Mesenchymal Stem Cells as New Therapeutic Agents for the Treatment of Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease characterized by the progressive destruction of small- and medium-sized intrahepatic bile ducts with resultant cholestasis and progressive fibrosis. Ursodeoxycholic acid and obethicholic acid are the only agents approved by the US Food and Drug Administration (FDA) for the treatment of PBC. However, for patients with advanced, end-stage PBC, liver transplantation is still the most effective treatment. Accordingly, the alternative approaches, such as mesenchymal stem cell (MSC) transplantation, have been suggested as an effective alternative therapy for these patients. Due to their immunomodulatory characteristics, MSCs are considered as promising therapeutic agents for the therapy of autoimmune liver diseases, including PBC. In this review, we have summarized the therapeutic potential of MSCs for the treatment of these diseases, emphasizing molecular and cellular mechanisms responsible for MSC-based effects in an animal model of PBC and therapeutic potential observed in recently conducted clinical trials. We have also presented several outstanding problems including safety issues regarding unwanted differentiation of transplanted MSCs which limit their therapeutic use. Efficient and safe MSC-based therapy for PBC remains a challenging issue that requires continuous cooperation between clinicians, researchers, and patients.

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Practical strategies for pruritus management in the obeticholic acid-treated patient with PBC: proceedings from the 2018 expert panel

BMJ Open Gastroenterology ◽

10.1136/bmjgast-2018-000256 ◽

2019 ◽

Vol 6 (1) ◽

pp. e000256 ◽

Cited By ~ 1

Author(s):

Jennifer Pate ◽

Juilo A Gutierrez ◽

Catherine T Frenette ◽

Aparna Goel ◽

Sonal Kumar ◽

...

Keyword(s):

Liver Disease ◽

Patient Adherence ◽

Treated Patient ◽

Management Strategies ◽

Primary Biliary Cholangitis ◽

Cholestatic Liver Disease ◽

Common Symptom ◽

Obeticholic Acid ◽

Intrahepatic Bile Ducts ◽

Patient Health

Background and aimsThis article provides expert guidance on the management of pruritus symptoms in patients receiving obeticholic acid (OCA) as treatment for primary biliary cholangitis (PBC). PBC is a chronic, autoimmune cholestatic liver disease that affects intrahepatic bile ducts. If not adequately treated, PBC can lead to cholestasis and end-stage liver disease, which may require transplant. Timely treatment is therefore vital to patient health. Pruritus is a common symptom in patients with PBC. Additionally, the use of OCA to treat PBC can contribute to increased pruritus severity in some patients, adding to patient discomfort, decreasing patient quality of life (QoL), and potentially affecting patient adherence to OCA treatment.MethodsIn May 2018, a group of physician experts from the fields of gastroenterology, hepatology, and psychiatry met to discuss the management of pruritus in OCA-treated patients with PBC. Recognizing the importance of optimizing treatment for PBC, these experts developed recommendations for managing pruritus symptoms in the OCA-treated PBC patient based on their experience in clinical practice.ResultsThese recommendations include a comprehensive list of management strategies (including over-the-counter, prescription, and alternative therapies), guidance on titration of OCA to minimize pruritus severity, and an algorithm that outlines a practical approach to follow up with patients receiving OCA, to better assess and manage pruritus symptoms.ConclusionsPruritus associated with OCA therapy is dose dependent and often manageable, and with the proper education and tools, most pruritus cases can be effectively managed to minimize treatment discontinuation.

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Therapeutic Potential of Polyphenols in the Management of Diabetic Neuropathy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/9940169 ◽

2021 ◽

Vol 2021 ◽

pp. 1-20

Author(s):

Md. Tanvir Kabir ◽

Nuzhat Tabassum ◽

Md. Sahab Uddin ◽

Faissal Aziz ◽

Tapan Behl ◽

...

