Ohwia caudata inhibits doxorubicin-induced cardiotoxicity by regulating mitochondrial dynamics via the IGF-IIR/p-Drp1/PARP signaling pathway.

The most effective drug, doxorubicin (DOX), is widely used worldwide for clinical application as an anticancer drug. DOX-induced cytotoxicity is characterized by mitochondrial dysfunction. There is no alternative treatment against DOX-induced cardiac damage despite intensive research in the present decades. Ohwia caudata has emerged as a potential herbal remedy that prevents from DOX-induced cytotoxicity owing to its pharmacological action of sustaining mitochondrial dynamics by attenuating oxidative stress and inducing cellular longevity. However, its underlying mechanisms are unknown. The novel treatment provided here depends on new evidence from DOX-treated H9c2 cells, which significantly enhanced insulin-like growth factor (IGF) II receptor (IGF-IIR) pathways that activated calcineurin and phosphorylated dynamin-related protein 1 (p-Drp1) at ser616 (p-Drp1[ser616]); cells undergo apoptosis due to these factors, which translocate to mitochondria and disrupt their function and integrity, and in terms of herbal medicine treatment, which significantly blocked these phenomena. Thus, our findings indicate that maintaining integrity of mitochondria is an essential element in lowering DOX-induced cytotoxicity, which further emphasizes that our herbal medicine can successfully block IGF-IIR pathways and could potentially act as an alternative mechanism in terms of cardioprotective against doxorubicin.

Renal protective effects of Alpinate Oxyphyllae Fructus and mesenchymal stem cells co-treatment against D- galactose induced renal deterioration.

Age-related structural and functional changes in the kidney can eventually lead to development of chronic kidney disease, which is one of the leading causes of mortality among elderly people. For effective management of age-related kidney complications, it is important to identify new therapeutic interventions with minimal side-effects. The present study was designed to evaluate the synergistic effect of a traditional Chinese herb, Alpinate Oxyphyllae Fructus (AOF), and adipose-derived mesenchymal stem cells (ADMSCs) in ameliorating D-galactose (D-gal)-induced renal aging phenotypes in WKY rats. The study findings showed that D-gal-induced alteration in the kidney morphology was partly recovered by the AOF and ADMSC co-treatment. Moreover, the AOF and ADMSC co-treatment reduced the expression of proinflammatory mediators (NFkB, IL-6, and Cox2) and increased the expression of redox regulators (Nrf2 and HO-1) in the kidney, which were otherwise augmented by the D-gal treatment. Regarding kidney cell death, the AOF and ADMSC co-treatment was found to abolish the proapoptotic effects of D-gal by downregulating Bax and Bad expressions and inhibiting caspase 3 activation. Taken together, the study findings indicate that the AOF and ADMSC co-treatment protect the kidney from D-gal-induced aging by reducing cellular inflammation and oxidative stress and inhibiting renal cell death. This study can open up a new path toward developing novel therapeutic interventions using both AOF and ADMSC to effectively manage age-related renal deterioration.

Platycodi radix aqueous extract salvages doxorubicin-induced senescence by mitochondrial reactive oxygen species reduction in umbilical cord matrix stem cells.

Platycodi radix is a widely used herbal medicine that contains numerous phytochemicals beneficial to health. The health and biological benefits of P. radix have been found across various diseases. The utilization of umbilical cord stromal stem cells, derived from Wharton's jelly of the human umbilical cord, has emerged as a promising approach for treating degenerative diseases. Nevertheless, growing evidence indicates that the function of stem cells declines with age, thereby limiting their regenerative capacity. The primary objective in this study is to investigate the beneficial effects of P. radix in senescent stem cells. We conducted experiments to showcase that diminished levels of Lamin B1 and Sox-2, along with an elevation in p21, which serve as indicative markers for the senescent stem cells. Our findings revealed the loss of Lamin B1 and Sox-2, coupled with an increase in p21, in umbilical cord stromal stem cells subjected to a low-dose (0.1 µM) doxorubicin (Dox) stimulation. However, P. radix restored the Dox-damage in the umbilical cord stromal stem cells. P. radix reversed the senescent conditions when the umbilical cord stromal stem cells exposed to Dox-induced reactive oxygen species (ROS) and mitochondrial membrane potential are significantly changed. In Dox-challenged aged umbilical cord stromal stem cells, P. radix reduced senescence, increased longevity, prevented mitochondrial dysfunction and ROS and protected against senescence-associated apoptosis. This study suggests that P. radix might be as a therapeutic and rescue agent for the aging effect in stem cells. Inhibition of cell death, mitochondrial dysfunction and aging-associated ROS with P. radix provides additional insights into the underlying molecular mechanisms.

