Anti-Fibrotic Effects of Calotropis procera (Ait.) R.Br Roots Barks against Diethylnitrosamine-Induced Hepatic Fibrosis in Rats

Background: Liver diseases including chronic hepatitis, steatosis, fibrosis, cirrhosis and liver cancer are now a public health problem. In 2002, cirrhosis accounted for 27.63% of hepatobiliary diseases in Burkina Faso. In Africa and more particularly in Burkina Faso, the majority of the population (about 80%) uses medicinal plants for their primary health care. Calotropis procera (Ait.) R.Br (Apocynaceae) is a medicinal plant used in Burkina Faso in the treatment of liver problems. This work aims to evaluate the anti-fibrotic properties of Calotropis procera roots barks. Methods: The anti-fibrotic activity of the ethanolic extract of Calotropis procera roots barks was evaluated using diethylnitrosamine (DEN) to induce liver fibrosis in male Wistar rats. Serum biomarkers, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), Total protein, Albumin, Υ-Glutamyl transferase (GGT) were evaluated and the activities of antioxidant enzymes (Superoxide dismutase and catalase) as well as the level of malonedialdehyde (MDA) and that of nitric oxide (NO) were determined in the liver homogenate. Results: The treatment of rats suffering from hepatic fibrosis with the ethanolic extract leads to a significant restoration of the biomarkers of the hepatic function in particular, AST, ALP, GGT, Albumin. The extract also causes a reduction in oxidative stress in the liver through a significant increase in the activity rate of the antioxidant enzymes Superoxide dismutase (SOD) and catalase accompanied by a significant drop in the rate of MDA and NO suggesting the anti-oxidant effect of extract. Conclusion: The results of the study show that the ethanolic extract of the roots barks of Calotropis procera has anti-fibrotic properties.

Anti-fibrotic effect of adipose-derived stem cells on fibrotic scars

BACKGROUND Sustained injury,through radiotherapy,burns or surgical trauma,can result in fibrosis,displaying an excessive deposition of extracellular matrix(ECM),persisting inflammatory reaction,and reduced vascularization.The increasing recognition of fibrosis as a cause for disease and mortality,and increasing use of radiotherapy causing fibrosis,stresses the importance of a decent anti-fibrotic treatment.AIM To obtain an in-depth understanding of the complex mechanisms underlying fibrosis,and more specifically,the potential mechanisms-of-action of adiposederived stomal cells(ADSCs)in realizing their anti-fibrotic effect.METHODS A systematic review of the literature using PubMed,Embase and Web of Science was performed by two independent reviewers.RESULTS The injection of fat grafts into fibrotic tissue,releases ADSC into the environment.ADSCs’capacity to directly differentiate into key cell types(e.g.,ECs,fibroblasts),as well as to secrete multiple paracrine factors(e.g.,hepatocyte growth factor,basis fibroblast growth factor,IL-10),allows them to alter different mechanisms underlying fibrosis in a combined approach.ADSCs favor ECM degradation by impacting the fibroblast-to-myofibroblast differentiation,favoring matrix metalloproteinases over tissue inhibitors of metalloproteinases,positively influencing collagen organization,and inhibiting the pro-fibrotic effects of transforming growth factor-β1.Furthermore,they impact elements of both the innate and adaptive immune response system,and stimulate angiogenesis on the site of injury(through secretion of pro-angiogenic cytokines like stromal cell-derived factor-1 and vascular endothelial growth factor).CONCLUSION This review shows that understanding the complex interactions of ECM accumulation,immune response and vascularization,is vital to fibrosis treatments’effectiveness like fat grafting.It details how ADSCs intelligently steer this complex system in an anti-fibrotic or pro-angiogenic direction,without falling into extreme dilation or stimulation of a single aspect.Detailing this combined approach,has brought fat grafting one step closer to unlocking its full potential as a non-anecdotal treatment for fibrosis.