Keyword(s):

Diabetic Neuropathy ◽

Motor Neurons ◽

Therapeutic Potential ◽

Alternative Therapy ◽

Clinical Manifestations ◽

Polyol Pathway ◽

Acid Group ◽

Therapeutic Agents ◽

Trophic Factors ◽

Patients With Diabetes

Diabetic neuropathy (DN) is a common and serious diabetes-associated complication that primarily takes place because of neuronal dysfunction in patients with diabetes. Use of current therapeutic agents in DN treatment is quite challenging because of their severe adverse effects. Therefore, there is an increased need of identifying new safe and effective therapeutic agents. DN complications are associated with poor glycemic control and metabolic imbalances, primarily oxidative stress (OS) and inflammation. Various mediators and signaling pathways such as glutamate pathway, activation of channels, trophic factors, inflammation, OS, advanced glycation end products, and polyol pathway have a significant contribution to the progression and pathogenesis of DN. It has been indicated that polyphenols have the potential to affect DN pathogenesis and could be used as potential alternative therapy. Several polyphenols including kolaviron, resveratrol, naringenin, quercetin, kaempferol, and curcumin have been administered in patients with DN. Furthermore, chlorogenic acid can provide protection against glutamate neurotoxicity via its hydrolysate, caffeoyl acid group, and caffeic acid through regulating the entry of calcium into neurons. Epigallocatechin-3-gallate treatment can protect motor neurons by regulating the glutamate level. It has been demonstrated that these polyphenols can be promising in combating DN-associated damaging pathways. In this article, we have summarized DN-associated metabolic pathways and clinical manifestations. Finally, we have also focused on the roles of polyphenols in the treatment of DN.

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rs1944919 on chromosome 11q23.1 and its effector genes COLCA1/COLCA2 confer susceptibility to primary biliary cholangitis

Scientific Reports ◽

10.1038/s41598-021-84042-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yuki Hitomi ◽

Yoshihiro Aiba ◽

Yosuke Kawai ◽

Kaname Kojima ◽

Kazuko Ueno ◽

...

Keyword(s):

Genome Wide Association Study ◽

Susceptibility Gene ◽

Primary Biliary Cholangitis ◽

Cholestatic Liver Disease ◽

Autoimmune Reaction ◽

Expression Levels ◽

Intrahepatic Bile Ducts ◽

Genome Wide ◽

Functional Analyses

AbstractPrimary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease in which intrahepatic bile ducts are destroyed by an autoimmune reaction. Our previous genome-wide association study (GWAS) identified chromosome 11q23.1 as a susceptibility gene locus for PBC in the Japanese population. Here, high-density association mapping based on single nucleotide polymorphism (SNP) imputation and in silico/in vitro functional analyses identified rs1944919 as the primary functional variant. Expression-quantitative trait loci analyses showed that the PBC susceptibility allele of rs1944919 was significantly associated with increased COLCA1/COLCA2 expression levels. Additionally, the effects of rs1944919 on COLCA1/COLCA2 expression levels were confirmed using genotype knock-in versions of cell lines constructed using the CRISPR/Cas9 system and differed between rs1944919-G/G clones and -T/T clones. To our knowledge, this is the first study to demonstrate the contribution of COLCA1/COLCA2 to PBC susceptibility.

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The Pathogenesis of Primary Biliary Cholangitis: A Comprehensive Review

Seminars in Liver Disease ◽

10.1055/s-0039-1697617 ◽

2019 ◽

Vol 40 (01) ◽

pp. 034-048 ◽

Cited By ~ 4

Author(s):

Ana Lleo ◽

Patrick S.C. Leung ◽

Gideon M. Hirschfield ◽

Eric M. Gershwin

Keyword(s):

