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Tanshinone IIA is a diterpene extracted from Salvia miltiorrhiza, a popular and safe herb medicine that has been widely used in China and other Asian countries. Previous studies have demonstrated the pleiotropic effects of Tanshinone IIA on many disease treatments via its antitoxicity, anti-inflammation, anti-oxidative stress, as well as antifibrosis activities. However, its effect on acute kidney injury (AKI) has not been fully investigated. Here, we show for the first time that systemic administration of Tanshinone IIA can lead to improved kidney function in folic acid-induced kidney injury mice. In the acute phase of AKI, Tanshinone IIA attenuated renal tubular epithelial injury, as determined by histologic changes and the detection of Neutrophil gelatinase-associated lipocalin (NGAL) in the kidney and urine. Additionally, Tanshinone IIA treatment resulted in elevated proliferating cell nuclear antigen (PCNA) expression and decreased inflammatory cells infiltration as well as chemokine expression, suggesting that Tanshinone IIA promoted renal repair following AKI and inhibited local inflammatory response in the injured kidney. This led to decreased long-term fibrosis in the injured kidney, characterized by less accumulation of fibronectin and collagen I in tubulointerstitium. Taken together, these results suggest that Tanshinone IIA may represent a potential approach for AKI treatment.

Antrodia cinnamomea (A. cinnamomea), a popular medicinal mushroom in Taiwan, is widely used to prevent or treat liver diseases. Systematic studies on the anti-inflammatory effect of A. cinnamomea and its molecular mechanisms have not yet been fully investigated. HPLC fingerprint analysis identified seven ergostane-type triterpenoids from A. cinnamomea water extract (ACW), including high amounts of Antcin K (AC), Antcin C, Antcin H, Dehydrosulphurenic acid, Antcin B, Antcin A and Dehydroeburicoic acid. Here, we explored the effects and mechanisms of ACW and the highest content AC on N-nitrosodiethylamine (DEN) induced liver inflammation, fibrosis and carcinogenesis in rats. In the in vitro study, we measured how ACW and AC dose-dependently scavenged O${}_2^{-.}$, H₂O₂ and HOCl by a chemiluminescence analyzer. In the in vivo experiment, oral intake ACW and AC significantly inhibited DEN-enhanced hepatocellular inflammation, fibrosis and carcinoma by pathologic observation, the elevated bile and liver reactive oxygen species (ROS) amounts, plasma $\gamma$-glutamyl transpeptidase, and oxidative stress including 3-nitrotyrosine, 4-hydroxynonenal and Kuppfer cell infiltration (ED-1 stains) in the inflammatory livers. DEN enhanced nuclear factor-$\kappa$B (NF-$\kappa$B) translocation, whereas ACW and AC suppressed DEN-enhanced NF-$\kappa$B translocation through the inhibition of its upstream signaling of p85/phosphoinositide-3-kinase, mitogen activated protein kinase and CYP2E1 expression. In conclusion, DEN can induce hepatocellular inflammation, fibrosis and carcinoma by increasing NF-$\kappa$B translocation to the nucleus, and oxidative injury. ACW and its active component, Antcin K, counteract DEN-induced hepatic injury and inflammation by the protective and therapeutic mechanisms of a direct scavenging ROS activity and an upregulation of anti-oxidant defense mechanisms.

Platycodin D (PD) is the main active saponin isolated from Platycodon grandiflorum (PG) and is reported to exhibit anticancer, anti-angiogenic, anti-inflammation and anti-obesity biological effects. The current study aims to evaluate the therapeutic efficacy of PD in cardiac fibrosis and for hypertrophy in spontaneous hypertension rats (SHRs) and to verify inhibition of the signaling pathway. Significant increases in the cardiac functional indices of left ventricular internal diameter end diastole (LVIDd) and left ventricular internal diameter end systole (LVIDs); the eccentric hypertrophy marker p-MEK5; concentric hypertrophy markers, such as CaMKII$\alpha$ and calcineurin; and expression levels of NFATc3, p-GATA4 and BNP were observed in spontaneously hypertensive groups. PD treatment reversed these increases in SHRs. In addition, an increase in the fibrosis markers FGF2, uPA, MMP2, MMP9, TGF$\beta$-1 and CTGF during cardiac hypertrophy was detected by western blotting analyses. These results demonstrated that PD treatment considerably attenuates cardiac fibrosis. Histopathological examination revealed that PD treatment remarkably reduced collagen accumulation in contrast to spontaneously hypertensive groups. This study clearly suggests that PD provides myocardial protection by alleviating two damaging responses to hypertension, fibrosis and hypertrophy, in the heart.