Low-concentration imiquimod treatment promotes enhanced skin barrier functions through epidermal melanization reaction regulation.

The primary function of the skin is to form a mechanical, permeability, antimicrobial, and ultraviolet radiation barrier, which is essential for maintaining physiological homeostasis. Our previous studies demonstrated that cutaneous pigmentation could promote skin barrier function in addition to providing anti-ultraviolet irradiation defense. The present study aimed to develop a new regimen that enhances skin barrier function by regulating skin pigmentation using low-concentration imiquimod. Results showed that topical application of low-concentration imiquimod effectively induced skin hyperpigmentation in the dorsal skin and external ear of mice without inducing inflammatory cell infiltration. An in vitro study also revealed that low-concentration imiquimod did not induce any cytotoxic effects on melanoma cells but triggered excessive melanin synthesis. In coculture systems, low-concentration imiquimod was noted to increase tyrosinase activity in a broader cellular context, revealing the potential role of neighboring cells in melanin production. The next-generation sequencing result indicated that PKCη and Dnm3 might regulate melanin synthesis and release during imiquimod treatment. Overall, our study presents new insights into the regulation of melanin production by low-concentration imiquimod, both in a mice model and cultured cells. Furthermore, our study highlights the potential benefits of imiquimod in promoting melanin synthesis without causing skin disruptions or inducing inflammation, validating its potential to serve as a method for enhancing skin barrier functions by regulating the epidermal melanization reaction.

Cardiac-specific overexpression of insulin-like growth factor II receptor-α interferes with the regulation of calcium homeostasis in the heart under hyperglycemic conditions.

BACKGROUND: Diabetic cardiomyopathy is a progressive disease caused by inexplicit mechanisms, and a novel factor, insulin-like growth factor II receptor-α (IGF-IIRα), may contribute to aggravating its pathogenesis. We hypothesized that IGF-IIRα could intensify diabetic heart injury. METHODS AND RESULTS: To demonstrate the potential role of IGF-IIRα in the diabetic heart, we used (SD-TG [IGF-IIRα]) transgenic rat model with cardiac-specific overexpression of IGF-IIRα, along with H9c2 cells, to study the effects of IGF-IIRα in the heart under hyperglycemic conditions. IGF-IIRα was found to remodel calcium homeostasis and intracellular Ca2+ overload-induced autophagy disturbance in the heart during diabetes. IGF-IIRα overexpression induced intracellular Ca2+ alteration by downregulating phosphorylated phospholamban/sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (PLB/SERCA2a), resulting in the suppression of Ca2+ uptake into the endoplasmic reticulum. Additionally, IGF-IIRα itself contributed to Ca2+ withdrawal from the endoplasmic reticulum by increasing the expression of CaMKIIδ in the active form. Furthermore, alterations in Ca2+ homeostasis significantly dysregulated autophagy in the heart during diabetes. CONCLUSIONS: Our study reveals the novel role of IGF-IIRα in regulating cardiac intracellular Ca2+ homeostasis and its related autophagy interference, which contribute to the development of diabetic cardiomyopathy. In future, the present study findings have implications in the development of appropriate therapy to reduce diabetic cardiomyopathy.

Gemcitabine resistance in non-small cell lung cancer is mediated through activation of the PI3K/AKT/NF-κB pathway and suppression of ERK signaling by reactive oxygen species.

