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Background: Drug resistance remains a significant obstacle to Acute myeloid leukemia (AML) successful treatment, often leading to therapeutic failure. Our previous studies demonstrated that Glioma-associated oncogene-1 (GLI1) reduces chemotherapy sensitivity and promotes cell proliferation in AML cells. GANT61, an inhibitor of GLI1, emerges as a promising candidate in AML treatment. This study aims to explore the effects of the combination of GANT61 and Adriamycin (ADR) on AML cells resistance and elucidate the mechanisms through which GANT61 may potentiate the sensitivity of AML cells to ADR. Methods: AML cell lines and AML primary cells were studied to evaluate effects and mechanisms of GANT61. Flow cytometry assays were used to verify apoptosis. Cell Counting Kit-8 (CCK-8) and EDU+ staining were used to observe changes in cell viability and the cytotoxic effect to different drugs. The transcriptomic profiles of HL-60/ADR cells with or without GANT61 treatment were compared via RNA-Seq analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and Gene Set Enrichment Analysis (GSEA) were performed for differentially expressed genes (DEGs) to reveal the underlying mechanisms of GANT61 in AML cells. GLI1, BCL2, Bax protein and mRNA expression levels were assessed by Western blot and Real-time polymerase chain reaction (RT-PCR). Results: Our studies found that the combination of GANT61 and ADR synergistically inhibits proliferation while enhancing apoptosis in HL-60/ADR cells, and does not significantly exacerbate myelosuppression. Mechanistically, GSEA revealed enrichment of the gene set associated with the KEGG term "Apoptosis" and "Lysosome" in GANT61 treated cells. Meanwhile, "Apoptosis" was identified as the third most relevant pathway enriched by lysosomal DEGs, and BCL2 expression showed a negative correlation with these lysosomal DEGs in AML patients. RT-PCR and Western blot analysis disclosed that GANT61 significantly restrained BCL2 expression in AML cells. Lastly, we proved that venetoclax, a BCL2 inhibitor, co-treatment with GANT61 improved ADR sensitivity in HL-60/ADR cells. Conclusions: GANT61 effectively reversed ADR resistance in HL-60/ADR cells by upregulating lysosome activities and downgrading BCL2 expression, providing a new treatment strategy with acceptable toxicity for AML-resistant patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Doxorubicin is a widely used chemotherapeutic agent for breast cancer but is accompanied by significant side effects due to its systemic delivery. The expression of the transient receptor potential canonical 1 (TRPC1) cation channel subunit correlates with breast cancer progression. This study showed that brief magnetic exposure (10 min) increased doxorubicin uptake into breast cancer cells without harming healthy cells. Heightened TRPC1 expression was correlated with more advanced breast cancer grades as well as with greater doxorubicin uptake. Pharmacologically or genetically silencing TRPC1 activity reduced magnetically induced doxorubicin uptake, whereas overexpression of TRPC1 amplified doxorubicin uptake and increased cancer cell death. This study described a localized and non-invasive magnetic therapy paradigm that could potentially improve breast cancer chemotherapeutic efficacy with less systemically delivered doxorubicin. The loading of TRPC1-enriched cell-derived vesicles with doxorubicin upon magnetic exposure underscored the contribution of TRPC1 in the stimulated uptake of doxorubicin in a minimalized model system. Background/Objectives: Doxorubicin (DOX) is commonly used as a chemotherapeutic agent for the treatment of breast cancer. Nonetheless, its systemic delivery via intravenous injection and toxicity towards healthy tissues commonly result in a broad range of detrimental side effects. Breast cancer severity was previously shown to be correlated with TRPC1 channel expression that conferred upon it enhanced vulnerability to pulsed electromagnetic field (PEMF) therapy. PEMF therapy was also previously shown to enhance breast cancer cell vulnerability to DOX in vitro and in vivo that correlated with TRPC1 expression and mitochondrial respiratory rates. Methods: DOX uptake was assessed by measuring its innate autofluorescence within murine 4T1 or human MCF7 breast cancer cells following magnetic exposure. Cellular vulnerability to doxorubicin uptake was assessed by monitoring mitochondrial activity and cellular DNA content. Results: Here, we demonstrate that 10 min of PEMF exposure could augment DOX uptake into 4T1 and MCF7 breast cancer cells. DOX uptake could be increased by TRPC1 overexpression, whereas inhibiting the activity of TRPC1 channels with SKF-96356 or genetic knockdown, precluded DOX uptake. PEMF exposure enhances DOX-mediated killing of breast cancer cells, reducing the IC50 value of DOX by half, whereas muscle cells, representative of collateral tissues, were less sensitive to PEMF-enhanced DOX-mediated cytotoxicity. Vesicular loading of DOX correlated with TRPC1 expression. Conclusions: This study presents a novel TRPC1-mediated mechanism through which PEMF therapy may enhance DOX cytotoxicity in breast cancer cells, paving the way for the development of localized non-invasive PEMF platforms to improve cancer outcomes with lower systemic levels of DOX. [ABSTRACT FROM AUTHOR]

In this work, a facile and fast aqueous-phase synthetic method is proposed to prepare water-soluble ZnS quantum dots stabilized simultaneously with glutathione and L-cysteine (ZnS QDs-GSH/L-Cys). As-synthesized ZnS QDs-GSH/L-Cys were monodispersed spherical nanocrystals with a mean diameter of 5.0 ± 0.7 nm. Besides, the obtained ZnS QDs-GSH/L-Cys emitted more intensive blue fluorescence and exhibited an improved stability in aqueous solution compared with ZnS quantum dots merely stabilized with GSH (ZnS QDs-GSH). Interestingly, Adriamycin, a representative anticancer drug, was added into the solution of ZnS QDs-GSH/L-Cys, the blue fluorescence of ZnS QDs-GSH/L-Cys was greatly enhanced instead of being quenched, which indicated that ZnS QDs-GSH/L-Cys can be used as an enhanced-fluorescence nanoprobe for determining Adriamycin. The observed fluorescent enhancement could be attributed to the blocking of photoinduced electron transfer (PET) in ZnS QDs-GSH/L-Cys due to the electrostatic interaction between the -COO- groups on the surface of quantum dots and the -NH3+ groups in Adriamycin, followed by the coordination interaction among ZnS QDs-GSH/L-Cys and Adriamycin. The fluorescence intensity of ZnS QDs-GSH/L-Cys presented a good linear response with the concentration of Adriamycin ranging from 2.0 to 20 µg•mL−1. The proposed fluorescent nanoprobe exhibited an excellent sensitivity with the LOD of 0.1 µg•mL−1 and a good accuracy for detecting Adriamycin. [ABSTRACT FROM AUTHOR]

Objective To explore the role of ATM/hnRNPK signaling in the adriamycin resistance of acute myeloid leukemia. Methods Expression of ATM was examined in the adriamycin resistant and sensitive leukemia cell strains with Western blot. ATM expression was down-regulated by RNAi and ATM inhibitor in the adriamycin resistant cell strains. Expression level of hnRNPK and LC3Ⅰ/Ⅱ was detected by Western blot and adriamycin sensitivity was measured by CCK8 assay before and after modulation of ATM expression. Results ATM was overexpressed in adriamycin resistant leukemia cell strains. The decreased expression of ATM restored the sensitivity to adriamycin. Expression level of LC3Ⅱ and hnRNPK was consistent with the modulation of ATM expression. Conclusions The ATM/hnRNPK signaling pathway may play a role in the occurrence of adriamycin resistance in acute myeloid leukemia by regulating autophagy.

