[Retracted] Tanshinone IIA regulates colorectal cancer apoptosis via attenuation of Parkin­mediated mitophagy by suppressing AMPK/Skp2 pathways.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the immunofluorescence assay data shown in Fig. 4A on p. 1698 were strikingly similar to data that had already been submitted for publication in different form in another article written by different authors at different research institutes. In addition, there was an instance of apparent duplication of western blot data comparing between Fig. 5A and 5G, and the reader also had concerns regarding the presentation of the flow­cytometry cell­count histograms in Fig. 2A. Owing to the fact that the contentious data in the above article had already been submitted for publication elsewhere prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 18: 1692­1703, 2018; DOI: 10.3892/mmr.2018.9087].

Tumor Cell-Derived Exosomal Hybrid Nanosystems Loaded with Rhubarbic Acid and Tanshinone IIA for Sepsis Treatment.

Background: Sepsis continues to exert a significant impact on morbidity and mortality in clinical settings, with immunosuppression, multi-organ failure, and disruptions in gut microbiota being key features. Although rheinic acid and tanshinone IIA show promise in mitigating macrophage apoptosis in sepsis treatment, their precise targeting of macrophages remains limited. Additionally, the evaluation of intestinal flora changes following treatment, which plays a significant role in subsequent cytokine storms, has been overlooked. Leveraging the innate inflammation chemotaxis of tumor cell-derived exosomes allows for their rapid recognition and uptake by activated macrophages, facilitating phenotypic changes and harnessing anti-inflammatory effects. Methods: We extracted exosomes from H1299 cells using a precipitation method. Then we developed a tumor cell-derived exosomal hybrid nanosystem loaded with rhubarbic acid and tanshinone IIA (R+T/Lipo/EXO) for sepsis treatment. In vitro studies, we verify the anti-inflammatory effect and the mechanism of inhibiting cell apoptosis of nano drug delivery system. The anti-inflammatory effects, safety, and modulation of intestinal microbiota by the nanoformulations were further validated in the in vivo study. Results: Nanoformulation demonstrated enhanced macrophage internalization, reduced TNF-α expression, inhibited apoptosis, modulated intestinal flora, and alleviated immunosuppression. Conclusion: R+T/Lipo/EXO presents a promising approach using exosomal hybrid nanosystems for treating sepsis.

Efficacy of tanshinone IIA in rat models with myocardial ischemia-reperfusion injury: a systematic mini-review and meta-analysis.

Background: Myocardial ischemia-reperfusion injury (MIRI) refers to severe damage to the ischemic myocardium following the restoration of blood flow, and it is a major complication of reperfusion therapy for myocardial infarction. Notably, drugs such as metoprolol have been utilized to reduce ischemia-reperfusion injury. Tanshinone IIA is a major constituent extracted from Salvia miltiorrhiza Bunge. Recently, tanshinone IIA has been studied extensively in animal models for controlling MIRI. Therefore, we conducted a meta-analysis on the application of tanshinone IIA in rat models with MIRI to evaluate the therapeutic effects of tanshinone IIA. Methods: A comprehensive search was conducted across PubMed, Web of Science, Embase, the Cochrane Library, the China National Knowledge Infrastructure database, the Wanfang database, and the Chinese Scientific Journal Database to gather studies on tanshinone IIA intervention in rat models with MIRI.We employed SYRCLE's risk of bias tool to assess study quality. The primary outcome indicators were superoxide dismutase (SOD) and malondialdehyde (MDA). Myocardial infarction area was a secondary outcome indicator. This study was registered at PROSPERO (registration number CRD 42022344447). Results: According to the inclusion and exclusion criteria, 15 eligible studies were selected from 295 initially identified studies. In rat models with MIRI, tanshinone IIA significantly increased SOD levels while reducing MDA levels and myocardial infarction area. Moreover, the duration of myocardial ischemia influenced the effectiveness of tanshinone IIA. However, additional high-quality research studies are needed to establish the efficacy and definitive guidelines for the use of tanshinone IIA. Animal studies demonstrated that tanshinone IIA exerted a significant therapeutic effect when the ischemia duration was less than 40 minutes. Tanshinone IIA was found to be more effective when administered via intravenous, intraperitoneal, and intragastric routes at doses above 5 mg/kg. Additionally, treatment with tanshinone IIA at all stages-prior to myocardial ischemia, after ischemia but before reperfusion, prior to ischemia and after reperfusion, and after reperfusion-showed satisfactory results. Conclusions: Tanshinone IIA enhanced SOD activity and reduced MDA levels, thereby ameliorating oxidative stress damage during MIRI. Additionally, it reduced the myocardial infarction area, indicating its effectiveness in mitigating MIRI-induced damage in rats and demonstrating a myocardial protective effect. These findings contribute valuable insights for developing MIRI treatment strategies.