Lung cancer is one of the most common cancers in the world. Chemotherapy is a standard clinical treatment. However, tumor cells often develop multidrug resistance after chemotherapy, an inevitable bottleneck in cancer treatment. Therefore, this study used gemcitabine-resistant (GEM-R) CL1-0 lung cancer cells. First, we used flow cytometry and western blot analysis to examine differences in performance between resistant and parental cells. The results showed that compared with parental cells, GEM-R CL1-0 cells significantly enhanced the activation of the AKT pathway, which promoted survival and growth, and decreased the activation of the reactive oxygen species-extracellular signal-regulated kinase (ROS)-ERK pathway. Next, the AKT and ERK pathways' role in tumor growth was further explored in vivo using a xenograft model. The results showed that enhancing AKT and inhibiting ERK activation reduced GEM-induced inhibition of tumor growth. Finally, combining the above results, we found that GEM-R CL1-0 cells showed reduced sensitivity to GEM by activating the phosphatidylinositol 3-kinase/AKT/NF-kB pathway and inhibiting the ROS-ERK pathway leading to resistance against GEM. Therefore, the AKT and ERK pathways are potential targets for improving the sensitivity of cancer cells to anticancer drugs.

Fisetin attenuates doxorubicin-induced cardiotoxicity by inhibiting the insulin-like growth factor II receptor apoptotic pathway through estrogen receptor-α/-ß activation.

Doxorubicin (DOX), an effective chemotherapeutic drug, has been used to treat various cancers; however, its cardiotoxic side effects restrict its therapeutic efficacy. Fisetin, a flavonoid phytoestrogen derived from a range of fruits and vegetables, has been reported to exert cardioprotective effects against DOX-induced cardiotoxicity; however, the underlying mechanisms remain unclear. This study investigated fisetin's cardioprotective role and mechanism against DOX-induced cardiotoxicity in H9c2 cardiomyoblasts and ovariectomized (OVX) rat models. MTT assay revealed that fisetin treatment noticeably rescued DOX-induced cell death in a dose-dependent manner. Moreover, western blotting and TUNEL-DAPI staining showed that fisetin significantly attenuated DOX-induced cardiotoxicity in vitro and in vivo by inhibiting the insulin-like growth factor II receptor (IGF-IIR) apoptotic pathway through estrogen receptor (ER)-α/-ß activation. The echocardiography, biochemical assay, and H&E staining results demonstrated that fisetin reduced DOX-induced cardiotoxicity by alleviating cardiac dysfunction, myocardial injury, oxidative stress, and histopathological damage. These findings imply that fisetin has a significant therapeutic potential against DOX-induced cardiotoxicity.

Ohwia caudata extract relieves the IL-17A-induced inflammatory response of synoviocytes through modulation of SOCS3 and JAK2/STAT3 activation.

Fibroblast-like synoviocytes accumulation, proliferation and activation, and the subsequent inflammatory mediators production play a key role in the progression of rheumatoid arthritis (RA). It is well established that Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling triggers inflammation, and induces cytokine levels in RA. Ohwia caudata have long been used against many disorders. However, in RA, the effects of O. caudata have not been elucidated. In the current study, synoviocytes were used to evaluate the suppressive effects of O. caudate extract (OCE) on the pro-inflammatory cytokines production. In vitro, the underlying mechanisms by which OCE inhibits inflammatory response through regulation of suppressors of cytokine signaling 3 (SOCS3) and JAK2/STAT3 expression in IL-17A-treated HIG-82 synoviocytes were investigated. The results demonstrated that the proliferation of IL-17A-challenged cells were increased in comparison with non-stimulated control cells. The synoviocyte proliferation was decreased significantly of OCE concentrations in dose dependent manner. The p-JAK2, p-STAT3, interleukin (IL)-1ß, and IL-6 were reduced in IL-17A-challenged cells treated with OCE. Furthermore, AZD1480 (a JAK2-specific inhibitor) or WP1066 (a STAT3-specific inhibitor) affected the inflammatory mediators production in IL-17A-challenged synoviocytes, and OCE failed to mitigate the IL-17A-induced inflammatory mediators and SOCS3, acting as a feedback inhibitor of the JAK/STAT3 pathway, in the presence of SOCS3 siRNA, indicating that the beneficial effects of OCE on the regulation of inflammatory response homeostasis were dependent on SOCS3 and the JAK2/STAT3 signaling pathway. Our study also showed that SOCS3 was markedly activated by OCE in RA fibroblast-like synoviocytes, thereby decreasing the JAK/STAT3 pathway, and the IL-1ß, and IL-6 activation. Thus, O. caudate should be further investigated as a candidate anti-inflammatory and anti-arthritic agent.