Adriamycin is an anticancer anthracycline drug that inhibits the progression of topoisomerase II activity and causes apoptosis. The effective clinical application of the drug is very much limited by its adverse drug reactions on various tissues. Most importantly, Adriamycin causes cardiomyopathy, one of the life‐threatening complications of the drug. Altered expression of PPARγ in adipocytes inhibited the glucose and fatty acids uptake by down regulating GLUT4 and CD36 expression and causes cardiotoxicity. Therefore, the influence of Adriamycin in cardiac ailments was investigated in vivo and in vitro. Adriamycin treated rats showed altered ECG profile, arrhythmic heartbeat with the elevated levels of CRP and LDH. Dysregulated lipid profiles with elevated levels of cholesterol and triglycerides were also observed. Possibilities of cardiac problems due to cardiomyopathy were analyzed through histopathology. Adriamycin treated rats showed no signs for atheromatous plaque formation in aorta but disorganized cardiomyocytes with myofibrillar loss and inflammation in heart tissue, indicative of cardiomyopathy. Reduced levels of antioxidant enzymes confirmed the incidence of oxidative stress. Adriamycin treatment significantly reduced glucose and insulin levels, creating energy demand due to decreased glucose and insulin levels with increased fatty acid accumulation, ultimately resulting in oxidative stress mediated cardiomyopathy. Since PPARs play a vital role in regulating oxidative stress, the effect of Adriamycin on PPARγ was analyzed by western blot. Adriamycin downregulated PPARγ in a dose‐dependent manner in H9C2 cells in vitro. Overall, our study suggests that Adriamycin alters glucose and lipid metabolism via PPARγ inhibition that leads to oxidative stress and cardiomyopathy that necessitates a different therapeutic approach. [ABSTRACT FROM AUTHOR]

Adriamycin is a cytotoxic anthracycline antibiotic used to treat a wide variety of cancers. This study was made to detect the possible prophylactic effects of combining garlic and resveratrol in preventing adriamycin-induced pulmonary cytotoxicity. This study was conducted on a total number of 60 adult male albino rats. The rats were divided in an equally random manner into 6 groups: group I rats received nothing, group II received a dose of 50 mg/kg garlic extract orally for 3 weeks, group III received resveratrol in a dose of 20 mg/kg/day orally for 3 weeks, group IV rats were injected with 20 mg/kg adriamycin as a single dose via intraperitoneal route, group V received garlic extract for 3 weeks, then were injected with adriamycin in the same stated doses, and Group VI received garlic extract and resveratrol in same stated dose for 3 weeks, then were injected with adriamycin in the same stated dose. Lung specimens were processed for light microscopic, ultrastructural, and immunohistochemical studies. Adriamycin treatment caused histological alterations, thicker interstitial septa, extensive cellular infiltration, hypertrophied arterial wall, marked inducible Nitric Oxide Synthase immunoreaction, type I pneumocytes with destructed organelles as well as type II pneumocytes having large vacuoles. The combined garlic and resveratrol group demonstrated a considerable improvement in the changes to the histology and ultrastructure of adriamycin-induced lung injury. Combining garlic and resveratrol can prevent adriamycin-induced lung cytotoxicity in albino rats. [ABSTRACT FROM AUTHOR]

In this study, we investigated the potential therapeutic mechanism of ginsenoside Rg1 (GRg1) in chronic heart failure (CHF), focusing on its regulation of ERK1/2 protein phosphorylation. H9c2 cardiomyocytes and SD rats were divided into the control group, CHF (ADR) group, and CHF+ginsenoside Rg1 group using an isolated cardiomyocyte model and an in vivo CHF rat model induced by adriamycin (ADR). Cell viability, proliferation, apoptosis, and the expression of relevant proteins were measured to assess the effects of GRg1. The results showed that treatment with GRg1 increased cell activity and proliferation, while significantly reducing levels of inflammatory and apoptotic factors compared to the CHF (ADR) group. Moreover, the CHF+ginsenoside Rg1 group exhibited higher levels of Bcl-2 mRNA and protein expression, as well as lower levels of Caspase3 and Bax mRNA and protein expression, compared to the CHF (ADR) group. Notably, the CHF+ginsenoside Rg1 group displayed decreased serum NT-proBNP levels and heart weight/body weight (HW/BW) index. Furthermore, the electrocardiogram of rats in the CHF+ginsenoside Rg1 group resembled that of rats in the control group. Overall, our findings suggested that GRg1 alleviated CHF by inhibiting ERK1/2 protein phosphorylation, thereby inhibiting apoptosis, enhancing cell activity and proliferation, and reducing cardiac inflammatory responses. [ABSTRACT FROM AUTHOR]

Adriamycin (ADR) is widely used against breast cancer, but subsequent resistance always occurs. YAP, a downstream protein of angiomotin (AMOT), importantly contributes to ADR resistance, whereas the mechanism is largely unknown. MCF‐7 cells and MDA‐MB‐231 cells were used to establish ADR‐resistant cell. Then, mRNA and protein expressions of AMOT and YAP expressions were determined. After AMOT transfection alone or in combination with YAP, the sensitivity of the cells to ADR were evaluated in vitro by examining cell proliferation, apoptosis, and cell cycle, as well as in vivo by examining tumor growth. Additionally, the expressions of proteins in YAP pathway were determined in AMOT‐overexpressing cells. In the ADR‐resistant cells, the expression of AMOT was decreased while YAP was increased, respectively, and the nucleus localization of YAP was increased at the same time. After AMOT overexpression, these were inhibited, whereas the cell sensitivity to ADR was enhanced. However, the AMOT‐induced changes were significantly suppressed by YAP knockdown. The consistent results in vivo showed that AMOT enhanced the inhibition of ADR on tumor growth, and inhibited YAP signaling, evidenced by decreased levels of YAP, CycD1, and p‐ERK. Our data revealed that decreased AMOT contributed to ADR resistance in breast cancer cells, which was importantly negatively mediated YAP. These observations provide a potential therapy against breast cancer with ADR resistance. [ABSTRACT FROM AUTHOR]