Activation of SIRT3 by Tanshinone IIA ameliorates renal fibrosis by suppressing the TGF-ß/TSP-1 pathway and attenuating oxidative stress.

Although doxorubicin (DOX) is a common chemotherapeutic drug, the serious nephrotoxicity caused by DOX-induced renal fibrosis remains a considerable clinical problem. Tanshinone IIA (Tan IIA), a compound extracted from Salvia miltiorrhiza, has been reported to have an anti-fibrotic effect. Therefore, this study investigated the molecular pathway whereby Tan IIA protects the kidneys from DOX administration. DOX (3 mg/kg body weight) was intraperitoneally administered every 3 d for a total of 7 injections (cumulative dose of 21 mg/kg) to induce nephrotoxicity. Then, Tan IIA (5 or 10 mg/kg/d) was administered by intraperitoneal injection for 28 d. In an in vitro study, 293 T cells were cultured and treated with DOX and Tan IIA for 24 h. Tan IIA reduced the blood urea nitrogen levels elevated by DOX while increasing superoxide dismutase activity, down-regulating reactive oxygen species, ameliorating renal-tubule thickening, and rescuing mitochondrial morphology. Additionally, Tan IIA reduced the renal collagen deposition, increased ATP production and complex-I activity, down-regulated transforming growth factor-ß1 (TGF-ß1) and thrombospondin-1 (TSP-1), and up-regulated sirtuin 3 (SIRT3). Tan IIA significantly increased cell viability. Additionally, RNA interference was employed to silence the expression of SIRT3, which eliminated the effect of Tan IIA in suppressing the expression of TGF-ß1 and TSP-1. In conclusion, Tan IIA ameliorated DOX-induced nephrotoxicity by attenuating oxidative injury and fibrosis. The Tan IIA-induced rescue of mitochondrial morphology and function while alleviating renal fibrosis may be associated with the activation of SIRT3 to suppress the TGF-ß/TSP-1 pathway.

Endothelial TRPV4 channel mediates the vasodilation induced by Tanshinone IIA.

Tanshinone IIA (TSA), the main lipo-soluble component from the dried rhizome of Salvia miltiorrhiza, has been shown to induce vasodilation. However, the underlying mechanisms remains unclear. This study aimed to investigate the effect of TSA on the vasodilation of small resistant arteries ex vivo. Vascular myography revealed that endothelial denudation reduced significantly the vasodilatory effect of TSA. Blocking transient receptor potential vanilloid 4 (TRPV4) channels prevented TSA-induced vasodilation. Whole-cell patch-clamp analysis revealed that the current passing through TRPV4 channels increased after TSA treatment in endothelial cells (ECs). This was attributed to reduced TRPV4 protein degradation along with its increased expression. The TRPV4 inhibitor HC-067047 lowed nitric oxide (NO) production and TSA-induced expression of endothelial nitric oxide synthase (eNOS). Moreover, it increased the production of cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG). The present results indicate that TSA induces endothelium-dependent vasodilation, which is mediated by the TRPV4-NO-PKG signaling pathway. These findings highlight the potential of TSA, a compound known in traditional Chinese medicine as Danshen (Salvia miltiorrhiza), for future cardiovascular therapeutic strategies.

Tanshinone IIA promotes osteogenic differentiation potential and suppresses adipogenic differentiation potential of bone marrow mesenchymal stem cells.

