作者: Tansey, Malú G ; Butkovich, Laura M ; Bradner, Joshua M ; Goodfellow, Val ; Chang, Jianjun ; Caudle, W Michael ; Kline, Elizabeth M ; Gelbard, Harris

Dopaminergic neurons express mixed lineage kinases which regulate the expression of cell death genes. In Parkinson's disease, cell death via apoptosis is prevalent, and previous work testing mixed lineage kinase inhibitors in animal models suggested the inhibitors had some neuroprotective potential. CLFB-1134 is a new, brain-penetrant inhibitor specific for MLK3, tested here in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of dopaminergic depletion and nigral neuron death in mice. After ensuring that treatment with CLFB-1134 did not alter conversion of MPTP to MPP+, we demonstrated CLFB-1134's inhibition of MLK3 and neuroprotective efficacy. Specifically we evaluated the integrity of the nigrostriatal dopamine system following MPTP by assessing protein expression, high performance liquid chromatography, and immunohistology with stereology. We found that CLFB-1134 achieves protection of striatal dopaminergic terminals and nigral cell bodies when dosed simultaneously or following MPTP treatment. By preventing phosphorylation of JNK and other downstream targets of MLK3, CLFB-1134 protects against the neurotoxin MPTP. Inhibition of MLK3 may be a valid target for future work investigating treatment of Parkinson's disease.

2016-03-01·Hepatology (Baltimore, Md.)1区 · 医学

Mixed lineage kinase 3 mediates release of C‐X‐C motif ligand 10–bearing chemotactic extracellular vesicles from lipotoxic hepatocytes

1区 · 医学

Article

作者: Goodfellow, Val S ; Bronk, Steven F ; Harrison, Stephen A ; Ibrahim, Samar H ; Gores, Gregory J ; Werneburg, Nathan W ; Malhi, Harmeet ; Tomita, Kyoko ; Hirsova, Petra

Mixed lineage kinase 3 (MLK3) deficiency reduces macrophage‐associated inflammation in a murine model of nonalcoholic steatohepatitis (NASH). However, the mechanistic links between MLK3 activation in hepatocytes and macrophage‐driven inflammation in NASH are uncharted. Herein, we report that MLK3 mediates the release of (C‐X‐C motif) ligand 10 (CXCL10)‐laden extracellular vesicles (EVs) from lipotoxic hepatocytes, which induce macrophage chemotaxis. Primary mouse hepatocytes (PMHs) and Huh7 cells were treated with palmitate or lysophosphatidylcholine (LPC). Released EVs were isolated by differential ultracentrifugation. LPC treatment of PMH or Huh7 cells induced release of EVs, which was prevented by either genetic or pharmacological inhibition of MLK3. Mass spectrometry identified the potent chemokine, CXCL10, in the EVs, which was markedly enriched in EVs isolated from LPC‐treated hepatocytes versus untreated cells. Green fluorescent protein (GFP)‐tagged CXCL10 was present in vesicular structures and colocalized with the red fluorescent protein (RFP)‐tagged EV marker, CD63, after LPC treatment of cotransfected Huh‐7 cells. Either genetic deletion or pharmacological inhibition of MLK3 prevented CXCL10 enrichment in EVs. Treatment of mouse bone‐marrow–derived macrophages with lipotoxic hepatocyte‐derived EVs induced macrophage chemotaxis, an effect blocked by incubation with CXCL10‐neutralizing antisera. MLK3‐deficient mice fed a NASH‐inducing diet had reduced concentrations of total plasma EVs and CXCL10 containing EVs compared to wild‐type mice. Conclusions: During hepatocyte lipotoxicity, activated MLK3 induces the release of CXCL10‐bearing vesicles from hepatocytes, which are chemotactic for macrophages. (Hepatology 2016;63:731–744)

2014-04-01·Molecular immunology3区 · 医学

MLK3 regulates fMLP-stimulated neutrophil motility

3区 · 医学

Article

作者: Daiss, John L ; Kim, Minsoo ; Dewhurst, Stephen ; Lebron, Luis ; Goodfellow, Val ; Wong, Christopher ; Gelbard, Harris A ; Chamberlain, Jeffrey M ; Polesskaya, Oksana

INTRODUCTION:

Mixed lineage kinase 3 (MLK3) is part of the intracellular regulatory system that connects extracellular cytokine or mitogen signals received through G-protein coupled receptors to changes in gene expression. MLK3 activation stimulates motility of epithelial cells and epithelial-derived tumor cells, but its role in mediating the migration of other cell types remains unknown. Since neutrophils play a crucial role in innate immunity and contribute to the pathogenesis of several diseases, we therefore examined whether MLK3 might regulate the motility of mouse neutrophils responding to a chemotactic stimulus, the model bacterial chemoattractant fMLP.