The current study assessed the impact of cerium oxide nanoparticles (nanocerium, NC) on adriamycin (ADR)-induced nephropathy in addition to the physiological role of oxidative stress, Nrf2/HO-1 pathway, apoptosis, TGF-β, and Sirt-1 in its action. Forty adult male Sprague–Dawley rats were divided into four groups as follows: control, NC, ADR, and ADR + NC groups. At the end of the experiment, urine, blood samples, and kidney were taken for assessment of serum creatinine (Cr), blood urea nitrogen (BUN), and urinary protein. Also, malondialdehyde (MDA), reduced glutathione (GSH) and catalase (CAT) levels, histopathological examinations, immunohistochemical examinations for caspase-3, TGF-β, Sirt-1, and real-time PCR for the expression of Nrf2 and HO-1 antioxidant genes in kidney tissues were done. NC significantly improved the raised serum creatinine, BUN, and urinary proteins. Also, NC improved the expression of caspase-3 and markers of oxidative stress in kidney tissues, and it also reduced morphological renal damage. Moreover, NC caused a significant increase in the expression of SIRT1 and Nrf2/HO-1 in kidney tissues. Also, markedly decreased renal fibrosis. Nanocerium alleviates ADR nephropathy, which may be related to the antioxidant and anti-fibrotic action of NC. Also, upregulating and activating SIRT1, Nrf2/HO-1 signaling and reduction of apoptosis. [ABSTRACT FROM AUTHOR]

Background: Among the three most used anticancer drugs, cyclophosphamide, Adriamycin, and 5-Fluorouracil (CAF), the most significant outcome is chemobrain, caused by increased oxidative stress, inflammatory insult, and mitochondrial dysfunction. Objective: In this study, endogenous antioxidant coenzyme Q10 (CoQ10) was evaluated for its neuroprotective effects in CICI. Materials and methods: The chemobrain was induced in Swiss albino female mice by administering CAF (40 + 4 + 25 mg/kg) intraperitoneal (i.p.) in three cycles (single injection per week) followed by treatment with CoQ10 (40 mg/kg; p.o.) for up to 3 weeks followed by behavioral, biochemical, molecular and histopathological analysis. Results: Treatment with CoQ10 significantly improved cognition by improving exploring time in novel objects recognition test followed by increasing the time spent in the target quadrant in MWM test as compared to CAF-treated animals. Moreover, CoQ10 demonstrated antioxidant properties by reducing the expression of LPO while increasing levels of GSH, SOD, and catalase as compared to CAF-treated animals. While the levels of AChEs were significantly reduced after CoQ10 treatment in CAF-treated animals. In terms of its mechanism, it effectively counteracted the pro-inflammatory substances (TNF-α and IL-1β) triggered by CAF while also enhancing the levels of anti-inflammatory markers (IL-10 and Nrf2). Moreover, CoQ10 showed mitochondrial enhancers and it improved the level of Complex (I, II, and IV). Besides that, mitochondrial morphological analysis was done by TEM, and neuronal morphology along with quantification analysis was performed by H&E staining using Image J software to confirm the neuroprotective effect of CoQ10 over CAF-induced cognitive impairment. Conclusion: This study suggests CoQ10 can protect the mitochondria by imposing antioxidant, and anti-inflammatory properties, which could be a potential therapy for CICI. [ABSTRACT FROM AUTHOR]

Adriamycin (ADR) is a frequently employed chemotherapeutic agent for the management of breast cancer. Nevertheless, multidrug resistance (MDR) can impair its therapeutic efficacy in breast cancer. MDR is characterized by increased expression of the P‐glycoprotein (P‐gp) efflux pump, up‐regulation of anti‐apoptotic proteins, and downregulation of pro‐apoptotic proteins. Consequently, inhibition of ATP‐binding cassette (ABC) transporter proteins has been deemed the most efficacious approach to overcome MDR. In this study, we used MTT (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide), Western blots, flow cytometry, immunofluorescence, and constructed xenograft tumors to investigate whether ginsenoside Rg3‐near‐infrared photothermal (Rg3‐NIR) combination reversed multidrug resistance in MCF‐7/ADR breast cancer. In vivo and in vitro experiments, the results showed that Rg3‐NIR co‐treatment was effective in inducing the apoptosis of MCF‐7/ADR breast cancer cells. This was achieved by reversing the expression of drug resistance‐associated proteins, while also inhibiting cell proliferation, migration, and epithelial–mesenchymal transition (EMT) processes via attenuation of the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT) signaling pathway transduction. Ginsenoside Rg3 combined with near‐infrared photothermal therapy (NIR) effectively reverses multidrug resistance in breast cancer MCF‐7/ADR cells, providing a new therapeutic strategy for breast cancer drug resistance. [ABSTRACT FROM AUTHOR]

Objective: High-mobility group box-1 (HMGB1), known as an abundant and highly conserved nuclear protein, plays a pivotal role in initiating inflammation, tissue healing, and the immune response following various forms of cell damage. The chemokine C-X-C motif chemokine ligand 12 (CXCL12) forms a signaling axis known as CXCL12/CXCR4/CXCR7, along with the receptors CXCR4 and CXCR7. Our study aimed to explore the connection between HMGB1 and the involved chemokine axis, CXCR4, CXCL12, and CXCR7, in the context of adriamycin-induced cardiotoxicity. Materials and Methods: We performed RNA interference to suppress HMGB1 expression in H9c2 cardiac myoblast cells. Adriamycin, an anti-tumor antibiotic known for causing cardiotoxicity, was used in conjunction with HMGB1 suppression. We investigated the combined and individual effects of these factors. Gene expression analysis was conducted through qRT-PCR 36 and 48 h post-treatment. Results: Adriamycin treatment increased the expression of CXCL12, CXCR4, and CXCR7. Notably, our study observed significant changes in gene expression when HMGB1 was downregulated and adriamycin was administered. These findings suggest potential molecular mechanisms associated with adriamycin-induced cardiotoxicity, emphasizing the significance of the CXCR4/CXCL12 axis and the impact of HMGB1 modulation. Conclusion: Our study provides insights into the molecular interplay between HMGB1 and the CXCL12/CXCR4/CXCR7 ligand-receptor axis in the context of adriamycin-induced cardiotoxicity. The results shed light on further research to enhance therapeutic approaches or advance new strategies to address this cardiotoxicity. [ABSTRACT FROM AUTHOR]