Active Role ◽

Medium Size ◽

Primary Biliary Cholangitis ◽

Cholestatic Liver Disease ◽

Key Factors ◽

Intrahepatic Bile Ducts ◽

Autoimmune Destruction ◽

Chronic Cholestasis ◽

Immune Mediated ◽

Mitochondrial Antigens

AbstractPrimary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by autoimmune destruction of small to medium size intrahepatic bile ducts. The etiology of PBC remains unknown and pathogenesis features immune-mediated biliary injury, alongside the consequences of chronic cholestasis. PBC is strongly associated with the loss of immune tolerance against mitochondrial antigens and the subsequent presence of an articulated immunologic response that involves both humoral and cellular responses. Both environmental factors and genetic variants increase PBC susceptibility. Biliary epithelial cells have often been considered a passive target of the immune attack in PBC; however, cholangiocyte dedifferentiation, senescence, stress, and deoxyribonucleic acid damage have been recognized to play an active role in the pathogenesis of PBC. This review highlights and discusses the most relevant pathogenetic mechanisms in PBC, focusing on the key factors that lead to the onset of cholestasis and immune activation.

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Therapeutic Potential of Mesenchymal Stem Cells and Their Secretome in the Treatment of Glaucoma

Stem Cells International ◽

10.1155/2019/7869130 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

C. Randall Harrell ◽

Crissy Fellabaum ◽

Aleksandar Arsenijevic ◽

Bojana Simovic Markovic ◽

Valentin Djonov ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Visual Information ◽

Therapeutic Potential ◽

Current Knowledge ◽

Therapeutic Agents ◽

Dependent Manner ◽

Cellular Mechanisms ◽

Cell Based Therapy ◽

Glaucoma Treatment

Glaucoma represents a group of progressive optic neuropathies characterized by gradual loss of retinal ganglion cells (RGCs), the neurons that conduct visual information from the retina to the brain. Elevated intraocular pressure (IOP) is considered the main reason for enhanced apoptosis of RGCs in glaucoma. Currently used therapeutic agents are not able to repopulate and/or regenerate injured RGCs and, therefore, are ineffective in most patients with advanced glaucoma. Accordingly, several new therapeutic approaches, including stem cell-based therapy, have been explored for the glaucoma treatment. In this review article, we emphasized current knowledge regarding molecular and cellular mechanisms responsible for beneficial effects of mesenchymal stem cells (MSCs) and their secretome in the treatment of glaucoma. MSCs produce neurotrophins and in an exosome-dependent manner supply injured RGCs with growth factors enhancing their survival and regeneration. Additionally, MSCs are able to generate functional RGC-like cells and induce proliferation of retinal stem cells. By supporting integrity of trabecular meshwork, transplanted MSCs alleviate IOP resulting in reduced loss of RGCs. Moreover, MSCs are able to attenuate T cell-driven retinal inflammation providing protection to the injured retinal tissue. In summing up, due to their capacity for neuroprotection and immunomodulation, MSCs and their secretome could be explored in upcoming clinical studies as new therapeutic agents for glaucoma treatment.

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Genetic association of E26 transformation specific sequence 1 polymorphisms with the susceptibility of primary biliary cholangitis in China

Scientific Reports ◽

10.1038/s41598-019-56181-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Huan Xu ◽

Qian Niu ◽

Zhenzhen Su ◽

Fang Wang ◽

Junlong Zhang ◽

...

Keyword(s):

