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NACA attenuated CM-induced morphological changes. HE staining of kidney sections (magnification ×200) from CON rats (a), CIN rats (b), NAC+CIN rats (c), NACA1+CIN rats (d), and NACA2+CIN rats (e). Representative changes of ultrastructure by TEM (magnifications ×4200) from CON rats (f), CIN rats (g), NAC+CIN rats (h), NACA1+CIN rats (i), NACA2+CIN group (j), normal glomerular basement membrane and podocyte in CON rats (k), and CIN rats (l). Note the condensation of the nuclear chromatin (red arrow) and cytoplasm vacuoles (orange arrow) in CIN rats. Blue arrows refer to severe vacuolization of the renal cortex. Figures are representative of 5 to 8 rats from each group.
Source publication
Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury (AKI) due to apoptosis induced in renal tubular cells. Our previous study demonstrated the novel N-acetylcysteine amide (NACA); the amide form of N-acetyl cysteine (NAC) prevented renal tubular cells from contrast-induced apoptosis through inhibiting p38...
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N‑acetylcysteine (NAC) is a thiol‑containing antioxidant that modulates the intracellular redox state. NAC can scavenge reactive oxygen species (ROS) and maintain reduced glutathione (GSH) levels, in order to protect cardiomyocytes from oxidative stress. The present study aimed to determine whether NAC protects cardiomyocytes from oxidative damage...
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Murine protein serine-threonine kinase 38 (MPK38), an AMP‐activated protein kinase (AMPK)-related kinase, has been implicated in the induction of apoptosis signal-regulating kinase 1 (ASK1)-, transforming growth factor-β (TGF‐β)-, and p53-mediated activity involved in metabolic homeostasis. Here, zinc finger protein ZPR9 was found to be an activato...
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Objective:
LncRNA nuclear enriched abundant transcript 1 (NEAT1) has been reported to play an oncogenic role in the occurrence and development of diabetic nephropathy (DN). The aim of our study was to investigate the potential mechanism by which NEAT1 facilitates the progression of DN.
Patients and methods:
Quantitative Real-time polymerase chai...
Citations
... Oxidative stress is an important driving mechanism of CIN and is the pathological basis of antioxidant therapy for CIN [18]. In previous studies, we demonstrated the involvement of ROS in localized renal injury in a CIN model, indicated by a dramatic decrease in SOD and GSH and an increase in MDA in renal tissues [19]. Therefore, we hypothesize that the alleviation of CIN renal injury by TMP is accompanied by an attenuation of lipid peroxidation. ...
Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury (AKI). Recently ferroptosis was reported to be crucial for AKI pathogenesis. Our previous studies indicated antioxidant tetramethylpyrazine (TMP) prevent CIN in vivo. However, whether ferroptosis is involved in TMP nephroprotective mechanism against CIN is unclear. In present study we investigated the role of renal tubular epithelial cell ferroptosis in TMP reno-protective effect against CIN and the molecular mechanisms by which TMP regulates ferroptosis. Classical contrast-medium Iohexol was used to construct CIN models in rats and HK-2 cells. Results showed tubular cell injury was accompanied by ferroptosis both in vivo and in vitro, including the typical features of ferroptosis, Fe2+ accumulation, lipid peroxidation and decreased glutathione peroxidase 4 (GPX4). Ferroptosis inhibition by classic inhibitors Fer-1 and DFO promoted cell viability and reduced intracellular ROS production. Additionally, TMP significantly inhibited renal dysfunction, reduced AKI biomarkers, prevented ROS production, inhibited renal Fe2+ accumulation and increased GPX4 expression. Expressions of various proteins associated with iron ion metabolism, including transferrin receptor (TFRC), divalent metal transporter 1, iron-responsive element binding protein 2, ferritin heavy chain 1, ferroportin 1, and heat shock factor binding protein 1, were examined using mechanistic analyses. Among these, TFRC changes were the most significant after TMP pretreatment. Results of siRNA knockdown and plasmid overexpression of TFRC indicated TFRC is essential for TMP to alleviate ferroptosis and reduce LDH release, Fe2+ accumulation and intracellular ROS. Our findings provide crucial insights about the potential of TMP in treating AKI associated with ferroptosis.
