Management of Cardiorenal Metabolic Syndrome in Diabetes Mellitus: A Phytotherapeutic Perspective

Cardiorenal syndrome (CRS) is a complex disease in which the heart and kidney are simultaneously affected and their deleterious declining functions are reinforced in a feedback cycle, with an accelerated progression. Although the coexistence of kidney and heart failure in the same individual carries an extremely bad prognosis, the exact cause of deterioration and the pathophysiological mechanisms underlying the initiation and maintenance of the interaction are complex, multifactorial in nature, and poorly understood. Current therapy includes diuretics, natriuretic hormones, aquaretics (arginine vasopressin antagonists), vasodilators, and inotropes. However, large numbers of patients still develop intractable disease. Moreover, the development of resistance to many standard therapies, such as diuretics and inotropes, has led to an increasing movement toward utilization and development of novel therapies. Herbal and traditional natural medicines may complement or provide an alternative to prevent or delay the progression of CRS. This review provides an analysis of the possible mechanisms and the therapeutic potential of phytotherapeutic medicines for the amelioration of the progression of CRS.

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AB0953 CANNABINOIDS: FRIEND OR FOE OR A BYSTANDER?

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6449 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1774.2-1774

Author(s):

N. Jain ◽

N. Reddy ◽

A. Moorthy

Keyword(s):

Chronic Pain ◽

Complementary Medicine ◽

Health Care Professionals ◽

Primary Care Physicians ◽

Therapeutic Potential ◽

Current Therapy ◽

Common Diagnosis ◽

Patient Reported ◽

Ongoing Pain ◽

Primary Physicians

Background:Cannabinoids has recently gained popularity for use in chronic pain. There is a lot of inquisitiveness among our patients wherein health care professionals are asked about its efficacy, side effects and sometimes even ask for a prescription! As there is paucity of data and research about its use in rheumatology, patient reported outcome(PROM) can guide ahead in expanding our knowledge and experience.Objectives:To study usage of cannabinoids by rheumatology patientsTo study awareness among primary physicians regarding Cannabinoid usage in rheumatology.Methods:Cross sectional survey with two arms. Arm 1 Information from patients attending tertiary rheumatology clinic,including perception regarding the use of Cannabinoids.Arm 2 consisted of collecting data via web-based survey with20-question from 100 GPs of Leicestershire. Questions on demographics, perspectives on and knowledge of cannabinoid use. Statistical analysis SPSS software.Results:Arm1 Total 102 rheumatology patients with 60%were females and 45% secondary education. 48% were unemployed. 75% Caucasians, 18% Asians. RA most common diagnosis followed by OA and FMS. 40 % depression and anxiety in addition to Rheumatic disease. 94% reported ongoing pain with 6-8 on a VAS scale. 79% were satisfied with their current therapy. 65% had heard about complementary medicine and 15% reported using cannabinoids.Most common form Cannabinoids oil 60% followed by smoking 20%. 56% reported using >3 months and majority 72% use daily. Median age 55 years. 88% users Caucasians. Mean disease duration 6.25 years among users indicates chronicity of disease has a direct proportion in usage. All users had ongoing pain of 7 on VAS. 87% believed it helps them managing pain effectively with a pain free state. On an average spends between 50-100 pounds per week. More than half believe cannabinoids should be available as a prescription drug in NHS and 30% interested to know more about it.In Arm 2 consisting of Primary care physicians, response rate 50%. Average clinical experience 5 years. Only 20% heard about usage of complementary medicine by rheumatology patient. Most replied that 10% of their patients use Cannabinoids for pain management. Most did not believe use of cannabinoids benefited the patients. Only 4% recommend its usage. 25% think it should be available as prescription. 40% experienced patients asking about cannabinoids during appointment. 88% of respondents did not know much about cannabinoid usage in rheumatology and have never prescribed it in their practice.Conclusion:Cannabinoids widely used by the rheumatology patients with PROM favouring its efficacy for control of chronic pain. Preclinical data suggest that cannabinoids might have a therapeutic potential RA1, OA, FMS2. Clinical data regarding cannabinoid treatment for rheumatic diseases are scarce, therefore, recommendations concerning cannabinoid treatment cannot be made. All patients who reported using it suffered from moderate to severe chronic pain. Thus main indication of usage was pain rather than recreational purpose. Although a small survey it clearly highlights lack of knowledge among primary physicians. These results emphasise the need for further research regarding the benefits and risks of cannabinoids in rheumatology.References:[1]RichardsonD. etal Characterisation ofthe cannabinoid receptor system in synovial tissue andfluid in patients with OA and RA Arthritis Res.Ther. 10, R43 (2008).[2]Walitt, B etal Cannabinoids for fibromyalgia. Cochrane DatabaseSyst. Rev. 7, CD011694 (2016).Disclosure of Interests:Nibha Jain: None declared, Neelima Reddy: None declared, Arumugam Moorthy Speakers bureau: Abbvie, Novartis,UCB,MSD