Abstract Background Most patients with acute myeloid leukemia (AML) eventually develop drug resistance, leading to a poor prognosis. Dysregulated long gene non coding RNAs (lincRNAs) have been implicated in chemoresistance in AML. Unfortunately, the effects of lincRNAs which participate in regulating the Adriamycin (ADR) resistance in AML cells remain unclear. Thus, the purpose of this study is to determine LINC00987 function in ADR-resistant AML. Methods In this study, ADR-resistant cells were constructed. LINC00987, miRNAs, and HMGA2 mRNA expression were measured by qRT-PCR. P-GP, BCRP, and HMGA2 protein were measured by Western blot. The proliferation was analyzed by MTS and calculated IC50. Soft agar colony formation assay and TUNEL staining were used to analyze cell colony formation and apoptosis. Xenograft tumor experiment was used to analyze the xenograft tumor growth of ADR-resistant AML. Results We found that higher expression of LINC00987 was observed in AML patients and associated with poor overall survival in AML patients. LINC00987 expression was increased in ADR-resistant AML cells, including ADR/MOLM13 and ADR/HL-60 cells. LINC00987 downregulation reduces ADR resistance in ADR/MOLM13 and ADR/HL-60 cells in vitro and in vivo, while LINC00987 overexpression enhanced ADR resistance in MOLM13 and HL-60 cells. Additionally, LINC00987 functions as a competing endogenous RNA for miR-4458 to affect ADR resistance in ADR/MOLM13 and ADR/HL-60 cells. HMGA2 is a target of miR-4458. LINC00987 knockdown and miR-4458 overexpression reduced HMGA2 expression. HMGA2 overexpression enhanced ADR resistance, which reversed the function of LINC00987 silencing in suppressing ADR resistance of ADR/MOLM13 and ADR/HL-60 cells. Conclusions Downregulation of LINC00987 weakens ADR resistance by releasing miR-4458 to deplete HMGA2 in ADR/MOLM13 and ADR/HL-60. Therefore, LINC00987 may act as the therapeutic target for treating chemoresistant AML.

Background: Most patients with acute myeloid leukemia (AML) eventually develop drug resistance, leading to a poor prognosis. Dysregulated long gene non coding RNAs (lincRNAs) have been implicated in chemoresistance in AML. Unfortunately, the effects of lincRNAs which participate in regulating the Adriamycin (ADR) resistance in AML cells remain unclear. Thus, the purpose of this study is to determine LINC00987 function in ADR-resistant AML. Methods: In this study, ADR-resistant cells were constructed. LINC00987, miRNAs, and HMGA2 mRNA expression were measured by qRT-PCR. P-GP, BCRP, and HMGA2 protein were measured by Western blot. The proliferation was analyzed by MTS and calculated IC50. Soft agar colony formation assay and TUNEL staining were used to analyze cell colony formation and apoptosis. Xenograft tumor experiment was used to analyze the xenograft tumor growth of ADR-resistant AML. Results: We found that higher expression of LINC00987 was observed in AML patients and associated with poor overall survival in AML patients. LINC00987 expression was increased in ADR-resistant AML cells, including ADR/MOLM13 and ADR/HL-60 cells. LINC00987 downregulation reduces ADR resistance in ADR/MOLM13 and ADR/HL-60 cells in vitro and in vivo, while LINC00987 overexpression enhanced ADR resistance in MOLM13 and HL-60 cells. Additionally, LINC00987 functions as a competing endogenous RNA for miR-4458 to affect ADR resistance in ADR/MOLM13 and ADR/HL-60 cells. HMGA2 is a target of miR-4458. LINC00987 knockdown and miR-4458 overexpression reduced HMGA2 expression. HMGA2 overexpression enhanced ADR resistance, which reversed the function of LINC00987 silencing in suppressing ADR resistance of ADR/MOLM13 and ADR/HL-60 cells. Conclusions: Downregulation of LINC00987 weakens ADR resistance by releasing miR-4458 to deplete HMGA2 in ADR/MOLM13 and ADR/HL-60. Therefore, LINC00987 may act as the therapeutic target for treating chemoresistant AML. [ABSTRACT FROM AUTHOR]

Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1-deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions. [ABSTRACT FROM AUTHOR]

Novel strategies for treating triple-negative breast cancer (TNBC) are ongoing because of the lack of standard-of-care treatment. Nanoframed materials with a protein pillar are considered a valuable tool for designing multigoals of energy-absorbing/medication cargo and are a bridge to cross-conventional treatment strategies. Nanobioconjugates of gold nanoclusters–bovine serum albumin (AuNCs–BSA) and doxorubicin–AuNCs–BSA (Dox–AuNCs–BSA) were prepared and employed as a simultaneous double photosensitizer/sonosensitizer and triple chemotherapeutic/photosensitizer/sonosensitizer, respectively. The highly stable AuNCs–BSA and Dox–AuNCs–BSA have ζ potentials of –29 and –18 mV, respectively, and represent valuable photothermal and sonodynamic activities for the combination of photothermal therapy and sonodynamic therapy (PTT/SDT) and synchronized chemotherapy/photothermal therapy/sonodynamic therapy (CTX/PTT/SDT) of human TNBC cells, respectively. The efficiency of photothermal conversion of AuNCs–BSA was calculated to be a promising value of 32.9%. AuNCs–BSA and Dox–AuNCs–BSA were activated on either laser light irradiation or ultrasound exposure with the highest efficiency on the combination of both types of radiation. CTX/PTT/SDT of MCF-7 and MDA-MB-231 breast cancer cell lines by Dox–AuNCs–BSA were evaluated with the MTT cell proliferation assay and found to progress synergistically. Results of the MTT assay, detection of the generation of intracellular reactive oxygen species and occurrence of apoptosis in the cells confirmed that CTX/PTT/SDT by Dox–AuNCs–BSA was attained with lower needed doses of the drug and improved tumor cell ablation, which would result in the enhancement of therapeutic efficacy and overcoming of therapeutic resistance. [ABSTRACT FROM AUTHOR]

Objective(s): Due to its negative side effects, mainly nephrotoxicity, adriamycin (ADR) is used fairly infrequently. The purpose of this study is to investigate the effects of N-acetyl cysteine (NAC) on the immunoreactivity of spexin (SPX) in the kidney tissues of rats given ADR.Materials and Methods: A total of 28 male Sprague-Dawley rats were randomly assigned to four groups (n=7): control (no intervention), NAC (150 mg/kg/day, administered intraperitoneally), ADR (single dose of 15 mg/kg, administered intraperitoneally), and ADR+NAC (single dose of 15 mg/kg ADR + 150 mg/kg/day NAC, both administered intraperitoneally). The experiment was concluded on the 15th day. Results: The administration of ADR resulted in biochemical and histopathological alterations in the kidney. It was found that ADR treatment led to elevated levels of TOS (total oxidative stress), apoptosis, and SPX. Conversely, when NAC was administered as a treatment, it effectively reduced TOS, apoptosis, and SPX levels. These findings suggest that SPX may contribute to the development of ADR-induced kidney damage.Conclusion: Further investigations are warranted to gain a comprehensive understanding of kidney damage, and specifically to elucidate the role of SPX in this context. Additionally, these studies can pave the way for exploring novel therapeutic strategies targeting SPX to prevent and/or treat the development of kidney damage.