METHODS:

The expression of Mlk3 in mouse neutrophils was determined by immunocytochemistry and by RT-PCR. In vitro chemotaxis in a gradient of fMLP, fMLP-stimulated random motility, fMLP-stimulated F-actin formation were measured by direct microscopic observation using neutrophils pre-treated with a novel small molecule inhibitor of MLK3 (URMC099) or neutrophils obtained from Mlk3-/- mice. In vivo effects of MLK3 inhibition were measured by counting the fMLP-induced accumulation of neutrophils in the peritoneum following pre-treatment with URMC099 in wild-type C57Bl/6 or mutant Mlk3-/- mice.

RESULTS:

The expression of Mlk3 mRNA and protein was observed in neutrophils purified from wild-type C57Bl/6 mice but not in neutrophils from mutant Mlk3-/- mice. Chemotaxis by wild-type neutrophils induced by a gradient of fMLP was reduced by pre-treatment with URMC099. Neutrophils from C57Bl/6 mice pretreated with URMC099 and neutrophils from Mlk3-/- mice moved far less upon fMLP-stimulation and did not form F-actin as readily as untreated neutrophils from C57Bl/6 controls. In vivo recruitment of neutrophils into the peritoneum by fMLP was significantly reduced in wild-type mice treated with URMC099, as well as in untreated Mlk3-/- mice-thereby confirming the role of MLK3 in neutrophil migration.

CONCLUSIONS:

Mlk3 mRNA is expressed in murine neutrophils. Genetic or pharmacologic inhibition of MLK3 blocks fMLP-mediated motility of neutrophils both in vitro and in vivo, suggesting that MLK3 may be a therapeutic target in human diseases characterized by exuberant neutrophil migration.

项与 Califia Bio, Inc. 相关的新闻（医药）

2022-07-22

·BioSpace

Demand For Fiber Fortified Beverages Is Projected To Increase At A CAGR Of 5.6% From 2022 To 2032; States Fact.MR