Gene Polymorphisms ◽

Primary Biliary Cholangitis ◽

Cholestatic Liver Disease ◽

Nucleotide Polymorphisms ◽

Chinese Han ◽

Specific Sequence ◽

Low Level ◽

Intrahepatic Bile Ducts ◽

Homozygous Genotype ◽

High Level

AbstractPrimary biliary cholangitis (PBC) is a chronic and cholestatic liver disease characterized by an autoimmune-mediated destruction of intrahepatic bile ducts. E26 transformation specific sequence 1 (ETS-1) is a transcription factor regulating the expression of various immune-related genes. The aim of our study was to identify the associations between the gene polymorphisms of ETS-1 with the susceptibility and clinical characteristics of PBC in Chinese Han population. Three single nucleotide polymorphisms (rs4937333, rs11221332 and rs73013527) of ETS-1 were selected based on relevant studies. Genotyping was executed with polymerase chain reaction-high resolution melting (PCR-HRM) assay. SNP rs4937333 of ETS-1 was prominent correlation with the susceptibility of PBC (P = 0.007, OR = 1.44, 95%CI = 1.10–1.88). For rs4937333, PBC patients carrying the allele T assumed high-level TP (P = 0.020), and homozygous genotype TT assumed low-level RDW (P = 0.033). For rs11221332, PBC patients carrying the allele T assumed high-level TP and HDLC (P = 0.004, P = 0.015, respectively). For rs73013527, PBC patients carrying the allele T assumed low-level PLT (P = 0.002), and homozygous genotype TT assumed high-level RDW (P = 0.021). In conclusion, Gene polymorphisms of ETS-1 present relevant with the susceptibility of PBC, and affect the expression of TP, HDLC, PLT and RDW concentrations in patients with PBC.

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Flavonoids in adipose tissue inflammation and atherosclerosis: one arrow, two targets

Clinical Science ◽

10.1042/cs20200356 ◽

2020 ◽

Vol 134 (12) ◽

pp. 1403-1432 ◽

Cited By ~ 2

Author(s):

Manal Muin Fardoun ◽

Dina Maaliki ◽

Nabil Halabi ◽

Rabah Iratni ◽

Alessandra Bitto ◽

...

Keyword(s):

Adipose Tissue ◽

Fruits And Vegetables ◽

Metabolic Diseases ◽

Therapeutic Agents ◽

Adipose Tissue Inflammation ◽

Cellular Mechanisms ◽

Tissue Inflammation ◽

Cholesterol Levels ◽

Naturally Occurring ◽

Pro Inflammatory Cytokines

Abstract Flavonoids are polyphenolic compounds naturally occurring in fruits and vegetables, in addition to beverages such as tea and coffee. Flavonoids are emerging as potent therapeutic agents for cardiovascular as well as metabolic diseases. Several studies corroborated an inverse relationship between flavonoid consumption and cardiovascular disease (CVD) or adipose tissue inflammation (ATI). Flavonoids exert their anti-atherogenic effects by increasing nitric oxide (NO), reducing reactive oxygen species (ROS), and decreasing pro-inflammatory cytokines. In addition, flavonoids alleviate ATI by decreasing triglyceride and cholesterol levels, as well as by attenuating inflammatory mediators. Furthermore, flavonoids inhibit synthesis of fatty acids and promote their oxidation. In this review, we discuss the effect of the main classes of flavonoids, namely flavones, flavonols, flavanols, flavanones, anthocyanins, and isoflavones, on atherosclerosis and ATI. In addition, we dissect the underlying molecular and cellular mechanisms of action for these flavonoids. We conclude by supporting the potential benefit for flavonoids in the management or treatment of CVD; yet, we call for more robust clinical studies for safety and pharmacokinetic values.

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Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches

Cancers ◽

10.3390/cancers11111627 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1627 ◽

Cited By ~ 5

Author(s):

Anita Thyagarajan ◽

Mamdouh Salman A. Alshehri ◽

Kelly L.R. Miller ◽

Catherine M. Sherwin ◽

Jeffrey B. Travers ◽

...

Keyword(s):

Survival Rates ◽

Suppressor Cells ◽

Cell Types ◽

Therapeutic Agents ◽

Ductal Adenocarcinoma ◽

Cancer Therapies ◽

Myeloid Derived Suppressor Cells ◽

Tumor Resistance ◽

Cellular Mechanisms ◽

Immunosuppressive Cell

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating human malignancy with poor prognosis and low survival rates. Several cellular mechanisms have been linked with pancreatic carcinogenesis and also implicated in inducing tumor resistance to known therapeutic regimens. Of various factors, immune evasion mechanisms play critical roles in tumor progression and impeding the efficacy of cancer therapies including PDAC. Among immunosuppressive cell types, myeloid-derived suppressor cells (MDSCs) have been extensively studied and demonstrated to not only support PDAC development but also hamper the anti-tumor immune responses elicited by therapeutic agents. Notably, recent efforts have been directed in devising novel approaches to target MDSCs to limit their effects. Multiple strategies including immune-based approaches have been explored either alone or in combination with therapeutic agents to target MDSCs in preclinical and clinical settings of PDAC. The current review highlights the roles and mechanisms of MDSCs as well as the implications of this immunomodulatory cell type as a potential target to improve the efficacy of therapeutic regimens for PDAC.