Aims: Obese patients are highly sensitive to adriamycin (ADR)-induced cardiotoxicity. However, the potential mechanism of superimposed toxicity remains to be elucidated. Sestrin 2 (SESN2), a potential antioxidant, could attenuate stress-induced cardiomyopathy; therefore, this study aims to explore whether SESN2 enhances cardiac resistance to ADR-induced oxidative damage in high-fat diet (HFD)–induced obese mice. Results: The results revealed that obesity decreased SESN2 expression in ADR-exposed heart. And, HFD mice may predispose to ADR-induced cardiotoxicity, which was probably associated with inhibiting protein kinase B (AKT), glycogen synthase kinase-3 beta (GSK-3β) phosphorylation and subsequently blocking nuclear localization of nuclear factor erythroid-2 related factor 2 (NRF2), ultimately resulting in cardiac oxidative damage. However, these destructive cascades and cardiac oxidative damage effects induced by HFD/sodium palmitate combined with ADR were blocked by overexpression of SESN2. Moreover, the antioxidant effect of SESN2 could be largely abolished by sh-Nrf2 or wortmannin. And sulforaphane, an NRF2 agonist, could remarkably reverse cardiac pathological and functional abnormalities caused by ADR in obese mice. Innovation and Conclusion: This study demonstrated that SESN2 might be a promising therapeutic target for improving anthracycline-related cardiotoxicity in obesity by upregulating activity of NRF2 via AKT/GSK-3β/Src family tyrosine kinase signaling pathway. Antioxid. Redox Signal. 40, 598–615. [ABSTRACT FROM AUTHOR]

The Adriamycin (ADR) nephropathy model, which induces podocyte injury, is limited to certain mouse strains due to genetic susceptibilities, such as the PrkdcR2140C polymorphism. The FVB/N strain without the R2140C mutation resists ADR nephropathy. Meanwhile, a detailed analysis of the progression of ADR nephropathy in the FVB/N strain has yet to be conducted. Our research aimed to create a novel mouse model, the FVB-PrkdcR2140C, by introducing PrkdcR2140C into the FVB/NJcl (FVB) strain. Our study showed that FVB-PrkdcR2140C mice developed severe renal damage when exposed to ADR, as evidenced by significant albuminuria and tubular injury, exceeding the levels observed in C57BL/6J (B6)-PrkdcR2140C. This indicates that the FVB/N genetic background, in combination with the R2140C mutation, strongly predisposes mice to ADR nephropathy, highlighting the influence of genetic background on disease susceptibility. Using RNA sequencing and subsequent analysis, we identified several genes whose expression is altered in response to ADR nephropathy. In particular, Mmp7, Mmp10, and Mmp12 were highlighted for their differential expression between strains and their potential role in influencing the severity of kidney damage. Further genetic analysis should lead to identifying ADR nephropathy modifier gene(s), aiding in early diagnosis and providing novel approaches to kidney disease treatment and prevention. [ABSTRACT FROM AUTHOR]

Doxorubicin is a potent chemotherapeutic agent that can cause cardiotoxicity. Many documents (more than 14,000) have been published in the area of doxorubicin-induced cardiotoxicity (DIC) since 1970. A comprehensive bibliographic analysis of author keywords was used to describe better and understand the molecular mechanisms involved in DIC. The objective was to consider the state of the author keywords of research on the molecular mechanisms involved in DIC based on a bibliometrics study of articles published over the past fifty years. A bibliometrics analysis was conducted using VOSviewer with data collected from the Web of Science Core Collection database of over 14,000 documents (from 1970 to July 19, 2023). Using scientific publications retrieved about DIC, author keywords were assessed at the scientific field level. The current study showed that the annual number of DIC-related publications has increased over the past 50 years. The Journal of Clinical Oncology is the leading journal in this field. The top cited DIC document was published in 2004. The top keywords with high frequency were "doxorubicin," "cardiotoxicity," and "adriamycin." According to the results of this study, the most common mechanisms involved in DIC were as follows oxidative stress, apoptosis, inflammation, autophagy, mitophagy, endoplasmic reticulum stress, pyroptosis, and ferroptosis. The highest occurrences of regulators-related author keywords were "AKT," "Sirt1," and "AMPK." Based on the findings, oxidative stress, apoptosis, inflammation, autophagy, mitophagy, endoplasmic reticulum stress, pyroptosis, and ferroptosis were hot research mechanisms of DIC from 1970 to July 19, 2023. [ABSTRACT FROM AUTHOR]

Breast cancer is the most prevalent malignant tumor in women. Adriamycin (ADR) is a primary chemotherapy drug, but resistance limits its effectiveness. Ferroptosis, a newly identified cell death mechanism, involves the transferrin receptor (TFRC), closely linked with tumor cells. This study aimed to explore TFRC and ferroptosis's role in breast cancer drug resistance. Bioinformatics analysis showed that TFRC was significantly downregulated in drug-resistant cell lines, and patients with low TFRC expression might demonstrate a poor chemotherapeutic response to standard treatment. High expression of TFRC was positively correlated with most of the ferroptosis-related driver genes. The research findings indicate that ferroptosis markers were higher in breast cancer tissues than in normal ones. In chemotherapy-sensitive cases, Ferrous ion (Fe2+) and malondialdehyde (MDA) levels were higher than in resistant cases (all p < .05). TFRC expression was higher in breast cancer than in normal tissue, especially in the sensitive group (all p < .05). Cytological experiments showed increased hydrogen peroxide (H2O2) after ADR treatment in both sensitive and resistant cells, with varying MDA changes (all p < .05). Elevating TFRC increased Fe2+ and MDA in ADR-resistant cells, enhancing their sensitivity to ADR. However, TFRC upregulation combined with ADR increased proliferation and invasiveness in resistant cell lines (all p < .05). In conclusion, ADR resistance to breast cancer is related to the regulation of iron ion-mediated ferroptosis by TFRC. Upregulation of TFRC in ADR-resistant breast cancer cells activates ferroptosis and reverses ADR chemotherapy resistance of breast cancer. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to investigate the potential protective effects of N‐acetyl‐L‐cysteine (NAC) against apical periodontitis (AP) in rats with adriamycin (ADR)‐induced kidney and heart diseases. Methodology: Fourty‐eight Wistar albino rats were divided into six groups: (1) Control group, (2) ADR group (1 mg/kg/day ip for 10 days), (3) AP Group (1st mandibular molar tooth), (4) AP + ADR Group, (5) AP + NAC group (150 mg/kg/day ip), and (6) AP + ADR + NAC group. After 3 weeks, the rats were decapitated and blood and tissue samples (heart, kidney, and jaw) were collected. Tissue samples were evaluated by biochemical (inflammatory cytokines and hemodynamic parameters) and radiological analyses. One‐way anova with Tukey post hoc tests was used to compare data, considering p <.05 as statistically significant. Results: The serum levels of TNF‐α, IL‐1β, BUN, Creatinine, CK, and LDH were elevated in the test groups compared with the control group, and treatment with NAC reduced these levels (p <.05). Heart and kidney tissue analysis showed a higher heart‐to‐body weight ratio (HW/BW) and kidney‐to‐body weight ratio (KW/BW) in the test groups compared with the control group (p <.05). No significant differences in HW/BW and KW/BW were found between the control and AP + NAC groups. Volumetric apical bone resorption analysis showed an increase in periapical radiolucencies in AP‐induced groups indicating apical periodontitis. NAC treatment reduced the total area and volume of resorption cavities (p <.05). Conclusions: The results suggest that NAC's antioxidant and anti‐inflammatory effects can reduce adriamycin‐mediated heart and kidney damage and may have a positive effect on apical periodontitis in individuals with nephropathy and cardiomyopathy. [ABSTRACT FROM AUTHOR]