Tanshinone IIA (Tan IIA) may have therapeutic effects on avascular necrosis of the femoral head (ANFH) by targeting bone marrow mesenchymal stem cells (BMSCs). The effect and underlying mechanism of Tan IIA on adipogenesis and osteogenesis ability of BMSCs remain to be elucidated. In the present study BMSCs were treated with osteogenic or adipogenic differentiation medium with or without Tan IIA under hypoxic environment. Osteogenic differentiation potential was evaluated by alkaline phosphatase (ALP) measurement, alizarin red staining and reverse transcription­quantitative (RT­q) PCR of osteogenic marker genes. Adipogenic differentiation potential was evaluated with oil red staining and RT­qPCR of adipogenic marker genes. Detailed mechanism was explored by RNA­seq and small molecular treatment during osteogenesis and adipogenesis of BMSCs. ALP level, mineralized nodules and expression level of osteogenic marker genes significantly increased following Tan IIA treatment during osteogenic differentiation of BMSCs. Lipid droplet and expression levels of adipogenic marker genes significantly decreased following Tan IIA treatment during adipogenic differentiation of BMSCs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of RNA­seq data indicated increased Akt and TGFß signaling following Tan IIA treatment. Further western blot assay confirmed that Tan IIA significantly activated Akt/cAMP response element­binding protein signaling and TGFß/Smad3 signaling. Application of Akti1/2 (an Akt inhibitor) significantly decreased the promotion effect of osteogenesis induced by Tan IIA, while the addition of SB431542 significantly reduced inhibition effect of adipogenesis caused by Tan IIA. Tan IIA could promote osteogenic differentiation potential of BMSCs by activating AKT signaling and suppress adipogenic differentiation potential of BMSCs by activating TGFß signaling.

Effect of Harvest Time on Growth and Bioactive Compounds in Salvia miltiorrhiza.

Danshen (Salvia miltiorrhiza) is a perennial medicinal plant belonging to the Lamiaceae family. It is adapted to a wide range of soil pH with the potential to serve as an alternative crop in the United States. To enhance its cultivation and economic viability, it is crucial to develop production practices that maximize bioactive compound yields for danshen. The objective of this study was to investigate the effects of different harvest times on plant growth and subsequent yields of bioactive components of danshen. Three harvest times were selected (60, 120, or 180 days after transplanting [DAT]). In general, plants harvested at 180 DAT had higher plant growth index (PGI), shoot number, shoot weight, root number, maximum root length, maximum root diameter, and root weight compared to plants harvested at 60 or 120 DAT. However, plants harvested at 60 or 120 DAT had higher SPAD (Soil Plant Analysis Development) values. Plants harvested at 120 or 180 DAT had a higher content of tanshinone I, tanshinone IIA, cryptotanshinone, and salvianolic acid B compared to those harvested at 60 DAT. This study provides insights for optimizing the time of harvest of danshen to maximize plant growth and bioactive compound production.

Tanshinone IIA Promoted Autophagy and Inhibited Inflammation to Alleviate Podocyte Injury in Diabetic Nephropathy.

Purpose: Tanshinone IIA (Tan-IIA) is widely used in patients with diabetic nephropathy (DN), but its protective effect on podocytes in DN has not been well studied. In this study, the effects of Tan-IIA on autophagy and inflammation of glomerular podocytes in DN were observed in vivo and in vitro, and the underlying mechanisms were investigated. Irbesartan, an angiotensin II receptor blocker, is a representative medication for the clinical treatment of DN. So irbesartan was chosen as a positive control drug. Methods: Eight-week-old male db/db mice were randomly divided into a DN group, an irbesartan group, and three groups receiving different doses of Tan-IIA. The control group consisted of the db/m littermate mice. Blood, urine, and kidney samples were taken from the mice after 12 weeks of continuous administration. Renal protection of Tan-IIA was evaluated using enzyme-linked immunosorbent assay kits, haematoxylin and eosin staining, transmission electron microscopy, Western blotting, and immunohistochemistry. In vitro, the protective effect of Tan-IIA on podocytes was explored using MPC5 cells cultured with high glucose. Results: Tan-IIA significantly improved renal pathological injury and relieved the renal dysfunction in DN. Compared with the DN group, Tan-IIA could up-regulate the expression of Synaptopodin, Podocin, LC3II/I and Beclin-1 (p < 0.05), and down-regulate the expression of p62, F4/80, NF-κB p65, IL-1ß, TNF-α and IL-6 (p < 0.05) both in vivo and in vitro, suggesting that Tan-IIA treatment alleviated podocyte injury by promoting autophagy and inhibiting inflammation during DN. The levels of p-PI3K/PI3K, p-Akt/Akt and p-mTOR/mTOR in Tan-IIA group were lower than those in DN group (p < 0.05), indicating that Tan-IIA inhibited the PI3K/Akt/mTOR signalling pathway in podocytes, which was a key pathway in regulating both autophagy and inflammation. Conclusion: Tan-IIA prevented podocyte injury in DN by fostering autophagy and inhibiting inflammation, at least in part via inhibition of the PI3K/Akt/mTOR signalling pathway.