... Meanwhile, 8) NAC can reduce tubular cell injury caused by contrast media, which can help prevent CI-AKI. Finally, 9) NAC can reduce renal tubular cell apoptosis caused by contrast media, which can help prevent CI-AKI (13)(14)(15)(16)(17). ...
Contrast-induced acute kidney injury (CI-AKI) is a potential complication of medical imaging procedures that use contrast media. It is important to identify and manage risk factors for contrast-induced nephropathy and to monitor patients for signs of renal damage after contrast administration. N-acetylcysteine (NAC) can prevent CI-AKI through multiple mechanisms of action, including reducing oxidative stress, improving renal hemodynamics, reducing inflammation, reducing apoptosis and fibrosis, reducing oxidative stress-induced DNA damage, reducing tubular cell injury, and reducing renal tubular cell apoptosis. However, the exact mechanisms of action may vary based on the specific study or context. Further research is needed to fully elucidate the molecular mechanisms of NAC in preventing CI-AKI.
... With the advancement of clinical treatment for CIN, drugs such as N-acetylcysteine (NAC), 7 vitamin C 8 and statins 9 have been utilized. However, there is no strong evidence to prove that any drug can reduce the occurrence of CIN. ...
Contrast‐induced nephropathy (CIN) is a condition that causes kidney damage in patients receiving angiography with iodine‐based contrast agents. This study investigated the potential protective effects of berberine (BBR) against CIN and its underlying mechanisms. The researchers conducted both in vivo and in vitro experiments to explore BBR's renal protective effects. In the in vivo experiments, SD rats were used to create a CIN model, and different groups were established. The results showed that CIN model group exhibited impaired renal function, severe damage to renal tubular cells and increased apoptosis and ferroptosis. However, BBR treatment group demonstrated improved renal function, decreased apoptosis and ferroptosis. Similar results were observed in the in vitro experiments using HK‐2 cells. BBR reduced ioversol‐induced apoptosis and ferroptosis, and exerted its protective effects through Akt/Foxo3a/Nrf2 signalling pathway. BBR administration increased the expression of Foxo3a and Nrf2 while decreasing the levels of p‐Akt and p‐Foxo3a. In conclusion, this study revealed that BBR effectively inhibited ioversol‐induced apoptosis and ferroptosis in vivo and in vitro. The protective effects of BBR were mediated through the modulation of Akt/Foxo3a/Nrf2 signalling pathway, leading to the alleviation of CIN. These findings suggest that BBR may have therapeutic potential for protecting against CIN in patients undergoing angiography with iodine‐based contrast agents.
... Previous studies have reported that NAC, a precursor of GSH, inhibits the activation of p38 [24,25], suggesting that GSH acts on upstream signaling pathways for p38 inhibition. Additionally, transaldolase deficiency in mouse livers was reported to result in GSH depletion [9]. ...
In atherosclerosis, macrophage-derived foam cell formation is considered to be a hallmark of the pathological process; this occurs via the uptake of modified lipoproteins. In the present study, we aim to determine the role of transaldolase in foam cell formation and atherogenesis and reveal the mechanisms underlying its role. Bone marrow-derived macrophages (BMDMs) isolated from mice successfully form foam cells after treatment with oxidized low-density lipoprotein (80 μg/mL). Elevated transaldolase levels in the foam cell model are assessed by quantitative polymerase chain reaction and western blot analysis. Transaldolase overexpression and knockdown in BMDMs are achieved via plasmid transfection and small interfering RNA technology, respectively. We find that transaldolase overexpression effectively attenuates, whereas transaldolase knockdown accelerates, macrophage-derived foam cell formation through the inhibition or activation of cholesterol uptake mediated by the scavenger receptor cluster of differentiation 36 (CD36) in a p38 mitogen-activated protein kinase (MAPK) signaling-dependent manner. Transaldolase-mediated glutathione (GSH) homeostasis is identified as the upstream regulator of p38 MAPK-mediated CD36-dependent cholesterol uptake in BMDMs. Transaldolase upregulates GSH production, thereby suppressing p38 activity and reducing the CD36 level, ultimately preventing foam cell formation and atherosclerosis. Thus, our findings indicate that the transaldolase-GSH-p38-CD36 axis may represent a promising therapeutic target for atherosclerosis.