Phosphorylation of Bcl-2 by JNK confers gemcitabine resistance in lung cancer cells by reducing autophagy-mediated cell death.

The most common cancer-related death in the world is non-small cell lung cancer (NSCLC). Gemcitabine (GEM) is a common and effective first-line chemotherapeutic drug for the treatment of NSCLC. However, the long-term use of chemotherapeutic drugs in patients usually induces cancer cell drug resistance, leading to poor survival, and prognosis. In this study, to observe and explore the key targets and potential mechanisms of NSCLC resistance to GEM, we first cultured lung cancer CL1-0 cells in a GEM-containing medium to induce CL1-0 cells to develop GEM resistance. Next, we compared protein expression between the parental and GEM-R CL1-0 cell groups. We observed significantly lower expression of autophagy-related proteins in GEM-R CL1-0 cells than in parental CL1-0 cells, indicating that autophagy is associated with GEM resistance in CL1-0 cells. Furthermore, a series of autophagy experiments revealed that GEM-R CL1-0 cells had significantly reduced GEM-induced c-Jun N-terminal kinase phosphorylation, which further affected the phosphorylation of Bcl-2, thereby reducing the dissociation of Bcl-2 and Beclin-1 and ultimately reducing the generation of GEM-induced autophagy-dependent cell death. Our findings suggest that altering the expression of autophagy is a promising therapeutic option for drug-resistant lung cancer.

Insulin-like growth factor II receptor alpha overexpression in heart aggravates hyperglycemia-induced cardiac inflammation and myocardial necrosis.

Diabetes-induced cardiovascular complications are mainly associated with high morbidity and mortality in patients with diabetes. Insulin-like growth factor II receptor α (IGF-IIRα) is a cardiac risk factor. In this study, we hypothesized IGF-IIRα could also deteriorate diabetic heart injury. The results presented that both in vivo transgenic Sprague-Dawley rat model with specific IGF-IIRα overexpression in the heart and in vitro myocardium H9c2 cells were used to investigate the negative function of IGF-IIRα in diabetic hearts. The results showed that IGF-IIRα overexpression aided hyperglycemia in creating more myocardial injury. Pro-inflammatory factors, such as Tumor necrosis factor-alpha, Interleukin-6, Cyclooxygenase-2, Inducible nitric oxide synthase, and Nuclear factor-kappaB inflammatory cascade, are enhanced in the diabetic myocardium with cardiac-specific IGF-IIRα overexpression. Correspondingly, IGF-IIRα overexpression in the diabetic myocardium also reduced the PI3K-AKT survival axis and activated mitochondrial-dependent apoptosis. Finally, both ejection fraction and fractional shortening were be significantly decrease in diabetic rats with cardiac-specific IGF-IIRα overexpression. Overall, all results provid clear evidence that IGF-IIRα can enhance cardiac damage and is a harmful factor to the heart under high-blood glucose conditions. However, the pathophysiology of IGF-IIRα under different stresses and its downstream regulation in the heart still require further research.

Carboxyl terminus of HSP70-interacting protein attenuates advanced glycation end products-induced cardiac injuries by promoting NFκB proteasomal degradation.