Effects of tanshinone IIA on endothelial cell dysfunction in uremic condition.

An arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis in uremic patients, yet its dysfunction poses a significant clinical challenge. Venous stenosis, primarily caused by venous neointimal hyperplasia, is a key factor in the failure of vascular access. During vascular access dysfunction, endothelial cells (ECs) transform mechanical stimuli into intracellular signals and interact with vascular smooth muscle cells. Tanshinone IIA, an important compound derived from Salvia miltiorrhiza, has been widely used to treat cardiovascular diseases. However, its role in modulating ECs under uremic conditions remains incompletely understood. In this research, ECs were exposed to sodium tanshinone IIA sulfonate (STS) and subjected to shear stress and uremic conditions. The results indicate that STS can reduce the suppressive effects on the expression of NF-κB p65, JNK and Collagen I in uremia-induced ECs. Moreover, the downregulation of NF-κB p65, JNK and Collagen I can be enhanced through the inhibition of ERK1/2 and the upregulation of Caveolin-1. These findings suggest that tanshinone IIA may improve EC function under uremic conditions by targeting the Caveolin-1/ERK1/2 pathway, presenting tanshinone IIA as a potential therapeutic agent against AVF immaturity caused by EC dysfunction.

Sodium tanshinone IIA sulfonate protects vascular relaxation in ApoE-knockout mice by inhibiting the SYK-NLRP3 inflammasome-MMP2/9 pathway.

BACKGROUND: Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. METHODS: In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. RESULTS: Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. CONCLUSIONS: These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.

Developing a Tanshinone IIA Memetic by Targeting MIOS to Regulate mTORC1 and Autophagy in Glioblastoma.

Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy. Recently, T2A has been demonstrated to function through sestrin 2 (SESN) to inhibit mTORC1 activity, but its possible impact on autophagy through this pathway has not been investigated. Here, the model system Dictyostelium discoideum and GBM cell lines were employed to investigate the cellular role of T2A in regulating SESN to inhibit mTORC1 and activate autophagy through a GATOR2 component MIOS. In D. discoideum, T2A treatment induced autophagy and inhibited mTORC1 activity, with both effects lost upon the ablation of SESN (sesn-) or MIOS (mios-). We further investigated the targeting of MIOS to reproduce this effect of T2A, where computational analysis identified 25 novel compounds predicted to strongly bind the human MIOS protein, with one compound (MIOS inhibitor 3; Mi3) reducing cell proliferation in two GBM cells. Furthermore, Mi3 specificity was demonstrated through the loss of potency in the D. discoideum mios- cells regarding cell proliferation and the induction of autophagy. In GBM cells, Mi3 treatment also reduced mTORC1 activity and induced autophagy. Thus, a potential T2A mimetic showing the inhibition of mTORC1 and induction of autophagy in GBM cells was identified.

Role of TRIM59 in regulating PPM1A in the pathogenesis of silicosis and the intervention effect of tanshinone IIA.