... This in vitro cell model with CM being removed by medium replacement may also be useful for exploring potential treatments for CIN since previous studies only focused on the effect of medication compared to no treatment [27][28][29][30][31][32]. However, as the standard management in clinical settings, hydration has seldom been used as a control group in laboratory studies [11,[33][34][35][36]. CIN was initially regarded as a spontaneous recovery process among healthy people. ...
Contrast-induced nephropathy (CIN) is one of the most common causes of acute kidney injury (AKI). However, management is still limited, and the cellular response to radiocontrast removal for CIN remains unclear. This study aimed to explore the latent effects of iohexol in cultured renal tubular cells with or without the removal of iohexol by medium replacement. HK2 renal tubular cells were subcultured 24 h before use in CIN experiments. Three treatment groups were established: the control, a radiocontrast (iohexol)-only group at 75 mg I/mL (I-75), and iohexol exposure for 24 h with culture medium replacement (I-75/M). Cell cycle arrest, fibrogenic mediator assays, cell viability, cell function, and cell-cycle-related protein expression were compared between groups. Iohexol induced numerous changes in HK2 renal tubular cells, such as enlarged cell shape, cell cycle arrest, increased apoptosis, and polyploidy. Iohexol inhibited the expression of cyclins, CDKs, ZO-1, and E-cadherin but conversely enhanced the expression of p21 and fibrosis-related genes, including TGF-β1, CTGF, collagen I, collagen III, and HIF-1α within 60 hr after the exposure. Except for the recovery from cell cycle arrest and cell cycle gene expression, notably, the removal of iohexol by medium replacement could not fully recover the renal tubular cells from the formation of polyploid cells, the adhesion or spreading, or the expression of fibrosis-related genes. The present study demonstrates, for the first time, that iohexol exerts latent cytotoxic effects on cultured renal tubular cells after its removal, suggesting that these irreversible cell changes may cause the insufficiency of radiocontrast reduction in CIN, which is worth investigating further.
... Chlorogenic acid (CGA) is a phenolic compound widely found in fruits, vegetables, coffee, and tea, and it also has well-characterized antioxidant and anti-inflammatory properties [34,35]. Indeed, the antioxidant and anti-inflammatory properties of NAC [36,37] and CGA [38,39] have been demonstrated to promote nephroprotection. Few studies have recently linked the inflammasome pathway to their hepatoprotective effect [40,41]. ...
Background:
Cisplatin (Cp) is an antineoplastic agent with a dose-limiting nephrotoxicity. Cp-induced nephrotoxicity is characterized by the interplay of oxidative stress, inflammation, and apoptosis. Toll-4 receptors (TLR4) and NLPR3 inflammasome are pattern-recognition receptors responsible for activating inflammatory responses and are assigned to play a significant role with gasdermin (GSDMD) in acute kidney injuries. N-acetylcysteine (NAC) and chlorogenic acid (CGA) have documented nephroprotective effects by suppressing oxidative and inflammatory pathways. Therefore, the current study aimed to investigate the contribution of the upregulation of TLR4/inflammasomes/gasdermin signaling to Cp-induced nephrotoxicity and their modulation by NAC or CGA.
Methods:
A single injection of Cp (7 mg/kg, i.p.) was given to Wistar rats. Rats received either NAC (250 mg/kg, p.o.) and/or CGA (20 mg/kg, p.o.) one week before and after the Cp injection.
Results:
Cp-induced acute nephrotoxicity was evident by the increased blood urea nitrogen and serum creatinine and histopathological insults. Additionally, nephrotoxicity was associated with increased lipid peroxidation, reduced antioxidants, and elevated levels of inflammatory markers (NF-κB and TNF-α) in the kidney tissues. Moreover, Cp upregulated both TLR4/NLPR3/interleukin-1beta (IL-1β) and caspase-1/GSDMD-signaling pathways, accompanied by an increased Bax/BCL-2 ratio, indicating an inflammatory-mediated apoptosis. Both NAC and/or CGA significantly corrected these changes.