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Relevance of Translation Initiation in Diffuse Glioma Biology and its Therapeutic Potential

Cells ◽

10.3390/cells8121542 ◽

2019 ◽

Vol 8 (12) ◽

pp. 1542 ◽

Cited By ~ 3

Author(s):

Digregorio Marina ◽

Lombard Arnaud ◽

Lumapat Paul Noel ◽

Scholtes Felix ◽

Rogister Bernard ◽

...

Keyword(s):

Translation Initiation ◽

Protein Production ◽

Therapeutic Potential ◽

Environmental Stressors ◽

Current Therapy ◽

Diffuse Glioma ◽

Overall Survival Rate ◽

Malignant Cells ◽

Translational Machinery ◽

Initiation Step

Cancer cells are continually exposed to environmental stressors forcing them to adapt their protein production to survive. The translational machinery can be recruited by malignant cells to synthesize proteins required to promote their survival, even in times of high physiological and pathological stress. This phenomenon has been described in several cancers including in gliomas. Abnormal regulation of translation has encouraged the development of new therapeutics targeting the protein synthesis pathway. This approach could be meaningful for glioma given the fact that the median survival following diagnosis of the highest grade of glioma remains short despite current therapy. The identification of new targets for the development of novel therapeutics is therefore needed in order to improve this devastating overall survival rate. This review discusses current literature on translation in gliomas with a focus on the initiation step covering both the cap-dependent and cap-independent modes of initiation. The different translation initiation protagonists will be described in normal conditions and then in gliomas. In addition, their gene expression in gliomas will systematically be examined using two freely available datasets. Finally, we will discuss different pathways regulating translation initiation and current drugs targeting the translational machinery and their potential for the treatment of gliomas.

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GC-072, a Novel Therapeutic Candidate for Oral Treatment of Melioidosis and Infections Caused by Select Biothreat Pathogens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00834-19 ◽

2019 ◽

Vol 63 (12) ◽

Author(s):

Jeffry D. Shearer ◽

Michelle L. Saylor ◽

Christine M. Butler ◽

Anthony M. Treston ◽

Henry S. Heine ◽

...

Keyword(s):

Acute Phase ◽

Oral Treatment ◽

Lethal Dose ◽

Current Therapy ◽

Content Type ◽

Development Of Resistance ◽

Strong Candidate ◽

Oral Therapeutic ◽

Drug Resistant Strains

ABSTRACT Burkholderia pseudomallei, the etiological agent of melioidosis, is a Gram-negative bacterium with additional concern as a biothreat pathogen. The mortality rate from B. pseudomallei varies depending on the type of infection and extent of available health care; in the case of septicemia, left untreated, it can range from 50% to 90%. Current therapy for melioidosis is biphasic, consisting of parenteral acute-phase treatment for 2 weeks or longer, followed by oral eradication-phase treatment lasting several months. An effective oral therapeutic for outpatient treatment of acute-phase melioidosis is needed. GC-072 is a potent, 4-oxoquinolizine antibiotic with selective inhibitory activity against bacterial topoisomerases. GC-072 has demonstrated in vitro potency against susceptible and drug-resistant strains of B. pseudomallei and is also active against Burkholderia mallei, Bacillus anthracis, Yersinia pestis, and Francisella tularensis. GC-072 is bactericidal both extra- and intracellularly, with rapid killing noted within a few hours and reduced development of resistance compared to that for ceftazidime. GC-072, delivered intragastrically to mimic oral administration, promoted dose-dependent survival in mice using lethal inhalational models of B. pseudomallei infection following exposure to a 24- or 339-LD50 (50% lethal dose) challenge with B. pseudomallei strain 1026b. Overall, GC-072 appears to be a strong candidate for first-line oral treatment of melioidosis.

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Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin

Cancers ◽

10.3390/cancers12030608 ◽

2020 ◽

Vol 12 (3) ◽

pp. 608 ◽

Cited By ~ 6

Author(s):

Marta Mariniello ◽

Raffaella Petruzzelli ◽

Luca G. Wanderlingh ◽

Raffaele La Montagna ◽

Annamaria Carissimo ◽

...