Our previous report revealed that Gardenia jasminoides (GJ) has protective effects against acute pancreatitis. So, we examined whether aqueous extract of GJ has anti-inflammation and antifibrotic effects even against cerulein-induced chronic pancreatitis (CP). CP was induced in mice by an intraperitoneal injection of a stable cholecystokinin (CCK) analogue, cerulein, six times a day, four days per week for three weeks. GJ extract (0.1 or 1g/kg) or saline (control group) were intraperitoneally injected 1h before first cerulein injection. After three weeks of stimulation, the pancreas was harvested for the examination of several fibrotic parameters. In addition, pancreatic stellate cells (PSCs) were isolated using gradient methods to examine the antifibrogenic effects of GJ. In the cerulein-induced CP mice, the histological features of the pancreas showed severe tissue damage such as enlarged interstitial spaces, inflammatory cell infiltrate and glandular atrophy, and tissue fibrosis. However, treatment of GJ reduced the severity of CP such as pancreatic edema and inflammatory cell infiltration. Furthermore, treatment of GJ increased pancreatic acinar cell survival, and reduced pancreatic fibrosis and activation of PSC in vivo and in vitro. In addition, GJ treatment inhibited the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) in the PSCs. These results suggest that GJ attenuated the severity of CP and the pancreatic fibrosis by inhibiting JNK and ERK activation during CP.

Chronic pancreatitis (CP) is a multifactorial, inflammatory syndrome characterized by acinar atrophy and fibrosis. Activation of NOD-like receptors family pyrin domain-containing 3 (NLRP3) inflammasome is a central mediator of multiple chronic inflammatory responses and chronic fibrosis including pancreatic fibrosis in CP. The Psidium guajavaleaf is widely used in traditional medicine for the treatment of chronic inflammation, but the anti-inflammatory effect of Psidium guajavaleaf on CP has not yet been revealed. In this study, we investigated whether the extract of total flavonoids from Psidium guajava leaves (TFPGL) plays a therapeutic mechanism on CP through NLRP3 inflammasome signaling pathway in a mouse CP model. The H&E and acid-Sirius red staining indicted that TFPGL attenuated the inflammatory cell infiltration and fibrosis significantly. The results of immunohistological staining, western blot and RT-qPCR showed that the expressions of NLRP3 and caspase-1 were significantly increased in the CP model group, while TFPGL significantly decreased the NLRP3 and caspase-1 expression at both the gene and protein levels. Moreover, ELISA assay was used to examine the levels of NLRP3 inflammasome target genes, such as caspase-1, IL-1$\beta$ and IL-18. We found that TFPGL treatment decreased the expression of caspase-1, IL-1$\beta$ and IL-18, which is critical for the NLRP3 inflammasome signaling pathway and inflammation response significantly. These results demonstrated that TFPGL attenuated pancreatic inflammation and fibrosis via preventing NLRP3 inflammasome activation and TFPGL can be used as a potential therapeutic agent for CP.

Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus (DM), which can lead to renal failure in diabetic patients. At present, the first-line drugs for DN are mainly the renin–angiotensin system (RAS) inhibitors or angiotensin receptor blockers, and the latest approved aldosterone receptor antagonist finerenone, which delay the progression of DN to end-stage renal disease (ESRD), but the therapeutic effect is still not ideal. With a history of thousands of years, traditional Chinese medicine (TCM) has rich experience in the treatment of DN. Based on the theory of TCM, the clinical treatment of DN mainly focuses on generating fluid and nourishing blood, nourishing Qi and Yin, detoxifying and detumescent. In recently years, the therapeutic effects and mechanisms of TCM prescription, Chinese herbal medicine, and its active components on DN have received extensive attention in new drug development. This paper reviews the research progress of the mechanism of TCM on DN.

The formation of fibrotic tissue, characterized by the excessive accumulation of extracellular matrix (ECM) components such as collagen and fibronectin, is a normal and crucial stage of tissue repair in all organs. The over-synthesis, deposition, and remodeling of ECM components lead to organ dysfunction, posing a significant medical burden. Berberine, an isoquinoline alkaloid, is commonly used in the treatment of gastrointestinal diseases. With the deepening of scientific research, it has been gradually discovered that berberine also plays an important role in fibrotic diseases. In this review, we systematically introduce the effective role of berberine in fibrosis-related diseases. Specifically, this paper aims to provide a comprehensive review of the therapeutic role of berberine in treating fibrosis in organs such as the heart, liver, lungs, and kidneys. By summarizing its various pathways and mechanisms of action, including the inhibition of the transforming growth factor-$\beta$/Smad signaling pathway, PI3K/Akt signaling pathway, MAPK signaling pathway, RhoA/ROCK signaling, and mTOR/p70S6K signaling pathway, as well as its activation of the Nrf2-ARE signaling pathway, AMPK signaling pathway, phosphorylated Smad 2/3 and Smad 7, and other signaling pathways, this review offers additional evidence to support the treatment of fibrotic diseases.