Conclusions:
This study emphasizes that inhibition of TLR4/NLPR3/IL-1β/GSDMD might be a novel mechanism of the nephroprotective effects of NAC or CGA against Cp-induced nephrotoxicity in rats.
... However, with the development of research in the field of pharmacology, NAC which acts as an antioxidant by reducing or even preventing oxidative stress and as a scavanger of reactive oxygen species is also used to protect kidney function and is used in the field of cardiology (Samuni et al., 2013;Pedre et al., 2021). Based on a study conducted on animals, present a form of NAC amide (NACA) which has better activity as a renoprotective agent when compared to NAC itself by upregulating thioredoxin-1 and inhibition of signal-regulating kinase 1 (ASK1) which is an activator of the p38MAPK pathway in inhibiting apoptosis of renal cells, consequently it can significantly reduce serum creatinine elevation, blood urea nitrogen, biomarkers of AKI, and prevent histologic changes resulting from renal tubular injuries (Gong et al., 2016). A pharmacokinetic study of NAC, showed that there was a significant decrease in NAC clearance of up to 90% when oral NAC was administered to patients with end-stage renal disease (ESRD), although plasma NAC levels increased dose-related (Nolin et al., 2010). ...
The incidence of acute kidney injury (AKI) post-cardiopulmonary bypass (CPB) can cause an increase in the rate of renal replacement therapy (RRT) and mortality rate. Compared to brain and liver damage post-CPB, AKI has the highest incidence of 83%. Based on this phenomenon, various efforts have been made to reduce the incidence of AKI post-CPB, both pharmacologically and non-pharmacologically interventions. The purpose of this review is to emphasize several renal protector agents which under optimal conditions can provide significant benefits in reducing the incidence of AKI post-CPB. This article was obtained by conducting a study on several kinds of literature, including the original article, RCT study, systematic review and meta-analysis, and other review articles. There are five renal protector agents that are the focus of this article, those are fenoldopam which effectively works to prevent the incidence of AKI post-CPB, while furosemide has shown satisfactory results in patients with decreased renal function when administered in the Renal Guard (RG) system, mannitol, and nitric oxide, both of these can also effectively reduce the incidence of AKI post‐CPB by controlling its blood concentration and timing of administration, and another form of N-Acetylcysteine, namely N‐Acetylcysteine amide has better activity as a renoprotective agent than N‐Acetylcysteine itself. The benefits of these agents can be obtained by developing devices that can control drug levels in the blood and create optimal conditions for drugs during the use of a CPB machine.
... As a result, NAC is still commonly used in daily clinical practice as previously described [10]. Last but not least, promising results have been reported in several animal studies using NAC as either the main treatment under investigation or standard/conventional treatment (positive control) [11][12][13][14][15][16][17][18][19][20][21][22]. Apart from its antioxidant properties [23], supporting biological plausibility of efficacy relies on its vasodilatory effects [24], namely its ability to cause renal artery vasodilatation/renal blood flow increase, improving renal hemodynamics [10]. ...
... After acclimatization, all animals were divided into 5 equal groups (n = 5 animals in each group) and treated for 7 days as follows: The duration of treatment for VAR/AVA and NAC was based on the results obtained by our group for sildenafil and tadalafil [22] and on a previous study evaluating the renoprotective effect of NAC [14], respectively. The 1st group (Control group) received 0.5 mL corn oil once per day by oral gavage. ...
... The 3rd group received N-acetyl cysteine (NAC group) (Sigma-Aldrich, St. Louis, MO, USA) 100 mg/kg once per day by oral gavage before CIN induction. The dose of NAC was selected based on a previous study evaluating the renoprotective effect of NAC [14]. The 4th group received VAR (VAR group; ≥98% (high-performance liquid chromatography (HPLC))) (Sigma-Aldrich, St. Louis, MO, USA) 10 mg/kg once per day by oral gavage prior to CIN induction. ...