Keyword(s):

Amphotericin B ◽

Therapeutic Potential ◽

Synthetic Lethality ◽

Resistance Mechanisms ◽

Ovarian Cancer Cells ◽

Tumor Resistance ◽

Development Of Resistance ◽

Wide Range ◽

Important Challenge ◽

Approved Drugs

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.

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Vitamin D as a novel therapy in inflammatory bowel disease: new hope or false dawn?

Proceedings of The Nutrition Society ◽

10.1017/s0029665114001621 ◽

2014 ◽

Vol 74 (1) ◽

pp. 5-12 ◽

Cited By ~ 28

Author(s):

Maria O'Sullivan

Keyword(s):

Rheumatoid Arthritis ◽

Inflammatory Bowel Disease ◽

Vitamin D ◽

Bowel Disease ◽

Complex Disease ◽

Therapeutic Potential ◽

Severe Disease ◽

Novel Therapy ◽

Vitamin D Levels ◽

Inflammatory Bowel

There is increasing scientific interest in the field of vitamin D research, moving the focus beyond bone health to other disease processes. Low circulating vitamin D levels have been reported as a risk factor for several pathophysiologically divergent diseases, including cancers, diabetes, CVD, multiple sclerosis and inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease (IBD). But, therein, remains the challenge: can any single nutrient contribute to multiple complex disease mechanisms and, ultimately, have therapeutic potential? The aim of this review is to critically evaluate several strands of scientific evidence surrounding vitamin D and inflammation, primarily focusing on IBD. Epidemiological studies suggest an increased incidence of IBD and rheumatoid arthritis in countries of more northern latitudes, mirroring sunlight patterns. A considerable body of evidence supports the anti-inflammatory effects of vitamin D, at least in animal models of IBD. Although it is accepted that suboptimal vitamin D status is common in IBD, some studies suggest that this associates with more severe disease. With regard to treatment, the data are only beginning to emerge from randomised controlled trials to suggest that people with IBD may remain in remission longer when treated with oral vitamin D. In conclusion, several strands of evidence suggest that vitamin D may modify the immune response in IBD. There is a continued need for large well-designed clinical trials and mechanistic studies to determine if, and how, this emerging promise translates into tangible clinical benefits for people with chronic debilitating diseases such as IBD.

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Therapeutic potential of FGF21 in cardiorenal syndrome

International Journal of Cardiology ◽

10.1016/j.ijcard.2016.03.142 ◽

2016 ◽

Vol 214 ◽

pp. 70-71 ◽

Cited By ~ 1

Author(s):

Fanghua Li ◽

Chengyuan Tang ◽

Zheng Dong

Keyword(s):

Therapeutic Potential ◽

Cardiorenal Syndrome

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TEMPORAL DEVELOPMENT OF RESISTANCE TO PULMONARY TUBERCULOSIS IN SWISS ALBINO MICE

Journal of Experimental Medicine ◽

10.1084/jem.133.2.376 ◽

1971 ◽

Vol 133 (2) ◽

pp. 376-388 ◽

Cited By ~ 4

Author(s):

Takateru Izumi ◽

Richard Costello

Keyword(s):

Pulmonary Tuberculosis ◽

Temporal Development ◽

Swiss Albino Mice ◽

Early Stages ◽

Development Of Resistance ◽

Stage Of Development ◽

Large Numbers ◽

Pulmonary Immunity ◽

Albino Mice

The course of pulmonary tuberculosis was followed in control and BCG-vaccinated mice. Resistance was evaluated by determining the numbers of virulent mycobacteria recovered from the organs at various intervals after airborn infection. A limited but significant retardation of growth of challenge bacilli was observed in both pulmonary and splenic tissues of successfully vaccinated animals. This retardation was manifested chiefly during the early stages of the infection. However, the numbers of virulent organisms recovered from the organs of either vaccinated or control animals were much the same at later stages of the infection. The appearance of pulmonary immunity was related to the stage of development in vivo of the vaccinal population. Only after large numbers of vaccinal bacilli could be recovered from the tissues was heightened resistance observed.

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Mechanism of drug-induced liver injury and hepatoprotective effects of natural drugs

Chinese Medicine ◽

10.1186/s13020-021-00543-x ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Yongfeng Zhou ◽

Junnan Wang ◽

Dingkun Zhang ◽

Jiaxin Liu ◽

Qinghua Wu ◽

...

