the development of cardiovascular disease. The important role of Rho-kinase in vivo has been demonstrated in the pathogenesis of vasospasm, arteriosclerosis, ischemia-reperfusion injury, hypertension, pulmonary hypertension, stroke, and heart failure. Furthermore, the beneficial effects of fasudil, a selective Rho-kinase inhibitor, have been demonstrated for the treatment of several cardiovascular diseases in humans. Thus the Rho-kinase pathway is an important new therapeutic target in cardiovascular medicine.

scholarly journals Intestinal microbiota, diet and health

2013 ◽  
Vol 111 (3) ◽  
pp. 387-402 ◽  
Author(s):  
Susan E. Power ◽  
Paul W. O'Toole ◽  
Catherine Stanton ◽  
R. Paul Ross ◽  
Gerald F. Fitzgerald
Keyword(s):  
Gut Microbiota ◽  
Health Effect ◽  
Probiotic Strain ◽  
Therapeutic Modality ◽  
Future Research ◽  
Therapeutic Effects ◽  
Potential Health ◽  
Beneficial Effects ◽  
Treatment And Prevention ◽  
Probiotic Strains

The human intestine is colonised by 1013to 1014micro-organisms, the vast majority of which belong to the phyla Firmicutes and Bacteroidetes. Although highly stable over time, the composition and activities of the microbiota may be influenced by a number of factors including age, diet and antibiotic treatment. Although perturbations in the composition or functions of the microbiota are linked to inflammatory and metabolic disorders (e.g. inflammatory bowel diseases, irritable bowel syndrome and obesity), it is unclear at this point whether these changes are a symptom of the disease or a contributing factor. A better knowledge of the mechanisms through which changes in microbiota composition (dysbiosis) promote disease states is needed to improve our understanding of the causal relationship between the gut microbiota and disease. While evidence of the preventive and therapeutic effects of probiotic strains on diarrhoeal illness and other intestinal conditions is promising, the exact mechanisms of the beneficial effects are not fully understood. Recent studies have raised the question of whether non-viable probiotic strains can confer health benefits on the host by influencing the immune system. As the potential health effect of these non-viable bacteria depends on whether the mechanism of this effect is dependent on viability, future research needs to consider each probiotic strain on a case-by-case basis. The present review provides a comprehensive, updated overview of the human gut microbiota, the factors influencing its composition and the role of probiotics as a therapeutic modality in the treatment and prevention of diseases and/or restoration of human health.

scholarly journals Beneficial Effects of the Rho Kinase Inhibitor Y27632 in Murine Puromycin Aminonucleoside Nephrosis

2008 ◽  
Vol 31 (2) ◽  
pp. 111-121 ◽  
Author(s):  
Liming Wang ◽  
Mathew J. Ellis ◽  
Timothy A. Fields ◽  
David N. Howell ◽  
Robert F. Spurney
Keyword(s):  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Puromycin Aminonucleoside ◽  
Beneficial Effects ◽  
Rho Kinase Inhibitor ◽  
Aminonucleoside Nephrosis ◽  
Puromycin Aminonucleoside Nephrosis

scholarly journals Therapeutic Properties of Edible Mushrooms and Herbal Teas in Gut Microbiota Modulation

2021 ◽  
Vol 9 (6) ◽  
pp. 1262
Author(s):  
Emanuel Vamanu ◽  
Laura Dorina Dinu ◽  
Diana Roxana Pelinescu ◽  
Florentina Gatea
Keyword(s):  
Oxidative Stress ◽  
Gut Microbiota ◽  
Biologically Active ◽  
Edible Mushrooms ◽  
Therapeutic Effects ◽  
Beneficial Effects ◽  
Therapeutic Properties ◽  
Potential Strategy

Edible mushrooms are functional foods and valuable but less exploited sources of biologically active compounds. Herbal teas are a range of products widely used due to the therapeutic properties that have been demonstrated by traditional medicine and a supplement in conventional therapies. Their interaction with the human microbiota is an aspect that must be researched, the therapeutic properties depending on the interaction with the microbiota and the consequent fermentative activity. Modulation processes result from the activity of, for example, phenolic acids, which are a major component and which have already demonstrated activity in combating oxidative stress. The aim of this mini-review is to highlight the essential aspects of modulating the microbiota using edible mushrooms and herbal teas. Although the phenolic pattern is different for edible mushrooms and herbal teas, certain non-phenolic compounds (polysaccharides and/or caffeine) are important in alleviating chronic diseases. These specific functional compounds have modulatory properties against oxidative stress, demonstrating health-beneficial effects in vitro and/or In vivo. Moreover, recent advances in improving human health via gut microbiota are presented. Plant-derived miRNAs from mushrooms and herbal teas were highlighted as a potential strategy for new therapeutic effects.

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