The potential renoprotective effects of vardenafil (VAR) have been evaluated in a very limited number of studies using acute kidney injury animal models other than contrast-induced nephropathy (CIN) with promising results, while avanafil (AVA) has not been evaluated in this respect before. The purpose of this study was to evaluate for the first time the potential renoprotective effect of VAR and AVA in a rat model of CIN. Twenty-five male Wistar rats were equally assigned into five groups: control, CIN, CIN+N-acetyl cysteine (NAC) (100 mg/kg/day) as a positive control, CIN+VAR (10 mg/kg/day) and CIN+AVA (50 mg/kg/day). CIN was induced by dehydration, inhibition of prostaglandin and nitric oxide synthesis as well as exposure to the contrast medium (CM). Serum Cr (sCr) levels were measured at 24 and 48 h after CIN induction. At 48 h of CM exposure, animals were sacrificed. Matrix metalloproteinase (MMP) 2 (MMP-2) and MMP-9, kidney injury molecule 1 (KIM-1) and cystatin-C (Cys-C) were measured on renal tissue. Histopathological findings were evaluated on kidney tissue. All treatment groups had close to normal kidney appearance. sCr levels subsided in all treatment groups compared to CIN group at 48 h following CIN induction. A significant decline in the levels of MMP-2, MMP-9, KIM-1 and Cys-C compared to CIN group was observed. These results provide emerging evidence that VAR and AVA may have the potential to prevent CIN.
... However, accumulated reactive oxygen species ROS promote TXNIP binding to the endogenous antioxidant thioredoxin (Thioredoxin , TRX) and inhibiting the antioxidant activity of the protein by exchanging disul de bonds with Trx , thus participating in the pathogenesis of various diseases such as cancer, autoimmune diseases and diabetes (27). Thioredoxin 1 (Trx1) is localized in the cytoplasm, and reduced expression of Trx1 is a direct inhibitor or negative regulator of Apoptosis signalregulating kinase 1 (ASK1) (28, 29), which would activate ASK1, thereby promoting its downstream substrate p38 mitogen-activated protein kinase (p38 mitogen-activated protein kinase, p38 MAPK) phosphorylation, ultimately leading to the onset of apoptosis in renal tubular cells (30). Studies have shown that glucose can regulate the expression of TXNIP through histone acetylase, thus promoting the development of DKD (31). ...
... Previous evidences have been proved p38MAPK activation is related to renal injury, such as iohexolinduced (30,47,48) or diabetes-induced(49-52) apoptotic cell death. MAPK kinase (MAPK3k) acts as an upstream regulator of MAPKs. ...
... Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redoxsensitive serine threonine kinase. Studies have shown that activation of ASK1 (as a member of the MAP3K family) can target its substrate p38 MAPK, which is involved in the development of renal brosis (53), glomerular injury (54), tubular epithelial cell apoptosis, and in ammation (30). Recently, a new study found a signi cant increase in the expression of ASK1 and P38 in patients' venous tissues in maintenance hemodialysis patients, and p38MAPK signaling pathway may be involved in failure of autogenous arteriovenous stula caused by stenosis (55). ...
Background Contrast-induced acute kidney injury (CIAKI) is the third most common cause of hospital-acquired AKI. Diabetes mellitus (DM) is a major risk factor for CIAKI. Nevertheless, the mechanism of its role in diabetes susceptibility to CIAKI remains unclear. This study aimed to explore the role played by HDAC9 during the susceptibility of diabetic model to CIAKI.
Methods Both in vitro and in vivo model of diabetes were induced by treating human renal tubular epithelial cells (HK-2) with high glucose (HG, 50mM) and by feeding mice with a high-fat diet (HFD) followed by intraperitoneal injection of streptozotocin (STZ), respectively. CIAKI mice models were constructed by contrast-media (iohexol), and iohexol also was treated HK-2 cells. Then, BRD-4354 (an inhibitor of HDAC9) was added into treated cells and mice. Finally, knockdown HDAC9 in HK-2 cultured with HG, and iohexol was added. The pathological changes, oxidative stress and apoptosis levels in mice kidney tissues were assessed. Meanwhile, cellular reactive oxygen species and the activity of HK-2 cells was measured. Western blot was used to determine the expression of HDAC9 and TXNIP/Trx1/P-ASK1/p38MAPK signaling pathways in cells and kidneys.