Objective(s): Due to its negative side effects, mainly nephrotoxicity, adriamycin (ADR) is used fairly infrequently. The purpose of this study is to investigate the effects of N-acetyl cysteine (NAC) on the immunoreactivity of spexin (SPX) in the kidney tissues of rats given ADR. Materials and Methods: A total of 28 male Sprague-Dawley rats were randomly assigned to four groups (n=7): control (no intervention), NAC (150 mg/kg/day, administered intraperitoneally), ADR (single dose of 15 mg/kg, administered intraperitoneally), and ADR+NAC (single dose of 15 mg/kg ADR + 150 mg/kg/day NAC, both administered intraperitoneally). The experiment was concluded on the 15th day. Results: The administration of ADR resulted in biochemical and histopathological alterations in the kidney. It was found that ADR treatment led to elevated levels of TOS (total oxidative stress), apoptosis, and SPX. Conversely, when NAC was administered as a treatment, it effectively reduced TOS, apoptosis, and SPX levels. These findings suggest that SPX may contribute to the development of ADR-induced kidney damage. Conclusion: Further investigations are warranted to gain a comprehensive understanding of kidney damage, and specifically to elucidate the role of SPX in this context. Additionally, these studies can pave the way for exploring novel therapeutic strategies targeting SPX to prevent and/or treat the development of kidney damage. [ABSTRACT FROM AUTHOR]

MHY1485 is an mTOR activator that inhibits the autophagy process by inhibiting the fusion between autophagosomes and lysosomes. This study aimed to explore the role and mechanism of MHY1485 in hepatocellular carcinoma (HCC) and to provide an in-depth understanding of the mechanisms of autophagy regulation in relation to adriamycin (ADM) resistance, as well as the development of a molecularly targeted autophagy-modulating approach. Here, ADM was used to treat HepG2 cells and construct an ADM-resistant cell model. The HepG2/ADM cell line and HepG2 cells were treated with MHY1485 and ADM, respectively, and the proliferation and apoptosis of HCC cells were detected using CCK8, clone formation, flow cytometry, and 5-ethynyl-2′-deoxyuridine staining assays. Ki-67, mTOR phosphorylation, and LC3A expression were detected by IF staining; the expression or phosphorylation levels of autophagy-related proteins (i.e., GLUT1, PGI, PFK, END, and MTHFD2) and apoptosis-related proteins (caspase-3, caspase-8, and caspase-9) were detected by qPCR and western blotting. The number of autophagosomes was determined by monodansylcadaverine staining. Our results showed that MHY1485 can inhibit the proliferation and growth of liver cancer cells, and that MHY1485 combined with ADM can effectively inhibit the tolerance of HepG2/ADM cells to ADM and enhance the efficacy of ADM. The results of the detection of the autophagy-related protein LC3A also indicated that MHY1485 activates mTOR and can affect the phosphorylation level of ULK1, inhibit autophagy, and enhance the sensitivity of liver cancer cells to adriamycin. In summary, MHY1485 can enhance the sensitivity of adriamycin-resistant cells to adriamycin by activating mTOR and blocking the autophagy process in cells; therefore, mTOR may become a potential target for the treatment of liver cancer. [ABSTRACT FROM AUTHOR]

Anthracyclines exert cytotoxic effects on cancer cells through genotoxicity, inducing damage to their genetic material and impeding their reproductive capacity. The compound possesses a molecular framework consisting of an anthracycline ring system, which confers its pharmacological activity against cancer. Adriamycin is an anthracycline chemotherapeutic agent characterized by a structurally intricate chemical composition. In this article, we computed irregularity indices like the Albertson index, total irregularity index, Randić irregularity index and other degree-based irregularity indices to estimate the biological and chemical properties of Adriamycin. The findings are illustrated through the use of numerical figures and graphical representations. Further, we proposed the relationship between irregularity indices and the physicochemical properties of emetic drugs. We examined that the irregularity indices showed a statistically significant relationship with Molecular Weight, Monoisotopic Mass, Polar Surface Area, Heavy Atom Count, Complexity, Boiling Point, Enthalpy of Vaporization, Flash Point, Molar Refractivity and Polarizability based on the p-value (

Background: Transarterial chemoembolization (TACE) is a common treatment for hepatocellular carcinoma (HCC), but the best therapeutic agent for TACE treatment has not been determined. The neutrophil/lymphocyte ratio (NLR) is a systemic immune system marker; however, the ability of the NLR to predict the prognosis of patients with HCC is unknown, and no studies have been conducted to determine the most appropriate TACE regimen for HCC patients with different NLRs. Methods: The PubMed, Embase, Web of Science, and CNKI databases were searched through May 28, 2023. Comparisons of overall survival (OS) among cohort studies with different NLRs and different TACE treatment regimens were performed with a random effects model. Findings: Thirty-five studies involving 9210 patients were included in this meta-analysis. The results showed that Group 3–4 (NLR

Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors target SGLT2 in renal proximal tubules and promote glycosuria in type 2 diabetes mellitus in humans and animal models, resulting in reduced blood glucose levels. Although clinical trials have shown that SGLT2 inhibitors attenuate the progression of chronic kidney disease, there have been concerns regarding SGLT2-induced acute kidney injury. In this study, we investigated the effect of SGLT2 inhibitors on adriamycin-induced kidney injury in mice. Methods: Seven-week-old balb/c mice were injected with adriamycin 11.5 mg/kg via the tail vein. Additionally, dapagliflozin was administered via gavage for 2 weeks. The mice were divided into five groups: vehicle, dapagliflozin 3 mg/kg, adriamycin, adriamycin plus dapagliflozin 1 mg/kg, and adriamycin plus dapagliflozin 3 mg/kg. Results: Adriamycin injection reduced the body weight and food and water intakes. Dapagliflozin also decreased the body weight and food and water intakes. Fasting blood glucose and urine volume were not altered by either adriamycin or dapagliflozin. Once adriamycin-induced kidney injury had developed, there were no differences in systolic blood pressure among the groups. Dapagliflozin did not alleviate proteinuria in adriamycin-induced kidney injury. Adriamycin induced significant glomerular and interstitial injury, but dapagliflozin did not attenuate these changes in renal injury. Interestingly, SGLT2 expressions were different between the cortex and medulla of kidneys by dapagliflozin treatment. Dapagliflozin increased SGLT2 expression in medulla, not in cortex. Conclusion: Dapagliflozin had no effect on proteinuria or inflammatory changes such as glomerular and tubular damages in adriamycin-induced kidney injury. Our study suggests that dapagliflozin does not protect against adriamycin-induced kidney injury. More experimental studies regarding the effects of SGLT2 inhibitors on various kidney diseases are needed to clarify the underlying mechanisms.