This study examines the involvement of TRIM59 in silica-induced pulmonary fibrosis and explores the therapeutic efficacy of Tanshinone IIA (Tan IIA). In vivo experiments conducted on rats with silica-induced pulmonary fibrosis unveiled an increase in TRIM59 levels and a decrease in PPM1A levels. Subsequent investigations using in vitro silicosis cell models demonstrated that modulation of TRIM59 expression significantly impacts silicosis fibrosis, influencing the levels of PPM1A and activation of the Smad2/3 signaling pathway. Immunofluorescence and co-immunoprecipitation assays confirmed the interaction between TRIM59 and PPM1A in fibroblasts, wherein TRIM59 facilitated the degradation of PPM1A protein via proteasomal and ubiquitin-mediated pathways. Furthermore, employing a rat model of silica-induced pulmonary fibrosis, Tan IIA exhibited efficacy in mitigating lung tissue damage and fibrosis. Immunohistochemical analysis validated the upregulation of TRIM59 and downregulation of PPM1A in silica-induced pulmonary fibrosis, which Tan IIA alleviated. In vitro studies elucidated the mechanism by which Tan IIA regulates the Smad2/3 signaling pathway through TRIM59-mediated modulation of PPM1A. Treatment with Tan IIA in silica-induced fibrosis cell models resulted in concentration-dependent reductions in fibrotic markers and attenuation of relevant protein expressions. Tan IIA intervention in silica-induced fibrosis cell models mitigated the TRIM59-induced upregulation of fibrotic markers and enhanced PPM1A expression, thereby partially reversing Smad2/3 activation. Overall, the findings indicate that while overexpression of TRIM59 may activate the Smads pathway by suppressing PPM1A expression, treatment with Tan IIA holds promise in counteracting these effects by inhibiting TRIM59 expression.

The Role of Traditional Chinese Medicine in the Management of Cervical Cancer.

Globally, cervical cancer poses a substantial public health challenge, with low and middle-income countries bearing the highest burden [Rajkhowa, P., D.S. Patil, S.M. Dsouza, P. Narayanan and H. Brand. Evidence on factors influencing HPV vaccine implementation in South Asia: a scoping review. Glob. Public Health 18: 2288269, 2023]. The incidence rate ranks second highest among female malignant tumors in China, following only breast cancer. The prognosis of advanced cervical cancer is extremely poor, with a 5-year progression-free survival (PFS) rate of only 15%, and the treatment of advanced recurrent or metastatic cervical cancer remains a huge challenge. An increasing amount of evidence suggests that traditional Chinese medicine (TCM) can significantly enhance sensitivity to chemotherapeutic drugs, strengthen antitumor effects, and notably improve adverse reactions associated with cancer such as fatigue and bone marrow suppression. In recent years, the therapeutic effects and mechanisms of Chinese herbal medicines, such as the Guizhi-Fuling-decoction, the compound Yangshe granule, Huangqi, and Ginseng, herbal monomers (e.g., Ginsenoside Rh2, Tanshinone IIA, and Tetrandrine), and the related extracts and compound formulations, have received extensive attention for the treatment of cervical cancer. This paper reviews the research progress of TCM in cervical cancer. In addition, we reported a case of an advanced cervical cancer patient with multiple abdominal and pelvic metastasis who initially received chemotherapy, was then treated with TCM alone, and subsequently survived for 22 years. The model of whole-process management with TCM can enable more cancer patients to obtain longer survival periods.

Expression of RIPK1 and FADD are associated with chemosensitivity and survival in head and heck squamous cell carcinoma via tanshinone IIA-mediated modulation of the RIPK1-FADD-Caspase 8 complex.

Tanshinone IIA (Tan IIA), a main active ingredient of salvia miltiorrhiza, has a wide range of antitumor effects, while its specific role and mechanism in head and neck squamous cell carcinomas (HNSCC) is not fully understood. Totally 59 primary HNSCC patients underwent two courses of induction chemotherapy before surgery. The association between expression of Fas-Associated Death Domain (FADD) and receptor interacting protein kinase 1 (RIPK1) and chemotherapy resistance and survival were evaluated. The cell counting kit-8 was used to detect the effect of Tan IIA on the activity of cisplatin in chemoresistant HNSCC cells through a series of in vitro experiments. The quantitative real-time reverse-transcription polymerase chain reaction, Western blot analysis and flow cytometry were used. FADD and RIPK1 expressions were differentially expressed in Chemosensitive and drug-resistant patients. Furthermore, patients with tumors exhibiting high expression of FADD and RIPK1 had significantly greater risk for chemoresistance and mortality than patients with tumors that had low levels of these proteins. Moreover, Tan IIA reduced the expression of RIPK1 and FADD in HNSCC chemoresistant cell lines, which could increase the chemosensitivity of cisplatin and promote apoptosis. Overexpression of RIPK1 led to attenuation of therapeutic effects of Tan IIA, which were mainly realized through regulation of the RIPK1-FADD-Caspase 8 complex. This study is the first to demonstrate the clinical value and role of FADD and RIPK1 in the treatment of HNSCC. This work establishes the proapoptotic effects of Tan IIA and its potential to enhance chemosensitivity in HNSCC by modulating the RIPK1-FADD-Caspase 8 complex.

