• Journal of Applied Biological Chemistry
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• v.65 no.4
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• pp.357-365
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• 2022

We examined the lung anti-fibrotic properties of flavanones and flavones, which are flavonoid compounds, in bleomycin- and TGF-β1-stimulated A549 cells. Taken together, treatment with Bleomycin and TGF-β1 increased intracellular ROS by increasing the expression of various NOX families in A549 cells; further, the increased ROS levels resulted in increased fibrosis markers and induced pulmonary fibrosis. Flavonoid treatment has been demonstrated to alleviate or inhibit pulmonary fibrosis by modulating Smad-dependent and -non-dependent TGF-β mechanisms by modulating intracellular NOX expression.

• Journal of Ginseng Research
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• v.47 no.4
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• pp.543-551
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• 2023

Background: Panax ginseng Meyer is a representative Chinese herbal medicine with antioxidant and anti-inflammatory activity. 20(S)-Protopanaxadiol (PPD) has been isolated from ginseng and shown to have promising pharmacological activities. However, effects of PDD on pulmonary fibrosis (PF) have not been reported. We hypothesize that PDD may reverse inflammation-induced PF and be a novel therapeutic strategy. Methods: Adult male C57BL/6 mice were used to establish a model of PF induced by bleomycin (BLM). The pulmonary index was measured, and histological and immunohistochemical examinations were made. Cell cultures of mouse alveolar epithelial cells were analyzed with Western blotting, coimmunoprecipitation, immunofluorescence, immunohistochemistry, siRNA transfection, cellular thermal shift assay and qRT-PCR. Results: The survival rate of PPD-treated mice was higher than that of untreated BLM-challenged mice. Expression of fibrotic hallmarks, including α-SMA, TGF-β1 and collagen I, was reduced by PPD treatment, indicating attenuation of PF. Mice exposed to BLM had higher STING levels in lung tissue, and this was reduced by phosphorylated AMPK after activation by PPD. The role of phosphorylated AMPK in suppressing STING was confirmed in TGF-b1-incubated cells. Both in vivo and in vitro analyses indicated that PPD treatment attenuated BLM-induced PF by modulating the AMPK/STING signaling pathway. Conclusion: PPD ameliorated BLM-induced PF by multi-target regulation. The current study may help develop new therapeutic strategies for preventing PF.

• Herbal Formula Science
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• v.9 no.1
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• pp.231-250
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• 2001

In order to determine the effects of annexing bile extracts of bears on the anti-fibrotic effect of Injinhotang. Mix compound of Injinhotang and bile extracts of bears were administered to the carbon tetrachloride ($CCl_4$)-induced cirrhotic rats during 20 days and the changes of serum levels of GOT (glutamic-oxalacetic transaminase), GPT (glutamic pyruvic transaminase), LDH (lactate dehydrogenase), ALP (alanine phosphatase), GGT (gamma glutamyl transpeptidase) and T-BIL (total bilirubin) were monitored with comparison to the results of Injinhotang administered group. The results were summarized as follows. 1. A significant (p<0.01) increase of serum GOT levels were observed in control group compared to those of normal group but these increased levels were dramatically decreased in Injinhotang and Injinhotang with Fel Ursi-administered group. In addition, a significant (p<0.05) increase were also detected In Injinhotang with Fel Ursi-administered group compared to that of Injinhotang-administered group. 2. A significant (p<0.01) increase of serum GPT levels were observed in control group compared to those of normal group but these increased levels were dramatically decreased in Injinhotang and Injinhotang with Fel Ursi-administered group. Although significances were not recorded, increase of serum GPT levels were also detected in Injinhotang with Fel Ursi-administered group compared to that of Injinhotang-administered group. 3. A significant (p<0.01) increase of serum LDH levels were observed in control group compared to those of normal group but these increased levels were dramatically decreased in Injinhotang and Injinhotang with Fel Ursi-administered group. Although significances were not recorded, increase of serum LDH levels were also detected in Injinhotang with Fel Ursi-administered group compared to that of Injinhotang-administered group. 4. A significant (p<0.01 or p<0.05) increase of serum ALP levels were observed in control group compared to those of normal group but these increased levels were dramatically decreased in Injinhotang and Injinhotang with Fel Ursi-administered group. In addition, a significant (p<0.05) increase were also detected in Injinhotang with Fel Ursi-administered group compared to that of Injinhotang-administered group. 5. A significant (p<0.01) increase of serum GGT levels were observed in control and Injinhotang-administered group compared to those of normal group but these increased levels were dramatically decreased in Injinhotang with Fel Ursi-administered group. 6. A significant (p<0.01) increase of serum T-BIL levels were observed in control group compared to those of normal group but these increased levels were dramatically decreased in Injinhotang and Injinhotang with Fel Ursi-administered group. Although significances were not recorded, increase of serum T-BIL levels were also detected in Injinhotang with Fel Ursi-administered group compared to that of Injinhotang-administered group. In conclusion, it is considered that bile extract of bears has some additional effect to the anti-fibrotic effect of Injinhotang but to know the exact mechanism of suitable dose and duration of administration, further studies such as pharmacokinetics and dose-dependent pharmacological studies were needed