Selective phytochemicals targeting pancreatic stellate cells as new anti-fibrotic agents for chronic pancreatitis and pancreatic cancer

Activated pancreatic stellate cells(PSCs)have been widely accepted as a key precursor of excessive pancreatic fibrosis,which is a crucial hallmark of chronic pancreatitis(CP)and its formidable associated disease,pancreatic cancer(PC).Hence,anti-fibrotic therapy has been identified as a novel therapeutic strategy for treating CP and PC by targeting PSCs.Most of the anti-fibrotic agents have been limited to phaseⅠ/Ⅱclinical trials involving vitamin analogs,which are abundant in medicinal plants and have proved to be promising for clinical application.The use of phytomedicines,as new anti-fibrotic agents,has been applied to a variety of complementary and alternative approaches.The aim of this review was to present a focused update on the selective new potential anti-fibrotic agents,including curcumin,resveratrol,rhein,emodin,green tea catechin derivatives,metformin,eruberin A,and ellagic acid,in combating PSC in CP and PC models.It aimed to describe the mechanism(s)of the phytochemicals used,either alone or in combination,and the associated molecular targets.Most of them were tested in PC models with similar mechanism of actions,and curcumin was tested intensively.Future research may explore the issues of bioavailability,drug design,and nano-formulation,in order to achieve successful clinical outcomes with promising activity and tolerability.

Inflammation and fibrosis in chronic liver diseases including nonalcoholic fatty liver disease and hepatitis C

At present chronic liver disease(CLD),the third commonest cause of premature death in the United Kingdom is detected late,when interventions are ineffective,resulting in considerable morbidity and mortality.Injury to the liver,the largest solid organ in the body,leads to a cascade of inflammatory events.Chronic inflammation leads to the activation of hepatic stellate cells that undergo transdifferentiation to become myofibroblasts,the main extra-cellular matrix producing cells in the liver;over time increased extra-cellular matrix production results in the formation of liver fibrosis.Although fibrogenesis may be viewed as having evolved as a“wound healing”process that preserves tissue integrity,sustained chronic fibrosis can become pathogenic culminating in CLD,cirrhosis and its associated complications.As the reference standard for detecting liver fibrosis,liver biopsy,is invasive and has an associated morbidity,the diagnostic assessment of CLD by non-invasive testing is attractive.Accordingly,in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice.Due to differing disease prevalence and treatment efficacy,disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection.To facilitate this,a review of the pathogenesis of both conditions is also conducted.Finally,the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed,including the current use of antifibrotic therapy.

Codonopsis tangshen Oliv.Amelioration Effect on Diabetic Kidney Disease Rats Induced by High Fat Diet Feeding Combined with Streptozotocin

Diabetic kidney disease(DKD)is the most serious microvascular complication during the development of diabetes with the characterizations of glomerular basement membrane thickening,mesangial expansion,and glomerular sclerosis,eventually leading to end-stage renal disease.This study aimed to investigate the melioration effect of Codonopisis tangshen Oliv.(COD)on the DKD model,which was established by unilateral nephrectomy(UN)-high fat diet feeding(HFD)combined with streptozotocin(STZ).After the DKD rats were oral treated with COD at a dose of 2.7 mg/kg for 4 consecutive weeks,the blood glucose,lipid metabolism,renal function,inflammatory mediators,and fibrosis-associated proteins were examined.In vivo,the COD administration obviously relieved the weight loss,water intake,and blood glucose;decreased the total cholesterol,triglyceride,and low-density lipoprotein cholesterol levels;and improved the renal function by reducing the expression of serum creatinine,uric acid,and urinary protein compared with the model group.The levels of pro-inflammatory cytokines of tumor necrosis factor-a,interleukin-1β,and IL-6 were significantly inhibited by COD.Meanwhile,the deposition of collagen fiber was markedly increased,and the protein and mRNA expressions of transforming growth factor-b1 and a-smooth muscle actin were markedly elevated in DKD rats,but they were decreased to some extent after the COD treatment.In conclusion,COD exhibited a protective effect on the UN-HFD feeding combined with STZ-induced DKD model by improving the blood glucose and lipid metabolism,relieving the inflammatory response,and mitigating the renal fibrosis,which provided scientific evidence for its applications in clinic.