Advanced glycation end products (AGEs), which are highly reactive molecules resulting from persistent high-glucose levels, can lead to the generation of oxidative stress and cardiac complications. The carboxyl terminus of HSP70 interacting protein (CHIP) has been demonstrated to have a protective role in several diseases, including cardiac complications; however, the role in preventing AGE-induced cardiac damages remains poorly understood. Here, we found that elevated AGE levels impaired cardiac CHIP expression in streptozotocin-induced diabetes and high-fat diet-administered animals, representing AGE exposure models. We used the TUNEL assay, hematoxylin and eosin, Masson's trichrome staining, and western blotting to prove that cardiac injuries were induced in diabetic animals and AGE-treated cardiac cells. Interestingly, our results collectively indicated that CHIP overexpression significantly rescued the AGE-induced cardiac injuries and promoted cell survival. Moreover, CHIP knockdown-mediated stabilization of nuclear factor κB (NFκB) was attenuated by overexpressing CHIP in the cells. Furthermore, co-immunoprecipitation and immunoblot assay revealed that CHIP promotes the ubiquitination and proteasomal degradation of AGE-induced NFκB. Importantly, fluorescence microscopy, a luciferase reporter assay, electrophoretic mobility shift assay, and subcellular fractionation further demonstrated that CHIP overexpression inhibits AGE-induced NFκB nuclear translocation, reduced its binding ability with the promoter sequences of the receptor of AGE, consequently inhibiting the translocation of the receptor AGE to the cell membrane for its proper function. Overall, our current study findings suggest that CHIP can target NFκB for ubiquitin-mediated proteasomal degradation, and thereby potentially rescue AGE-induced cardiac damages.

Perturbed ER homeostasis by IGF-IIRα promotes cardiac damage under stresses.

The heart is a very dynamic pumping organ working perpetually to maintain a constant blood supply to the whole body to transport oxygen and nutrients. Unfortunately, it is also subjected to various stresses based on physiological or pathological conditions, particularly more vulnerable to damages caused by oxidative stress. In this study, we investigate the molecular mechanism and contribution of IGF-IIRα in endoplasmic reticulum stress induction in the heart under doxorubicin-induced cardiotoxicity. Using in vitro H9c2 cells, in vivo transgenic rat cardiac tissues, siRNAs against CHOP, chemical ER chaperone PBA, and western blot experiments, we found that IGF-IIRα overexpression enhanced ER stress markers ATF4, ATF6, IRE1α, and PERK which were further aggravated by DOX treatment. This was accompanied by a significant perturbation in stress-associated MAPKs such as p38 and JNK. Interestingly, PARKIN, a stress responsive cellular protective mediator was significantly downregulated by IGF-IIRα concomitant with decreased expression of ER chaperone GRP78. Furthermore, ER stress-associated pro-apoptotic factor CHOP was increased considerably in a dose-dependent manner followed by elevated c-caspase-12 and c-caspase-3 activities. Conversely, treatment of H9c2 cells with chemical ER chaperone PBA or siRNA against CHOP abolished the IGF-IIRα-induced ER stress responses. Altogether, these findings suggested that IGF-IIRα contributes to ER stress induction and inhibits cellular stress coping proteins while increasing pro-apoptotic factors feeding into a cardio myocyte damage program that eventually paves the way to heart failure.

Protective effects of CHIP overexpression and Wharton's jelly mesenchymal-derived stem cell treatment against streptozotocin-induced neurotoxicity in rats.

Diabetic neuropathy is a common complication of diabetes mellitus, posing a challenge in treatment. Previous studies have indicated the protective role of mesenchymal stem cells against several disorders. Although they can repair nerve injury, their key limitation is that they reduce viability under stress conditions. We recently observed that overactivation of the carboxyl terminus of heat shock protein 70 (Hsp70) interacting protein (CHIP) considerably rescued cell viability under hyperglycemic stress and played an essential role in promoting the beneficial effects of Wharton's jelly-derived mesenchymal stem cells (WJMSCs). Thus, the present study was designed to unveil the protective effects of CHIP-overexpressing WJMSCs against neurodegeneration using in vivo animal model based study. In this study, western blotting observed that CHIP-overexpressing WJMSCs could rescue nerve damage observed in streptozotocin-induced diabetic rats by activating the AMPKα/AKT and PGC1α/SIRT1 signaling pathway. In contrast, these signaling pathways were downregulated upon silencing CHIP. Furthermore, CHIP-overexpressing WJMSCs inhibited inflammation induced in the brains of diabetic rats by suppressing the NF-κB, its downstream iNOS and cytokines signaling nexus and enhancing the antioxidant enzyme system. Moreover, TUNEL assay demonstrated that CHIP carrying WJMSCs suppressed the apoptotic cell death induced in STZ-induced diabetic group. Collectively, our findings suggests that CHIP-overexpressing WJMSCs might exerts beneficial effects, which may be considered as a therapeutic strategy against diabetic neuropathy complications.