• Korean Journal of Medicinal Crop Science
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• v.17 no.4
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• pp.243-250
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• 2009

Fifty percent ethanol extract of Lythrum salicaria Linne root (LSR) was tested in vitro on antioxidant activity, and furthermore was investigated on antioxidative and fibrosis protecting activities in $CCL_4$-induced liver fibrosis rat model. Ratio of hepatic GSH/GSSG (reduced glutathione/oxidized glutathione) as bio-parameter of antioxidant level in $CCL_4$ plus LSR-treated rats for 6 weeks significantly increased from 2.8- to 5.7-fold than that of $CCL_4$-treated rats at p < 0.05. Thiobarbituric acid reactive substances (TBARS) contents in $CCL_4$ plus LSR-treated rats ranged from 1.57- to 2.19-fold of normal rats and were lower than those in $CCL_4$ plus silymarin-treated rats ($1.78{\sim}2.46$-fold of normal rats) (p < 0.05). Amounts of hydroxyproline of liver tissue showing the content of total collagen, a parameter of fibrosis, in $CCL_4$ plus LSR-administrated rat livers were $4.9{\sim}8.8{\mu}g$/mg ($-47{\sim}-71%$, compared with that in $CCL_4$-treated rat livers ($16.6{\mu}g$/mg tissue), which were significantly lower than those in $CCL_4$ plus silymarin-administrated rats being $8.4{\sim}11.7{\mu}g$/mg ($-30{\sim}-50%$). This collagen reducing effect of liver tissue in $CCL_4$ plus LSR-treated rats was supported by histological observation using microscopy assay. From the results, we conclude that the root of L. salicaria have efficient antioxidant potential and effective antifibrotic activities.

• Archives of Plastic Surgery
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• v.37 no.5
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• pp.519-525
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• 2010

Purpose: Of various effects of relaxin, we assumed that anti-fibrotic effects, neovascularization effects and vasodilatation effects of relaxin might enhance the survival rate of skin flap. In the current study, we used adenovirus expressing relaxin genes to examine whether these genes could enhance the survival rate of a skin flap. Methods: A total of 30 Sprangue-Dawley rats were divided into three groups: RLX group (10; relaxin virus injected group), CTR group (10; no gene coded virus injection group), and PBS group (10; PBS injected group). Each group was intradermally injected with the virus ($10^7$ PFU) and PBS 48 hours before and immediately before the flap elevation. A distally based flap $3{\times}9\;cm$ in size was elevated on the dorsal aspect of each rat. Following this, a flap was placed in the original location and then sutured using a #4-0 Nylon. A surviving area of the flap was measured and then compared on postoperative days 3, 7 and 10. Using a laser Doppler, the amount of blood flow was measured. On postoperative day 10, tissues were harvested for histologic examination and the number of blood vessels was counted. Results: There was a significant increase in the area of the flap survival in the RLX group on postoperative days 3 and 7. The Doppler measurement also showed significantly increased blood flow immediately after the operation and on postoperative days 7 and 10. The number of blood vessels was significantly greater in the RLX group in the tissue harvested on postoperative day 10. The VEGF concentration was significantly higher in the RLX group than others in the tissues harvested on postoperative day 10. Conclusion: Following an analysis of the effects of relaxin-secreting adenovirus on the survival of a flap, the surviving area of the flap and the blood flow also increased. A histopathology also showed an increase in the number of blood vessels and the concentration of VEGF.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.6
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• pp.607-616
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• 2018