Chemical components in cultivated Cordyceps sinensis and their effects on fibrosis

Objective:Cultivated Cordyceps sinensis powder has been used as clinical drug and healthy food to nourish the lung and kidney,which solves the problem of serious shortage of wild C.sinensis.This study aims to explore the chemical components and compared their anti-fibrotic effects in cultivated C.sinensis.Methods:Nucleosides,sterols and polysaccharides were separated and purified from cultivated C.sinensis,and analyzed by high performance liquid chromatography,gas chromatography-mass spectrometry and chemical chromogenic methods,respectively.In high glucose-induced rat mesangial cell models,fibronectin and type 1 collagen were used as evaluation indicators.Results:There were 10 kinds of nucleosides and one sterol in cultivated C.sinensis.The contents of nucleosides,sterols and polysaccharides in the cultivated C.sinensis were close to 2%,0.55%and 4.4%,respectively.Furthermore,nucleoside,sterol and polysaccharide components exhibited varying degrees of antifibrotic activity.The nucleoside components and sterol components inhibited the expression of extracellular matrix more effectively in the three main components.Conclusion:Cultivated C.sinensis remains the similar compounds with the wild C.sinensis,and nucleosides and sterols may be the main active substances that contribute to its anti-fibrotic effects.The project of this study may provide valuable information on further optimization of more effective remedies with few side effects based on cultivated C.sinensis.

Role of ferroptosis in fibrosis:From mechanism to potential therapy

Fibrosis,which is a manifestation of the physiological response to injury characterized by excessive accumulation of extracellular matrix components,is a ubiquitous outcome of the repair process.However,in cases of repetitive or severe injury,fibrosis may become dysregulated,leading to a pathological state and organ failure.In recent years,a novel form of regulated cell death,referred to as ferroptosis,has been identified as a possible contributor to fibrosis;it is characterized by iron-mediated lipid peroxidation.It has garnered attention due to the growing body of evidence linking ferroptosis and fibrogenesis,which is believed to be driven by underlying inflammation and immune responses.Despite the increasing interest in the relationship between ferroptosis and fibrosis,a comprehensive understanding of the precise role that ferroptosis plays in the formation of fibrotic tissue remains limited.This review seeks to synthesize previous research related to the topic.We categorized the different direct and indirect mechanisms by which ferroptosis may contribute to fibrosis into three categories:(1)iron overload toxicity;(2)ferroptosis-evoked necroinflammation,with a focus on ferroptosis and macrophage interplay;and(3)ferroptosis-associated pro-fibrotic factors and pathways.Furthermore,the review considers the potential implications of these findings and highlights the utilization of ferroptosis-targeted therapies as a promising strategy for mitigating the progression of fibrosis.In conclusion,novel anti-fibrotic treatments targeting ferroptosis could be an effective treatment for fibrosis.

Plant-derived phosphocholine facilitates cellular uptake of anti-pulmonary fibrotic HJT-sRNA-m7

Pulmonary fibrosis, a progressive chronic disease with a high mortality rate, has limited treatment options. Currently, lung transplantation remains the only effective treatment. Here we report that a small RNA, HJT-sRNA-m7, from a Chinese herbal medicine Hong Jing Tian(HJT, RHODIOHAE CRENULATAE RADIX ET RHIZOMA, Rhodiola crenulata) can effectively reduce the expressions of fibrotic hallmark genes and proteins both in alveolar in vitro and in mouse lung tissues in vivo. We also discovered over one hundred oil-soluble chemicals from HJT decoctions, most of which are found in lipid extracts from other Chinese herbals decoctions, including Pu Gong Ying(PGY, TARAXACI HERBA, Taraxacum mongolicum), Chuan Xin Lian(CXL, changed to "ANDROGRAPHIS HERBA, Andrographis paniculata"), and Jin Yin Hua(JYH, lonicera japonica or Honeysuckle). We identified the active component in these decoctions as two forms of phosphocholines, PC(18:0/18:2) and PC(16:0/18:2). These PCs potentially could form liposomes with small RNAs to enter human alveolar and gastric cells. Our experimental results suggest an unprecendent lipid complex route through which botanic small RNA can enter human bodies.Our results provide an innovative treatment strategy for oral delivery of siRNAs as therapeutic medication.