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Botulinum Toxin in Movement Disorders: An Update

Toxins ◽

10.3390/toxins13010042 ◽

2021 ◽

Vol 13 (1) ◽

pp. 42

Author(s):

Charenya Anandan ◽

Joseph Jankovic

Keyword(s):

Botulinum Toxin ◽

Movement Disorders ◽

Neurological Disorders ◽

Active Drug ◽

Therapeutic Agents ◽

Therapeutic Modality ◽

Review Of The Literature ◽

Pilot Studies ◽

The Us ◽

Novel Applications

Since its initial approval in 1989 by the US Food and Drug Administration for the treatment of blepharospasm and other facial spasms, botulinum toxin (BoNT) has evolved into a therapeutic modality for a variety of neurological and non-neurological disorders. With respect to neurologic movement disorders, BoNT has been reported to be effective for the treatment of dystonia, bruxism, tremors, tics, myoclonus, restless legs syndrome, tardive dyskinesia, and a variety of symptoms associated with Parkinson’s disease. More recently, research with BoNT has expanded beyond its use as a powerful muscle relaxant and a peripherally active drug to its potential central nervous system applications in the treatment of neurodegenerative disorders. Although BoNT is the most potent biologic toxin, when it is administered by knowledgeable and experienced clinicians, it is one of the safest therapeutic agents in clinical use. The primary aim of this article is to provide an update on recent advances in BoNT research with a focus on novel applications in the treatment of movement disorders. This comprehensive review of the literature provides a critical review of evidence-based clinical trials and highlights recent innovative pilot studies.

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Widespread gaps in the quality of care for primary biliary cholangitis in UK

Frontline Gastroenterology ◽

10.1136/flgastro-2020-101713 ◽

2021 ◽

pp. flgastro-2020-101713

Author(s):

Mathuri Sivakumar ◽

Akash Gandhi ◽

Eathar Shakweh ◽

Yu Meng Li ◽

Niloufar Safinia ◽

...

Keyword(s):

Quality Of Care ◽

Medical Records ◽

Clinical Symptoms ◽

Primary Biliary Cholangitis ◽

Cholestatic Liver Disease ◽

Patient Demographics ◽

Risk Patients ◽

Wide Scale ◽

The Uk

ObjectivePrimary biliary cholangitis (PBC) is a progressive, autoimmune, cholestatic liver disease affecting approximately 15 000 individuals in the UK. Updated guidelines for the management of PBC were published by The European Association for the Study of the Liver (EASL) in 2017. We report on the first national, pilot audit that assesses the quality of care and adherence to guidelines.DesignData were collected from 11 National Health Service hospitals in England, Wales and Scotland between 2017 and 2020. Data on patient demographics, ursodeoxycholic acid (UDCA) dosing and key guideline recommendations were captured from medical records. Results from each hospital were evaluated for target achievement and underwent χ2 analysis for variation in performance between trusts.Results790 patients’ medical records were reviewed. The data demonstrated that the majority of hospitals did not meet all of the recommended EASL standards. Standards with the lowest likelihood of being met were identified as optimal UDCA dosing, assessment of bone density and assessment of clinical symptoms (pruritus and fatigue). Significant variations in meeting these three standards were observed across UK, in addition to assessment of biochemical response to UDCA (all p<0.0001) and assessment of transplant eligibility in high-risk patients (p=0.0297).ConclusionOur findings identify a broad-based deficiency in ‘real-world’ PBC care, suggesting the need for an intervention to improve guideline adherence, ultimately improving patient outcomes. We developed the PBC Review tool and recommend its incorporation into clinical practice. As the first audit of its kind, it will be used to inform a future wide-scale reaudit.

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