Calycosin alleviates H2 O2 -induced astrocyte injury by restricting oxidative stress through the Akt/Nrf2/HO-1 signaling pathway.

Oxidative stress-induced brain cell damage is a crucial factor in the pathogenesis of reactive oxygen species (ROS)-associated neurological diseases. Further, studies show that astrocytes are an important immunocompetent cell in the brain and play a potentially significant role in various neurological diseases. Therefore, elimination of ROS overproduction might be a potential strategy for preventing and treating neurological diseases. Accumulating evidence indicates that calycosin, a main active ingredient in the Chinese herbal medicine Huangqi (Radix Astragali Mongolici), is a potential therapeutic candidate with anti-inflammation and/or anticancer effects. Here, we investigated the protective effect of calycosin in brain astrocytes by mimicking in vitro oxidative stress using H2 O2 . The results revealed that H2 O2 significantly induced ROS and inflammatory factor (tumor necrosis factor [TNF]-α and interleukin [IL]-1ß) production, whereas post-treatment with calycosin dramatically and concentration-dependently suppressed H2 O2 -induced damage by enhancing cell viability, repressing ROS and inflammatory factor production, and increasing superoxide dismutase (SOD) expression. Additionally, we found that calycosin facilitated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and promoted its nuclear translocation, thereby inducing the expression of antioxidant molecules (heme oxygenase [HO]-1 and SOD) following H2 O2 treatment. Moreover, calycosin did not attenuated H2 O2 -induced astrocyte damage and ROS production in the presence of the ML385 (a Nrf2-specific inhibitor) and following Nrf2 silencing. Furthermore, calycosin failed to increase Akt phosphorylation and mitigate H2 O2 -induced astrocyte damage in the presence of the LY294002 (a selective phosphatidylinositol 3-kinase inhibitor), indicating that calycosin-mediated regulation of oxidative-stress homeostasis involved Akt/Nrf2/HO-1 signaling. These findings demonstrated that calycosin protects against oxidative injury in brain astrocytes by regulating oxidative stress through the AKT/Nrf2/HO-1 signaling pathway.

Tanshinone IIA inhibits Leu27IGF-II-induced insulin-like growth factor receptor II signaling and myocardial apoptosis via estrogen receptor-mediated Akt activation.

Different stress condition stimulates the expression level of insulin-like growth factor receptor II (IGF-IIR) in cardiomyoblasts that lead to apoptosis. Tanshinone IIA (TSN), a pharmacologically active component from Danshen, has been shown cardioprotective effects against cardiac apoptosis induced by several stress conditions. Therefore, this study was conducted to assess the cardioprotective effects of TSN IIA mediated through the estrogen receptor (ER) in order to inhibit the Leu27IGF-II-enhanced IGF-IIR-mediated cardiac apoptosis. The estrogenic activity of TSN IIA was examined after myocardial cells were pretreated with the ER antagonist, and inhibited the phospho-inositide-3 kinase (PI3K). Here, we found that TSN IIA significantly induced ER that phosphorylated Akt. Further, Akt activation considerably suppressed the Leu27IGF-II induced IGF-IIR expression level and the downstream effectors, including Gαq and calcineurin as well as mitochondrial dependent apoptosis proteins including Bad, cytochrome c, and active caspase-3 that result in cardiac apoptosis resistance. However, the western blot analysis, JC-1 staining, and terminal deoxynucleotide transferase-mediated dUTP nick end labeling assay revealed that TSN IIA attenuated Leu27IGF-II-induced IGF-IIR mediated cardiac apoptosis was reversed by an ER antagonist such as ICI 182780, and PI3K inhibition. All these findings demonstrate that TSN IIA exerts estrogenic activity, which can activate PI3K-Akt pathway, and thereby inhibits Leu27IGFII induced IGF-IIR mediated cardiac apoptosis. Thus, TSN IIA can be considered as an effective therapeutic strategy against IGF-IIR signaling cascade to suppress cardiac apoptosis.