Shipments Of Fiber Fortified Beverages Are Expected To Progress At A CAGR Of 5.6% Through 2032. Increasing demand for functional beverages that promote digestive health has increased owing to the rising focus on preventive healthcare and this is expected to positively influence fiber fortified beverage market potential. Fact.MR – A Market Research and Competitive Intelligence Provider: The global fiber fortified beverages market accounts for a total valuation of US$ 6.98 billion and is anticipated to attain an estimated revenue total of US$ 12.1 billion by the end of 2032. Fiber-based foods and beverages are also projected to witness a rise over the coming years as the focus on health and fitness bolsters across the forecast period. Increasing awareness of health benefits associated with fiber intake is expected to push more consumers to adopt fiber fortified drinks and foods over the coming years. Increasing availability of fiber fortified products, rising incidence of digestive disorders, the prevalence of chronic diseases, and rising per capita disposable income are other factors that further boost fiber fortified beverages market growth throughout the forecast period. For more insights into the Market, Request Brochure of this Report Key Takeways from Market Study Report The fiber fortified beverages market in Europe holds a major market share of 26.5% in 2022 and accounts for a total valuation of US$ 1.85 billion. Germany, Italy, France, and the United Kingdom are anticipated to be the key markets in this region over the coming years. At present, the fiber fortified beverages market in this region stands at a revenue total of US$ 1.62 billion and holds a market share of 23.3%. China fiber fortified beverages market stands at a revenue total of US$ 447.1 million in 2022 and accounts for a market share of 6.4% in the global industry landscape. The rising prevalence of digestive disorders and other chronic diseases in this region is expected to further boost demand for fiber fortified drinks over the years to come. What Opportunities are Present in the Market for New Players? “Start-ups Can Aim for Collaborations to Create Novel Offerings” In February 2022, Britvic a British soft drink manufacturer, announced a collaboration with Xampla, a technology company responsible for developing innovative pea protein packaging. Britvic through this collaboration will use Xampla’s novel technology to bottle its fortified beverages in clear packaging that it introduced to promote sustainability and recycling. New entrants could focus on such unique collaborations that create innovative solutions to the present-day problems that fiber fortified beverage suppliers and manufacturers face. Incoming market players could focus on sustainability to create a market presence for themselves as consumers and companies look for sustainability-compliant solutions and products. For Comprehensive Insights Ask An Analyst Here Which Distribution Channel is Slated to Lead Fiber Fortified Beverage Sales? “Hypermarkets & Supermarkets Expected to Lead Fiber Fortified Drink Shipments” The fiber fortified beverages market based on distribution channel is bifurcated into hypermarkets/supermarkets, convenience stores, food & drink specialty stores, specialty stores, online retail, and others. High availability of variety and consumer preference to shop from hypermarkets and supermarkets is projected to drive sales of fiber fortified beverages via these distribution channels. Sales from convenience stores are also expected to perform well over the years to come. Online retail sales are expected to speed up owing to the increasing expansion of e-commerce and rising preference for online shopping. Competitive Landscape: Fiber fortified beverage manufacturers are expected to launch new products to meet the increasing demand from rising health-conscious consumers across the world. This research by analysts at Fact.MR, a market research and competitive intelligence provider has assessed a complete survey of fiber fortified beverages market’s competitive landscape while profiling key companies such as Sanitarium, Abbott Laboratories, Califia Farms, Coca-Cola Company, Karma Wellness Water, and hello water, among others. Key Segments Covered in Fiber Fortified Beverages Industry Research Fiber Fortified Beverages Market by Type: Regular Flavored Tropical Fruits Berries Others Milk-based Drinks Fiber Fortified Beverages Market by Distribution Channel: Hypermarkets/Supermarkets Convenience Stores Food & Drink Specialty Stores Specialty Stores Online Retail Others Fiber Fortified Beverages Market by Region: North America Latin America Europe APAC MEA Get Customization on this Report for Specific Research Solutions Explore Fact.MR’s Coverage on the Healthcare Domain Orthopedic Implants Market - Orthopedic Implants Market Analysis by Product Type (Hip Reconstruction, Knee Reconstruction, Shoulder Implants), by Fixation Type (Cement, Cementless, Hybrid), by End User (Hospitals, Orthopedic Clinics, Ambulatory Surgical Centers, Others) and by Region- 2022 to 2032 Disposable Endoscopes Market - Disposable Endoscopes Market Report By End-Use (Hospitals, Clinics, Diagnostic Centers), Application (Bronchoscopy, Urologic Endoscopy, Arthroscopy, GI Endoscopy, ENT Endoscopy, Others) and By Region- 2022 to 2032 Medical Device Complaint Management Market - Medical Device Complaint Management Market Size, Share & Trends Analysis Report By Service Type (Product Surveillance & Regulatory Compliance, Complaint Log/Intake), By Region, And Segment Forecasts, 2022 - 2032 Endoscopes Market - Endoscopes Market Analysis By Product (Rigid Endoscopes, Flexible Endoscopes), By Application (Gastrointestinal Endoscopy, Laparoscopy, Gynecology Endoscopy, Urology Endoscopy, Arthroscopy), By End Use, By Region - Global Insights 2022 to 2032 Huntington's Disease Treatment Market - Huntington's Disease Treatment Market Analysis by Treatment (Symptomatic Treatment of Huntington's disease, Disease-Modifying Therapies for Huntington's disease), by Region - Global Forecast 2022-2032 Animal Vaccines Market - Animal Vaccines Market Analysis by Product (Attenuated, Recombinant, DNA, Inactivated, Subunit Animal Vaccines), by Animal Type (Livestock, Companion Animal Vaccines), by Route of Administration (Subcutaneous, Intranasal, Intramuscular) & Regional Forecast 2022-2032 Veterinary Artificial Insemination Market - Veterinary Artificial Insemination Market Analysis by Animal Type (Cattle, Swine, Ovine, Equine Veterinary Artificial Insemination), by Product (Normal Semen, Sexed Semen), by End User & Region - Global Forecast 2022-2032 Amniotic Membrane Market - Amniotic Membrane Market Analysis by Product (Cryopreserved, Dehydrated Amniotic Membrane), by Application (Surgical Wounds, Ophthalmology), by End Use, by Region - Global Forecast 2022-2032 Liposuction Surgery Devices Market - Liposuction Surgery Devices Market Analysis by Product Type (Stand-alone, Portable Liposuction Surgery Devices), by Technology (Tumescent, Ultrasound-assisted, Laser-assisted, Power-assisted, Water Assisted) & Regional Forecast 2022-2032 Mental Health Apps Market - Mental Health Apps Market Analysis by Platform Type (Mental Health Apps for Android, iOS), by Application Type (Depression and Anxiety Management, Stress Management, Meditation Management, Wellness Management), by Region - Global Forecast 2022-2032 About Fact.MR Fact.MR is a market research and consulting agency with deep expertise in emerging market intelligence. 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