Local Application of Tanshinone IIA protects mesenchymal stem cells from apoptosis and promotes fracture healing in ovariectomized mice.

BACKGROUND: Elderly patients suffering from osteoporotic fractures are more susceptible to delayed union or nonunion, and their bodies then are in a state of low-grade chronic inflammation with decreased antioxidant capacity. Tanshinone IIA is widely used in treating cardiovascular and cerebrovascular diseases in China and has anti-inflammatory and antioxidant effects. We aimed to observe the antioxidant effects of Tanshinone IIA on mesenchymal stem cells (MSCs), which play important roles in bone repair, and the effects of local application of Tanshinone IIA using an injectable biodegradable hydrogel on osteoporotic fracture healing. METHODS: MSCs were pretreated with or without different concentrations of Tanshinone IIA followed by H2O2 treatment. Ovariectomized (OVX) C57BL/6 mice received a mid-shaft transverse osteotomy fracture on the left tibia, and Tanshinone IIA was applied to the fracture site using an injectable hydrogel. RESULTS: Tanshinone IIA pretreatment promoted the expression of nuclear factor erythroid 2-related factor 2 and antioxidant enzymes, and inhibited H2O2-induced reactive oxygen species accumulation in MSCs. Furthermore, Tanshinone IIA reversed H2O2-induced apoptosis and decrease in osteogenic differentiation in MSCs. After 4 weeks of treatment with Tanshinone IIA in OVX mice, the bone mineral density of the callus was significantly increased and the biomechanical properties of the healed tibias were improved. Cell apoptosis was decreased and Nrf2 expression was increased in the early stage of callus formation. CONCLUSIONS: Taken together, these results indicate that Tanshinone IIA can activate antioxidant enzymes to protect MSCs from H2O2-induced cell apoptosis and osteogenic differentiation inhibition. Local application of Tanshinone IIA accelerates fracture healing in ovariectomized mice.

Effectiveness and mechanism of the Chinese medicine Weiren Xiaoyou formula in improving palmoplantar warts.

Background: Palmoplantar warts (PWs) are a usual skin disease associated with human papillomavirus (HPV) that can affect patients' quality of life. The traditional Chinese medicine (TCM) Weiren Xiaoyou formula (WRXYF) is a relatively gentle and effective therapy that has achieved good therapeutic effects in clinical practice, but its mechanism has not yet been studied. Methods: A meta-analysis was carried out to identify the potential advantages of topical TCM for PW treatment. Clinical cases suggested that WRXYF was an effective therapeutic agent against PWs. Network pharmacology was utilized to predict potential targets for the main bioactive compound, tanshinone IIA (Tan IIA), in WRXYF. High-performance liquid chromatography with electrospray mass spectrometry (HPLC/ESI-MS) was applied to detect major components. The bioactivity of Tan IIA against PWs was then validated with quantitative polymerase chain reaction (q-PCR), fluorescence in situ hybridization (FISH), electron microscopy and Western blotting. Results: A meta-analysis was conducted on 10 randomized clinical trials (RCTs) involving 2260 participants suggested that topical TCM could more effectively treat PWs than conventional medications. Network pharmacology identified Tan IIA as a candidate agent from 17 major compounds assessed by HPLC/ESI-MS because of its stable binding with 10 PW targets. HPV2, HPV27, and HPV57 were the main infectious strains in tissues obtained from PW patients and in HPV-infected HaCaT cells. Tan IIA treatment effectively destroyed viral particles and reduced the viral copy numbers of the three HPV subtypes. The results shown that Tan IIA has the ability to halt the cell cycle of HPV-infected HaCaT cells specifically in the G0/G1 phase. A total of 6 cell cycle-related proteins were regulated after Tan IIA treatment, demonstrating the role of Tan IIA in inhibiting the cell cycle. Conclusion: Tan IIA, the primary bioactive constituent in WRXYF, enhances PWs by halting the cell cycle in the G0/G1 phase via modulation of the p53 signaling pathway.