Decorin prevents the development of CCl4-induced liver fibrosis in mice

Background Liver fibrosis normally progresses to cirrhosis and destroys the normal architecture of the liver, resulting inliver dysfunction and irreversible cirrhosis. The aim of this study was to investigate the anti-fibrosis effect and the possibleunderlying mechanisms of decorin.

Efficient drug and gene delivery to liver fibrosis:rationale, recent advances, and perspectives

Liver fibrosis results from chronic damages together with an accumulation of extracellular matrix,and no specific medical therapy is approved for that until now.Due to liver metabolic capacity for drugs,the fragility of drugs,and the presence of insurmountable physiological obstacles in the way of targeting,the development of efficient drug delivery systems for anti-fibrotics seems vital.We have explored articles with a different perspective on liver fibrosis over the two decades,then collected and summarized the information by providing corresponding in vitro and in vivo cases.We have discussed the mechanism of hepatic fibrogenesis with different ways of fibrosis induction in animals.Furthermore,the critical chemical and herbal anti-fibrotics,biological molecules such as micro-RNAs,siRNAs,and growth factors,which can affect cell division and differentiation,are mentioned.Likewise,drug and gene delivery and therapeutic systems on in vitro and in vivo models are summarized in the data tables.This review article enlightens recent advances in emerging drugs and nanocarriers and represents perspectives on targeting strategies employed in liver fibrosis treatment.

Mesenchymal stem cell as a novelapproach to systemic sclerosis;currentstatus and future perspectives

Systemic sclerosis is a rare chronic autoimmune disease with extensive microvascular injury, damage of endothelialcells, activation of immune responses, and progression of tissue fibrosis in the skin and various internal organs.According to epidemiological data, women’s populations are more susceptible to systemic sclerosis than men. Untilnow, various therapeutic options are employed to manage the symptoms of the disease. Since stem cell-basedtreatments have developed as a novel approach to rescue from several autoimmune diseases, it seems that stemcells, especially mesenchymal stem cells as a powerful regenerative tool can also be advantageous for systemicsclerosis treatment via their remarkable properties including immunomodulatory and anti-fibrotic effects.Accordingly, we discuss the contemporary status and future perspectives of mesenchymal stem cell transplantationfor systemic sclerosis.

Modeling drug-induced liver injury and screening for anti-hepatofibrotic compounds using human PSC-derived organoids

Preclinical models that can accurately predict the toxicity and efficacy of candidate drugs to human liver tissue are in urgent need.Human liver organoid(HLO)derived from human pluripotent stem cells offers a possible solution.Herein,we generated HLOs,and demonstrated the utility of these HLOs in modeling a diversity of phenotypes associated with drug-induced liver injury(DILI),including steatosis,fibrosis,and immune responses.Phenotypic changes in HLOs after treatment with tool compounds such as acetaminophen,fialuridine,methotrexate,or TAK-875 showed high concordance with human clinical data in drug safety testings.Moreover,HLOs were able to model liver fibrogenesis induced by TGFβ or LPS treatment.We further devised a high-content analysis system,and established a high-throughput anti-fibrosis drug screening system using HLOs.SD208 and Imatinib were identified that can significantly suppress fibrogenesis induced by TGFβ,LPS,or methotrexate.Taken together,our studies demonstrated the potential applications of HLOs in drug safety testing and anti-fibrotic drug screening.