Overexpression of cardiac-specific IGF-IIRα accelerates the development of liver dysfunction through STZ-induced diabetic hepatocyte damage in transgenic rats.

This study reports the effect of cardiac-specific insulin-like growth factor-II receptor α (IGF-IIRα) overexpression on the development of liver dysfunction in transgenic rats via STZ-induced diabetic hepatocyte damage. The cardio-hepatic syndrome comprises a number of heart and liver illnesses in which an acute or chronic disease in one organ can lead to acute or chronic disease in the other. However, the molecular mechanism involved in such a set of conditions is unclear. In this study, we developed a transgenic rat model with cardiac-specific overexpression of IGF-IIRα, which is a supplementary splicing variant of insulin-like growth factor-II receptor (IGF-IIR), expressed in pathological hearts, to investigate the relationship between late fetal gene expression in diabetic hearts and their influence on diabetic hepatopathy. STZ (55 mg/kg) was intraperitoneally delivered into IGF-IIR overexpressed transgenic (TG) and non-transgenic (NTG) animal models developed in Sprague-Dawley (SD) rats after an overnight fast. The relationship among IGF-IIRα overexpression and hepatocyte damages have been determined based on the complexity of damage in the liver. Our findings revealed that overexpression of the cardiac-specific IGF-IIRα enhances diabetes-induced morphological alterations and hepatic inflammation in the livers. The diabetic transgenic rats demonstrated the development of pathological conditions such as thick collagen fiber deposition, bridging fibrosis, and elevation of α-SMA and MMP1 related liver fibrosis mechanisms. Our data suggest that IGF-IIRα overexpression in the heart during a pathological state may worsen diabetic hepatopathy in rats.

Isoliquiritigenin ameliorates advanced glycation end-products toxicity on renal proximal tubular epithelial cells.

Diabetic nephropathy is a serious chronic complication affecting at least 25% of diabetic patients. Hyperglycemia associated advanced glycation end-products (AGEs) increase tubular epithelial-myofibroblast transdifferentiation (TEMT) and extracellular matrix synthesis and thereby causes renal fibrosis. The chalcone isoliquiritigenin, found in many herbs of Glycyrrhiza family, is known for potential health-promoting effects. However, their effects on AGE-associated renal proximal tubular fibrosis are not known yet. In this study, the effect of isoliquiritigenin on AGE-induced renal proximal tubular fibrosis was determined in cultured HK-2 cell line. The results show that 200 µg/mL of AGE-induced TEMT and the formed myofibroblasts synthesized collagen to increase extracellular matrix formation thereby lead to renal tubular fibrosis. However, treatment with 200 nM of isoliquiritigenin considerably inhibited the TEMT and suppressed the TGFß/STAT3 mechanism to inhibit collagen secretion. Therefore, isoliquiritigenin effectively suppressed AGE-induced renal tubular fibrosis.

Artemisia argyi extract ameliorates IL-17A-induced inflammatory response by regulation of NF-κB and Nrf2 expression in HIG-82 synoviocytes.

Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease that results in joint destruction and disability in the adult population. RA is characterized by the accumulation and proliferation of fibroblast-like synoviocytes. Many pro-inflammatory mediators are associated with RA, such as interleukin (IL)-1ß, IL-6, IL-17, cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB). Furthermore, IL-17 upregulates the production of other pro-inflammatory mediators, including IL-1ß and IL-6, and promotes the recruitment of neutrophils in RA. Artemisia argyi, a traditional Chinese herbal medicine, is used for the treatment of diseases associated with inflammation and microbial infections. In this study, synoviocytes (HIG-82) were treated with varying doses of A. argyi extract (AAE) following IL-17A stimulation. Proliferation of the IL-17A-stimulated cells was increased compared to that of the non-stimulated control cells. However, cell proliferation decreased significantly in a dose-dependent manner following AAE treatment. Treatment of IL-17A-stimulated cells with AAE resulted in decreased levels of phosphorylated (p)-NF-κB, p-IκB-α, and COX-2. Enzyme-linked immunosorbent assay results showed that IL-1ß and IL-6 levels were increased in the IL-17A-stimulated group but decreased in the AAE treatment group. Additionally, we found that AAE facilitated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and promoted its nuclear translocation, thereby inducing the expression of heme oxygenase-1. Moreover, AAE did not attenuate IL-17A-induced inflammatory mediator production in the presence of ML385, an Nrf2-specific inhibitor. These results suggest that the downregulation of expression of pro-inflammatory cytokines and the transcription factor NF-κB by AAE may be a potential therapeutic strategy for reducing inflammation associated with RA.

Antioxidant Sirt1/Akt axis expression in resveratrol pretreated adipose-derived stem cells increases regenerative capability in a rat model with cardiomyopathy induced by diabetes mellitus.

High-glucose (HG) suppresses mesenchymal stem cell (MSC) functions, resulting in a decrease in cardiac regenerative capability for MSC in diabetes mellitus (DM). Resveratrol enhances MSC functions under stress. This study explores if cardiac regenerative capability can be enhanced in MSCs pretreated with resveratrol in DM rats receiving MSCs. In vitro evidence confirms that HG decreases MSCs capability through suppression of survival markers, AMP-activated protein kinase (AMPK)/Sirtuin 1 (Sirt1) axis, and expression of apoptotic markers. All of these markers are improved when MSCs are cocultured with resveratrol. Wistar male rats were randomly divided into Sham, DM (DM rats), DM rats with autologous transplantation of adipose-derived stem cells (DM + ADSC), and DM rats with resveratrol pretreated ADSC (DM + RSVL-ADSC). Compared to the Sham, DM induces pathological pathways (including fibrosis, hypertrophy, and apoptosis) and suppresses survival as well as the AMPK/Sirt1 axis in the DM group. DM + ADSC slightly improves the above pathways whereas DM + RSVL-ADSC significantly improves the above pathways when compared to the DM group. These results illustrate that resveratrol pretreated with MSCs may show clinical potential in the treatment of heart failure in patients with DM.

miR-145-5p targets paxillin to attenuate angiotensin II-induced pathological cardiac hypertrophy via downregulation of Rac 1, pJNK, p-c-Jun, NFATc3, ANP and by Sirt-1 upregulation.

Pathological cardiac hypertrophy is associated with many diseases including hypertension. Recent studies have identified important roles for microRNAs (miRNAs) in many cardiac pathophysiological processes, including the regulation of cardiomyocyte hypertrophy. However, the role of miR-145-5p in the cardiac setting is still unclear. In this study, H9C2 cells were overexpressed with microRNA-145-5p, and then treated with Ang-II for 24 h, to study the effect of miR-145-5p on Ang-II-induced myocardial hypertrophy in vitro. Results showed that Ang-II treatment down-regulated miR-145-5p expression were revered after miR-145-5p overexpression. Based on results of bioinformatics algorithms, paxillin was predicted as a candidate target gene of miR-145-5p, luciferase activity assay revealed that the luciferase activity of cells was substantial downregulated the following co-transfection with wild paxillin 3'UTR and miR-145-5p compared to that in scramble control, while the inhibitory effect of miR-145-5p was abolished after transfection of mutant paxillin 3'UTR. Additionally, overexpression of miR-145-5p markedly inhibited activation of Rac-1/ JNK /c-jun/ NFATc3 and ANP expression and induced SIRT1 expression in Ang-II treated H9c2 cells. Jointly, our study suggested that miR-145-5p inhibited cardiac hypertrophy by targeting paxillin and through modulating Rac-1/ JNK /c-jun/ NFATc3/ ANP / Sirt1 signaling, therefore proving novel downstream molecular pathway of miR-145-5p in cardiac hypertrophy.