Tanshinone IIA alleviates pulmonary fibrosis by modulating glutamine metabolic reprogramming based on [U-13C5]-glutamine metabolic flux analysis.

INTRODUCTION: Glutamine metabolic reprogramming, mediated by glutaminase (GLS), is an important signal during pulmonary fibrosis (PF) progression. Tanshinone IIA (Tan IIA) is a naturally lipophilic diterpene with antioxidant and antifibrotic properties. However, the potential mechanisms of Tan IIA for regulating glutamine metabolic reprogramming are not yet clear. OBJECTIVES: This study aimed was to evaluate the role of Tan IIA in intervening in glutamine metabolic reprogramming to exert anti-PF and to explore the potential new mechanisms of metabolic regulation. METHODS: Fibrotic characteristics was detected via immunofluorescence and western blotting analysis. Cell proliferation was examined with EdU Assay. Cell metabolites were labeled by using stable isotope [U-13C5]-glutamine. By utilizing 100% 13C glutamine tracers and employing network analysis to investigate the activation of metabolic pathways in fibroblasts, as well as evaluating the impact of Tan IIA on these pathways, we accurately quantified the absolute flux of glutaminolysis, proline synthesis, and the TCA cycle pathway using isotopomer network compartmental analysis (INCA), a user-friendly software tool for 13C metabolic flux analysis (13C-MFA). Molecular docking was used for identifying the binding of Tan IIA with target protein. RESULTS: Tan IIA ameliorate TGF-ß1-induced myofibroblast proliferation, reduce collagen I and III and α-SMA protein expression in MRC-5 and NIH-3T3 cells. Furthermore, Tan IIA regulate mitochondrial energy metabolism by modulating TGF-ß1-stimulated glutamine metabolic reprogramming in NIH-3T3 cells and inhibiting GLS1 expression, which reduced the metabolic flux of glutamine into mitochondria in myofibroblasts, and also targeted inhibited the expression of Δ1-pyrroline-5-carboxylate synthase (P5CS), P5C reductase 1 (PYCR1), and phosphoserine aminotransferase 1 (PSAT1), and reduced proline hydroxylation and blocked the collagen synthesis pathway. CONCLUSION: Tan IIA reverses glutamine metabolic reprogramming, reduces mitochondrial energy expenditure, and inhibits collagen matrix synthesis by modulating potential targets in glutamine metabolism. This novel perspective sheds light on the essential role of glutamine metabolic reprogramming in PF.

Tanshinone IIA from Salvia miltiorrhiza alleviates follicular maturation arrest symptoms in zebrafish via binding to the human androgen receptors and modulating Tox3 and Dennd1a.

Follicular maturation arrest is a prevalent endocrine disorder characterized by hormonal imbalance, ovarian dysfunction, and metabolic disturbances leading to Polycystic ovarian syndrome (PCOS). Tanshinone IIA (TIIA), a bioactive compound derived from Salvia miltiorrhiza, has shown promising therapeutic potential in various diseases, including cardiovascular diseases and cancer. However, its effects on reproductive health and gynecological disorders, particularly PCOS, remain poorly understood. In this study, we investigated the potential therapeutic effects of TIIA on ovarian function. Using a combination of experimental and computational approaches, we elucidated the molecular mechanisms underlying TIIA's pharmacological impact on ovarian function, follicular development, and androgen receptor signaling. Molecular docking and dynamics simulations revealed that TIIA interacts with the human androgen receptor (HAR), modulating its activity and downstream signaling pathways. Our results demonstrate that TIIA treatment alleviates PCOS-like symptoms in a zebrafish model, including improved follicular development, lowered GSI index, improved antioxidant status (SOD, CAT), decreased LDH levels, and enhanced AChE levels by regulating Tox3 and Dennd1a pathway. Our findings suggest that TIIA may hold promise as a novel therapeutic agent for the management of PCOS or ovulation induction.