Keyword(s):

Liver Injury ◽

Current Knowledge ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Health Products ◽

Hepatoprotective Effects ◽

Clinical Drugs ◽

Traditional Natural ◽

Natural Drugs ◽

Natural Medicines

AbstractDrug-induced liver injury (DILI) is a common adverse drug reaction (ADR) and a serious threat to health that affects disease treatments. At present, no targeted clinical drugs are available for DILI. Traditional natural medicines have been widely used as health products. Some natural medicines exert specific hepatoprotective effects, with few side effects and significant clinical efficacy. Thus, natural medicines may be a promising direction for DILI treatment. In this review, we summarize the current knowledge, common drugs and mechanisms of DILI, as well as the clinical trials of natural drugs and their bioactive components in anticipation of the future development of potential hepatoprotective drugs.

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Potential of miRNA-Based Nanotherapeutics for Uveal Melanoma

Cancers ◽

10.3390/cancers13205192 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5192

Author(s):

Chun Yang ◽

Rui Wang ◽

Pierre Hardy

Keyword(s):

Signaling Pathways ◽

Uveal Melanoma ◽

Intracellular Signaling ◽

Complex Disease ◽

Therapeutic Potential ◽

Cancer Therapeutics ◽

Delivery Systems ◽

Epigenetic Mechanism ◽

Target Cells ◽

Effective Delivery

Uveal melanoma (UM) is the most common adult intraocular cancer, and metastatic UM remains deadly and incurable. UM is a complex disease associated with the deregulation of numerous genes and redundant intracellular signaling pathways. As understanding of epigenetic dysregulation in the oncogenesis of UM has increased, the abnormal expression of microRNAs (miRNAs) has been found to be an epigenetic mechanism underlying UM tumorigenesis. A growing number of miRNAs are being found to be associated with aberrant signaling pathways in UM, and some have been investigated and functionally characterized in preclinical settings. This review summarizes the miRNAs with promising therapeutic potential for UM treatment, paying special attention to the therapeutic miRNAs (miRNA mimics or inhibitors) used to restore dysregulated miRNAs to their normal levels. However, several physical and physiological limitations associated with therapeutic miRNAs have prevented their translation to cancer therapeutics. With the advent of nanotechnology delivery systems, the development of effective targeted therapies for patients with UM has received great attention. Therefore, this review provides an overview of the use of nanotechnology drug delivery systems, particularly nanocarriers that can be loaded with therapeutic miRNAs for effective delivery into target cells. The development of miRNA-based therapeutics with nanotechnology-based delivery systems may overcome the barriers of therapeutic miRNAs, thereby enabling their translation to therapeutics, enabling more effective targeting of UM cells and consequently improving therapeutic outcomes.

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A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates

10.21203/rs.3.rs-737717/v1 ◽

2021 ◽

Author(s):

Simon Ströbel ◽

Radina Kostadinova ◽

Katia Fiaschetti-Egli ◽

Jana Rupp ◽

Manuela Bieri ◽

...

Keyword(s):

Complex Disease ◽

Therapeutic Potential ◽

Expression Patterns ◽

Therapeutic Interventions ◽

Type I ◽

Drug Candidates ◽

Procollagen Type ◽

Alcoholic Steatohepatitis ◽

Inflammatory Stimuli

Abstract Non-alcoholic steatohepatitis (NASH) is a progressive and severe liver disease, characterized by lipid accumulation, inflammation, and downstream fibrosis. Despite its increasing prevalence, there is no approved treatment yet available for patients. This has been at least partially due to the lack of predictive preclinical models for studying this complex disease. Here, we present a 3D in vitro microtissue model that uses spheroidal, scaffold free co-culture of primary human hepatocytes, Kupffer cells, liver endothelial cells and hepatic stellate cells. Upon exposure to defined and clinically relevant lipotoxic and inflammatory stimuli, these microtissues develop key pathophysiological features of NASH within 10 days, including an increase of intracellular triglyceride content and lipids, and release of pro-inflammatory cytokines. Furthermore, fibrosis was evident through release of procollagen type I, and increased deposition of extracellular collagen fibers. Whole transcriptome analysis revealed changes in the regulation of pathways associated with NASH, such as lipid metabolism, inflammation and collagen processing. Importantly, treatment with anti-NASH drug candidates (Selonsertib and Firsocostat) decreased the measured specific disease parameter, in accordance with clinical observations. These drug treatments also significantly changed the gene expression patterns of the microtissues, thus providing mechanisms of action and revealing therapeutic potential. In summary, this human NASH model represents a promising drug discovery tool for understanding the underlying complex mechanisms in NASH, evaluating efficacy of anti-NASH drug candidates and identifying new approaches for therapeutic interventions.

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