The effect of melatonin on juveniles with cardio fibrosis is poorly understood. We investigated whether HDACs participate in the anti-fibrotic processes regulated by melatonin during hypertrophic remodeling. Abdominal aortic constriction (AAC) was employed in juvenile rats resulting in pressure overload-induced ventricular hypertrophy and melatonin was subsequently decreased via continuous light exposure for 5 weeks after surgery. AAC rats displayed an increased cross-sectional area of myocardial fibers and significantly elevated collagen deposition compared to sham-operated rats, as measured by HE and Masson Trichrome staining. Continuous light exposure following surgery exacerbated the increase in the cross-sectional area of myocardial fibers. The expression of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 genes were all significantly enhanced in AAC rats with light exposure relative to the other rats. Moreover, the protein level of $TNF-{\alpha}$ was also upregulated in the AAC light exposure groups when compared with the sham. However, Smad4 protein expression was unchanged in the juveniles' hearts. In contrast, beginning 5 weeks after the operation, the AAC rats were treated with melatonin (10 mg/kg, intraperitoneal injection every evening) or vehicle 4 weeks, and sham rats were given vehicle. The changes in the histological measures of cardio fibrosis and the gene expressions of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 were attenuated by melatonin administration. The results reveal that melatonin plays a role in the development of cardio fibrosis and the expression of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 in cardiomyocytes.

• Childhood Kidney Diseases
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• v.15 no.2
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• pp.125-137
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• 2011

Purpose : Men are generally more prone to chronic renal disease and progression to end stage renal disease than women. The purpose of this study is to prove the effect of gender and sex hormone on renal fibrosis in mice with unilateral ureteral obstruction (UUO) and to elucidate the specific underlying mechanisms. Methods :We compared the expression of ${\alpha}$-smooth muscle actin (${\alpha}$-SMA) in female and male mice with complete UUO (day 7). After this, we estimated the changes of renal fibrosis in the female mice with oophorectomy and in the female mice with oophorectomy and replacement of $17{\beta}$-estradiol, respectively. Results : The level of ${\alpha}$-SMA in the female kidney with UUO was significantly lower than that in the male kidney with UUO. oophorectomy and replacement of $17{\beta}$-estradiol did not change the expression of angiotensin II type 1 (AT1) receptor in the female kidney with UUO, whereas the expression of angiotensin II type 2 (AT2) receptor was significantly more elevated in the intact female (IF) and the oophorectomized female with estrogen (OF+E) than that in the oophorectomized female (OF). The expressions of inducible nitric oxide synthase (iNOS) in the IF and OF+E mice were significantly more elevated than that in the OF mice, which was similar to the expression of AT2 receptor. Conclusion : The female gender is associated with resistance to renal fibrosis in obstructive uropathy and this gender difference may originate from the existence of $17{\beta}$-estradiol, which has an anti-fibrotic effect via upregulation of the AT2 receptor and iNOS.