Tanshinone IIA positively regulates the Keap1-Nrf2 system to alleviate pulmonary fibrosis via the sestrin2-sqstm1 signaling axis-mediated autophagy.

BACKGROUND: Activation of myofibroblasts, linked to oxidative stress, emerges as a pivotal role in the progression of pulmonary fibrosis (PF). Our prior research has underscored the therapeutic promise of tanshinone IIA (Tan-IIA) in mitigating PF by enhancing nuclear factor-erythroid 2-related factor 2 (Nrf2) activity. Nevertheless, the molecular basis through which Tan-IIA influences Nrf2 activity has yet to be fully elucidated. METHODS: The influence of Tan-IIA on PF was assessed in vivo and in vitro models. Inhibitors, overexpression plasmids, and small interfering RNA (siRNA) were utilized to probe its underlying mechanism of action in vitro. RESULTS: We demonstrate that Tan-IIA effectively activates the kelch-like ECH-associated protein 1 (Keap1)-Nrf2 antioxidant pathway, which in turn inhibits myofibroblast activation and ameliorates PF. Notably, the stability and nucleo-cytoplasmic shuttling of Nrf2 is shown to be dependent on augmented autophagic flux, which is in alignment with the observation that Tan-IIA induces autophagy. Inhibition of autophagy, conversely, fosters the activation of extracellular matrix (ECM)-producing myofibroblasts. Further, Tan-IIA initiates an autophagy program through the sestrin 2 (Sesn2)-sequestosome 1 (Sqstm1) signaling axis, crucial for protecting Nrf2 from Keap1-mediated degradation. Meanwhile, these findings were corroborated in a murine model of PF. CONCLUSION: Collectively, we observed for the first time that the Sqstm1-Sesn2 axis-mediated autophagic degradation of Keap1 effectively prevents myofibroblast activation and reduces the synthesis of ECM. This autophagy-dependent degradation of Keap1 can be initiated by the Tan-IIA treatment, which solidifies its potential as an Nrf2-modulating agent for PF treatment.

Tanshinone IIA suppresses ferroptosis to attenuate renal podocyte injury in diabetic nephropathy through the embryonic lethal abnormal visual-like protein 1 and acyl-coenzyme A synthetase long-chain family member 4 signaling pathway.

AIMS/INTRODUCTION: Tanshinone IIA (TIIA) is one of the main components of the root of the red-rooted Salvia miltiorrhiza Bunge. However, the molecular mechanisms underlying TIIA-mediated protective effects in diabetic nephropathy (DN) are still unclear. MATERIALS AND METHODS: High glucose (HG)-induced mouse podocyte cell line (MPC5) cells were used as the in vitro model of DN and treated with TIIA. Cell viability, proliferation and apoptosis were detected using 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine and flow cytometry assays. The protein levels were assessed using western blot assay. The levels of inflammatory factors were deleted by enzyme-linked immunoassay. Fe+ level, reactive oxygen species, malondialdehyde and glutathione products were detected using special assay kits. After ENCORI prediction, the interaction between embryonic lethal abnormal visual-like protein 1 (ELAVL1) and acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) was verified using co-immunoprecipitation assay and dual-luciferase reporter assays. ACSL4 messenger ribonucleic acid expression was measured using real-time quantitative polymerase chain reaction. RESULTS: TIIA repressed HG-induced MPC5 cell apoptosis, inflammatory response and ferroptosis. ACSL4 upregulation relieved the repression of TIIA on HG-mediated MPC5 cell injury and ferroptosis. ELAVL1 is bound with ACSL4 to positively regulate the stability of ACSL4 messenger ribonucleic acid. TIIA hindered HG-triggered MPC5 cell injury and ferroptosis by regulating the ELAVL1-ACSL4 pathway. TIIA blocked DN progression in in vivo research. CONCLUSION: TIIA treatment restrained HG-caused MPC5 cell injury and ferroptosis partly through targeting the ELAVL1-ACSL4 axis, providing a promising therapeutic target for DN treatment.