This paper deals with the modeling of a wound healing disease, the keloid, which may provoke onset of malignant cells with higher progression feature, thus generating cells with heterogeneous phenotype. According to medical hypothesis, it is assumed that viruses and the genetic susceptibility of patients are the main causes that trigger the formation. The mathematical model is developed by means of the tools of the kinetic theory for active particles. The competition of the immune system cells with viruses, keloid fibroblast cells, and malignant cells is taken into account. Numerical simulations, obtained by considering the sensitivity analysis of the parameters in the model, show the emerging phenomena that are typical of this disease.

Biomechanical evaluation of the subsynovial connective tissue (SSCT) provides insight into the causes of carpal tunnel syndrome. Studies of carpal tunnel mechanics have been performed using fresh-frozen cadaver tissue. Freezing can affect mechanical properties of some tissues, but its effect on SSCT is unknown. A total of 16 rabbit paws were harvested from eight New Zealand rabbits and subjected to mechanical testing consisting of three repeated tendon excursions in sets of three different excursion magnitudes. One paw from each animal was unfrozen. The contralateral paw was frozen and thawed before testing. Force, energy and stiffness of the first cycle of each set were evaluated, as were ratios of the second to first cycle for each parameter. Two-factor ANOVA with repeated measures over both factors was performed. No significant interactions between factors were found. There were no significant differences between fresh and frozen paws for any parameters, though there were significant differences between excursion amplitudes. The damage threshold was not different between fresh and frozen paws. This study demonstrated that freezing rabbit subsynovial connective tissue does not significantly change its mechanical properties. The same may be true for human cadaver tissues. Results of cadaver mechanical testing may not be influenced by this preservation technique.

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ASIA – Singapore scientists make major breakthrough to treat fibrotic diseases that cause organ impairment and failure.

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Human fibrocytes exhibit mixed phenotypic characteristics of haematopoietic stem cells, monocytes and fibroblasts, and originate from a precursor of the monocyte lineage. They constitutively produce chemokines and growth factors that are known to modulate inflammatory reactions or promote angiogenesis and the deposition of extracellular matrix molecules. Upon exposure to transforming growth factor-β₁ and endothelin-1, fibrocytes produce large quantities of extracellular matrix components and acquire a contractile phenotype. Such differentiation of fibrocytes into myofibroblast-like cells occurs at the tissue sites during repair processes and has been found to contribute to wound healing in vivo. Fibrocytes and fibrocyte-derived myofibroblasts are also involved in the pathogenesis of lung disorders characterised by chronic inflammation and extensive remodelling of the bronchial wall, like asthma, or progressive fibrosis with destruction of the pulmonary architecture, like idiopathic pulmonary fibrosis. They participate in tumour-induced stromal reactions and may either promote or inhibit the metastatic progression of cancers. Prevention of excessive extracellular matrix deposition and detrimental tissue remodelling in pulmonary diseases may be achieved by inhibiting the accumulation of fibrocytes in the lungs. Moreover, in vitro expanded fibrocytes may serve as vehicles for the delivery of gene constructs to improve ineffective lung repair or be used in anti-cancer cell therapy.

The pathogenesis of systemic sclerosis(SSc) is not clarified yet, although some cytokines seemed to be closely related to the fibrotic process of this disorder. Transforming growth factor β(TGF-β) has received many attentions as an essential factor in the pathogenesis of various fibrotic disorders. In addition, we have shown that connective tissue growth factor (CCN2) is closely related to the pathogenesis of SSc as follows: (i) CCN2 mRNA expression was observed in the fibrotic lesions but not in the early non-fibrotic lesions or atrophic lesions; (ii) Serum CCN2 protein concentrations were significantly elevated, and this was correlated with skin sclerosis and lung fibrosis; and (iii) In our animal model, TGF-β induced subcutaneous fibrosis and subsequent CCN2 application caused persistent fibrosis, which was correlated with upregulation of procollagene mRNA promotor activities. Based on these data, we hypothesize that a two-step process of fibrosis occurs in SSc, that is TGF-β induces fibrosis in the early stage, and afterwards CCN2 acts to maintain tissue fibrosis.