Results HDAC9 was increased in both diabetic kidney tissues and HGinduced HK-2 cells. In vitro experiment indicated that HK-2 exposed to HG attenuated further damage to apoptosis and oxidative stress by iohexol via knockdown and inhibiting HDAC9. In vivo assay revealed that BRD4354 reduced diabetic mice sensitivity to CI-AKI. Mechanically, HDAC9 could activate TXNIP/Trx1/P-ASK1/p38MAPK signaling pathway involving in the susceptibility of diabetes to CIAKI.
Conclusion HDAC9 promotes the sensitivity of diabetes to CIAKI; and may be involved in oxidative stress and apoptosis through regulation of the TXNIP/Trx1/P-ASK1/p38MAPK pathway.
... However, accumulated reactive oxygen species ROS promote TXNIP binding to the endogenous antioxidant thioredoxin (Thioredoxin , TRX) and inhibiting the antioxidant activity of the protein by exchanging disul de bonds with Trx , thus participating in the pathogenesis of various diseases such as cancer, autoimmune diseases and diabetes (27). Thioredoxin 1 (Trx1) is localized in the cytoplasm, and reduced expression of Trx1 is a direct inhibitor or negative regulator of Apoptosis signalregulating kinase 1 (ASK1) (28, 29), which would activate ASK1, thereby promoting its downstream substrate p38 mitogen-activated protein kinase (p38 mitogen-activated protein kinase, p38 MAPK) phosphorylation, ultimately leading to the onset of apoptosis in renal tubular cells (30). Studies have shown that glucose can regulate the expression of TXNIP through histone acetylase, thus promoting the development of DKD (31). ...
... Previous evidences have been proved p38MAPK activation is related to renal injury, such as iohexolinduced (30,47,48) or diabetes-induced(49-52) apoptotic cell death. MAPK kinase (MAPK3k) acts as an upstream regulator of MAPKs. ...
... Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redoxsensitive serine threonine kinase. Studies have shown that activation of ASK1 (as a member of the MAP3K family) can target its substrate p38 MAPK, which is involved in the development of renal brosis (53), glomerular injury (54), tubular epithelial cell apoptosis, and in ammation (30). Recently, a new study found a signi cant increase in the expression of ASK1 and P38 in patients' venous tissues in maintenance hemodialysis patients, and p38MAPK signaling pathway may be involved in failure of autogenous arteriovenous stula caused by stenosis (55). ...
Background Contrast-induced acute kidney injury (CIAKI) is the third most common cause of hospital-acquired acute kidney injury. Diabetes mellitus (DM) is a major risk factor for CIAKI. Nevertheless, the mechanism of its role in diabetes susceptibility to CIAKI remains unclear. This study aimed to explore the role played by Histone deacetylase 9 (HDAC9) during the susceptibility of diabetic model to CIAKI. Methods Both in vitro and in vivo model of diabetes were induced by treating human renal tubular epithelial cells (HK-2) with high glucose (HG, 50mM) and by feeding mice with a high-fat diet (HFD) followed by intraperitoneal injection of streptozotocin (STZ), respectively. CIAKI mice models were constructed by contrast-media (iohexol), and iohexol also was treated HK-2 cells. Then, BRD-4354 (an inhibitor of HDAC9) was added into treated cells and mice. Finally, knockdown HDAC9 in HK-2 cultured with HG, and iohexol was added. The pathological changes, oxidative stress and apoptosis levels in mice kidney tissues were assessed. Meanwhile, cellular reactive oxygen species and the activity of HK-2 cells was measured. Western blot was used to determine the expression of HDAC9 and TXNIP/Trx1/P-ASK1/p38MAPK signaling pathways in cells and kidneys. Results HDAC9 was increased in both diabetic kidney tissues and HG-induced HK-2 cells. In vitro experiment indicated that HK-2 exposed to HG attenuated further damage to apoptosis and oxidative stress by iohexol via knockdown and inhibiting HDAC9. In vivo assay revealed that BRD-4354 reduced diabetic mice sensitivity to CI-AKI. Mechanically, HDAC9 could activate TXNIP/Trx1/P-ASK1/p38MAPK signaling pathway involving in the susceptibility of diabetes to CIAKI. Conclusion HDAC9 promotes the sensitivity of diabetes to CIAKI; and may be involved in oxidative stress and apoptosis through regulation of the TXNIP/Trx1/P-ASK1/p38MAPK pathway.