• Parasites, Hosts and Diseases
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• v.53 no.3
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• pp.321-327
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• 2015

A 50-year-old male visited the outpatient clinic and complained of fever, poor oral intake, and weight loss. A chest X-ray demonstrated streaky and fibrotic lesions in both lungs, and chest CT revealed multifocal peribronchial patchy ground-glass opacities with septated cystic lesions in both lungs. Cell counts in the bronchoalveolar lavage fluid revealed lymphocyte-dominant leukocytosis, and further analysis of lymphocyte subsets showed a predominance of cytotoxic T cells and few T helper cells. Video-assisted wedge resection of the left upper lobe was performed, and the histologic examination was indicative of a Pneumocystis jirovecii infection. Trimethoprim-sulfamethoxazole (TMP-SMX) was orally administered for 3 weeks; however, the patient complained of cough, and the pneumonia was aggravated in the follow-up chest X-ray and chest CT. Molecular studies demonstrated mutations at codons 55 and 57 of the dihydropteroate synthase (DHPS) gene, which is associated with the resistance to TMP-SMX. Clindamycin-primaquine was subsequently administered for 3 weeks replacing the TMP-SMX. A follow-up chest X-ray showed that the pneumonia was resolving, and the cough was also alleviated. A positive result of HIV immunoassay and elevated titer of HCV RNA indicated HIV infection as an underlying condition. This case highlights the importance of careful monitoring of patients with P. jirovecii pneumonia (PCP) during the course of treatment, and the molecular study of DHPS mutations. Additionally, altering the anti-PCP drug utilized as treatment must be considered when infection with drug-resistant P. jirovecii is suspected. To the best of our knowledge, this is the first case of TMP-SMX-resistant PCP described in Korea.

• Journal of Life Science
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• v.22 no.10
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• pp.1371-1377
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• 2012

Fibrosis in kidney by internal and external factors causes progressive loss of renal function. Renal fibrosis is the inevitable consequence of an excessive accumulation of the extracellular matrix. TGF-${\beta}$ plays an important role in the process of renal fibrosis and stimulates the synthesis of profibrotic factors, including collagens, fibronectin, and plasminogen activator inhibitor (PAI-1). We examined the effect of Moringa oleifera Lam (moringa) extracts in a rat kidney fibrosis model. We found that moringa root extract suppresses protein expression/mRNA levels of Type I collagen, fibronectin, and PAI-1 induced by TGF-${\beta}$ in renal fibroblasts. Moringa root extract selectively inhibited phosphorylation of TGF-${\beta}$-induced $T{\beta}RII$ and the downstream signaling pathway (e.g., Smad4), and phospho-ERK, but not JNK, p38, or PI3K/AKT. These results suggest that moringa root extract can act against TGF-${\beta}$-induced renal fibrosis in rat kidney fibroblast cells by a mechanism related to its antifibrotic activity, which regulates expression of fibronectin, Type I collagen, and PAI-1 through $T{\beta}RII$-Smad2/3-Smad4 and ERK. Therefore, moringa root extract is an effective substance for fibrosis therapy and provides a new therapeutic strategy for diseases associated with elevated profibrotic factor synthesis.

• Korean Journal of Food Science and Technology
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• v.53 no.5
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• pp.544-552
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• 2021

This study investigated the anti-fibrotic and antioxidant effects of Paeonia Radix Alba water extract (PR) on thioacetamide (TAA)-induced liver fibrosis in a mouse model and its underlying mechanisms. Liver fibrosis was induced by intraperitoneal injection of TAA (three times a week) for 8 weeks. Furthermore, silymarin (50 mg/kg body weight) and PR (200 mg/kg body weight) were administered for 8 weeks. PR treatment downregulated aspartate aminotransferase (AST), alanine aminotransferase (ALT), ammonia, and myeloperoxidase levels. Moreover, PR treatment downregulated NOX2 and p47phox and upregulated antioxidant enzymes by activating the Nrf2/Keap1 signaling pathway. Furthermore, PR inhibited the factors associated with fibrosis, such as α-SMA and collagen I. AMPK/SIRT1 was upregulated by PR treatment. Overall, these results suggest that PR attenuates liver fibrosis by regulating the Nrf2/Keap1 and AMPK/SIRT1/NF-κB signaling pathways through the inhibition of oxidative stress. Hence, PR has potential as a remedy for preventing and treating liver fibrosis.