ObjectiveThe aim of this study was to explore the protective effect of kaempferol against adriamycin-induced renal injury in rats and its underlying mechanism.MethodsA rat model of renal injury was established by adriamycin injection. The rats were divided into the model group； the low-， medium-， and high-dose kaempferol groups； and the high-dose kaempferol + EX527 （silence information regulator 1 ［SIRT1］-specific inhibitor） group. A blank control group was also used （n = 10）. Twenty-four-hour urine protein levels were measured on the day of modeling and at 1， 2， and 4 weeks after modeling. Serum creatinine and blood urea nitrogen concentrations were measured using an automatic biochemical analyzer. The levels of tumor necrosis factor-α （TNF-α） and interleukin-1β （IL-1β） were measured by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining was used to detect pathological changes in renal tissues. The ultrastructure of the kidneys was observed using transmission electron microscopy. Flow cytometry was used to observe renal cell apoptosis. Western blotting was used to detect the protein levels of SIRT1， p38-mitogen activated protein kinase （p38MAPK）， phosphorylated （p）-p38MAPK， nuclear factor-κB p65 （NF-κB p65）， p-NF-κB p65， B lymphocytoma-2 protein （Bcl-2）， Bcl-2-related X protein （Bax）， and caspase-3 in renal tissue.ResultsIn the first week， the 24 h urine protein level increased in the model group compared to that in the blank control group. In the second and fourth weeks， the levels of serum creatinine， blood urea nitrogen， TNF-α， and IL-1β increased. The renal tissue injury score and the apoptotic rate also increased. The protein levels of p-p38MAPK/p38MAPK， p-NF-κB p65/NF-κB p65， Bax， and caspase-3 increased. SIRT1 and Bcl-2 protein expression levels significantly decreased （P < 0.05）. After intervention with low， medium， and high doses of kaempferol in the model rats， the aforementioned changes were significantly reversed （P < 0.05）. The SIRT1-specific inhibitor EX527 significantly downregulated the expression level of SIRT1 and significantly weakened the protective effect of kaempferol against kidney injury （P < 0.05）.ConclusionKaempferol has a protective effect against adriamycin-induced renal injury， and the mechanism may be related to the upregulation of SIRT1 expression， the inhibition of p38MAPK signal pathway activation， and a reduction in renal cell apoptosis.

Objective: To investigate the therapeutic effect of Qidantongmai tablet (QDTM) on adriamycin-induced dilated cardiomyopathy (DCM) in rats and its effect on the expression of long non-coding RNA (lncRNA) X-inactive specific transcript (XIST). Methods: Rats were divided into Con group (n=12), DCM group (n=13), L-QDTM group (n=13), M-QDTM group (n=13), and H-QDTM group (n=13). Rats in Con group rats were normal control, and rats in other groups were doxorubicin-induced dilated cardiomyopathy model rats. Rats in Con group and DCM group were given normal saline, rats in L-QDTM group, M-QDTM group and H-QDTM group were given QDTM extractum powder of 500, 1000 and 2000 mg/kg/d, respectively. The rats of each group were given the drug once a day for 4 weeks. After treatment, The cardiac function parameters, serum myocardial injury indexes and myocardium tissue oxidative stress indicators of each group were detected, respectively. Myocardial morphology, fibrosis and apoptosis were observed by hematoxylin eosin (HE), Masson tricolor and TUNEL staining. The transcription levels of XIST, collagen I, collagen Ⅲ, TGF-β1, Bax and Bcl-2 in myocardial tissue were detected by RT-qPCR. Results: Compared with Con group, left ventricular ejection fraction (LVEF) and left ventricular short-axis shortening rate (FS) in DCM group decreased, left ventricular end-diastolic diameter (LVIDd) and left ventricular end-systolic diameter (LVIDs) increased, lactate dehydrogenase (LDH), creatine kinase (CK) and cardiac troponin I (cTnI) increased,myocardial injury was obvious, fibrosis area increased, collagen I, collagen Ⅲ and TGF-β1 m RNA levels increased, TUNEL positive rate increased, Bax m RNA level increased, Bcl-2 m RNA level decreased, superoxide dismutase (SOD) and catalase (CAT) levels decreased, malondialdehyde (MDA) level increased, and XIST level increased (all P＜0.05). Compared with DCM group, LVEF and FS in L-QDTM group, M-QDTM group and H-QDTM group increased, LVIDd and LVIDs decreased, LDH, CK and cTnI decreased, myocardial injury was alleviated, fibrosis area decreased, collagen I, collagen Ⅲ and TGF-β1 m RNA levels decreased, TUNEL positive rate decreased, Bax m RNA level decreased, Bcl-2 m RNA level increased, SOD and CAT levels increased, MDA level decreased, and XIST level decreased (all P＜0.05). Conclusion: This study indicates that Qidantongmai tablet is effective in the treatment of doxorubicin-induced dilated cardiomyopathy in rats, and the mechanism may be related to the inhibition of lncRNA XIST. [ABSTRACT FROM AUTHOR]

Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors target SGLT2 in renal proximal tubules and promote glycosuria in type 2 diabetes mellitus in humans and animal models, resulting in reduced blood glucose levels. Although clinical trials have shown that SGLT2 inhibitors attenuate the progression of chronic kidney disease, there have been concerns regarding SGLT2-induced acute kidney injury. In this study, we investigated the effect of SGLT2 inhibitors on adriamycin-induced kidney injury in mice. Methods: Seven-week-old balb/c mice were injected with adriamycin 11.5 mg/kg via the tail vein. Additionally, dapagliflozin was administered via gavage for 2 weeks. The mice were divided into five groups: vehicle, dapagliflozin 3 mg/kg, adriamycin, adriamycin plus dapagliflozin 1 mg/kg, and adriamycin plus dapagliflozin 3 mg/kg. Results: Adriamycin injection reduced the body weight and food and water intakes. Dapagliflozin also decreased the body weight and food and water intakes. Fasting blood glucose and urine volume were not altered by either adriamycin or dapagliflozin. Once adriamycin-induced kidney injury had developed, there were no differences in systolic blood pressure among the groups. Dapagliflozin did not alleviate proteinuria in adriamycin-induced kidney injury. Adriamycin induced significant glomerular and interstitial injury, but dapagliflozin did not attenuate these changes in renal injury. Interestingly, SGLT2 expressions were different between the cortex and medulla of kidneys by dapagliflozin treatment. Dapagliflozin increased SGLT2 expression in medulla, not in cortex. Conclusion: Dapagliflozin had no effect on proteinuria or inflammatory changes such as glomerular and tubular damages in adriamycin-induced kidney injury. Our study suggests that dapagliflozin does not protect against adriamycin-induced kidney injury. More experimental studies regarding the effects of SGLT2 inhibitors on various kidney diseases are needed to clarify the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Although adriamycin (ADR) is used to treat many cancers, it can be toxic to healthy organs including the testis. We investigated the effects of ADR on pluripotency in rat testis. Testicular damage was induced by either cumulative or single dose single dose administration of ADR in Wistar albino rats. Rats were divided randomly into three groups: untreated control, cumulative dose ADR group (2 mg/kg ADR every three days for 30 days) and single dose ADR group (15 mg/kg, single dose ADR). Testicular damage was evaluated and seminiferous tubule diameters were measured using light microscopy. Expression levels of Oct4, Sox2, Klf4, c-Myc, Utf1 and Dazl were assessed by immunohistochemistry and real time PCR. Serum testosterone levels were measured using ELISA assay. Histopathologic scores were lower and mean seminiferous tubule diameters were less compared to the ADR groups. Oct4, Sox2, Klf4 and Utf1 expressions were decreased significantly in spermatogenic cells of both cumulative and single dose ADR groups compared to the control group. We found that c-Myc expression in spermatogenic and Leydig cells were increased significantly in both ADR groups compared to the control group. Dazl expression was decreased in the cumulative adriamycin group compared to the control group, but increased in the single dose ADR group compared to both the control and cumulative ADR groups. Serum testosterone levels were decreased in both ADR groups compared to the control group. Our findings suggest that ADR is detrimental to regulation and maintenance of pluripotency in rat testis. [ABSTRACT FROM AUTHOR]

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Background: Recently the carcinogenic and toxic effects of some heavy metals such as chromium (Cr), and lead (Pb) through the mechanism of oxidative stress have been reported. Due to the various consequences of chemotherapeutic treatments on body hemostasis, the present study aimed to evaluate the effect of Adriamycin 60 mg/m2 and Cytoxan 600 mg/m2 (AC) chemotherapy on the serum levels of Cr, Pb, and the percent α-diphenyl-β-picrylhydrazyl (DPPH) inhibition. Methods: This study was performed on 50 patients with breast cancer at two separate sampling times, the first at the initiation of chemotherapy and the last at the end of three courses of the AC chemotherapy treatment. Serum levels of Cr and Pb were measured using atomic absorption spectrophotometry. The percent DPPH inhibition (% I) and also the effect of age and stage of the disease on the mentioned variables were evaluated. Statistical comparison of the obtained results before and after chemotherapy was performed using paired sample t-test. Intra-group evaluation of age and disease stages was done using an independent sample t-test. Results: A significant decrease was observed in the percent DPPH inhibition after 3 courses of chemotherapy (p

Chen Y, Deng Y, Chen L, Huang Z, Yan Y, Huang Z. J Inflamm Res. 2023;16:1077–1089. We, the Editors and Publisher of Journal of Inflammation Research, have retracted the following article. Following publication of the article, concerns were raised about the duplication of images from Figure 5D with images from another unrelated article. Specifically, The images for Figure 5D, have been duplicated with the images for Figure 4G from Wang M, Li Q, Yu S, et al. Coronin 3 Promotes the Development of Oncogenic Properties in Glioma Through the Wnt/β-Catenin Signaling Pathway. Onco Targets Ther. 2020;13:6661–6673. https://doi.org/10.2147/OTT.S257001. The authors did not respond to our queries and were unable to provide an explanation for the duplicated images or provide data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors were notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Pyrotinib (PYR) is a pan-HER kinase inhibitor that inhibits signaling via the RAS/RAF/MEK/MAPK and PI3K/AKT pathways. In this study, we aimed to investigate the antitumor efficacy of pyrotinib combined with adriamycin (ADM) and explore its mechanisms on HER2+ breast cancer. We investigated the effects of PYR and ADM on breast cancer in vitro and in vivo. MTT assay, Wound-healing, and transwell invasion assays were used to determine the effects of PYR, ADM or PYR combined with ADM on cell proliferation, migration, and invasion of SK-BR-3 and AU565 cells in vitro. Cell apoptosis and cycle were detected through flow cytometry. In vivo, xenograft models were established to test the effect of PYR, ADM, or the combined therapy on the nude mice. Western blotting was performed to assess the expression of Akt, p-Akt, p-65, p-p65, and FOXC1. The results indicated that PYR and ADM significantly inhibited the proliferation, migration, and invasion of SK-BR-3 and AU565 cells, and the inhibitory rate of the combination group was higher than each monotherapy group. PYR induced G1 phase cell-cycle arrest, while ADM induced G2 phase arrest, while the combination group induced G2 phase arrest. The combined treatment showed synergistic anticancer activities. Moreover, PYR significantly downregulated the expression of p-Akt, p-p65, and FOXC1. In clinical settings, PYR also exerts satisfactory efficacy against breast cancer. These findings suggest that the combination of PYR and ADM shows synergistic effects both in vitro and in vivo. PYR suppresses the proliferation, migration, and invasion of breast cancers through down-regulation of the Akt/p65/FOXC1 pathway.

The electrochemical behavior of fish sperm double-strand deoxyribonucleic acid (dsDNA) in the presence of adriamycin (ADR) is based on the reduction of the guanine?s oxidation peak signal and examined using electrochemical techniques with pencil graphite electrodes (PGEs). A hallmark for identifying Adriamycin was the reduction in the peak height of the guanine oxidation signal, following the interaction of the drug with dsDNA. Differential pulse voltammetry (DPV), electrochemical impedance spectroscopy (EIS), and cyclic voltammetry (CV) were the characterizing methods used in the investigation. The parameters employed for the optimization experiments to ascertain the electrochemical behavior of Adriamycin were Scan rate and pH investigations. The results of the characterization and optimization investigations demonstrated that the ADR immobilized at various concentrations on the electrode surface interacted with the 100 µg/mL dsDNA. According to the EIS findings, as dsDNA and ADR concentration increase, charge transfer resistance (Rct) decreases. When the electrochemical behavior of ADR was examined using different pH values and scan rates, peak currents at pH 4.0 were observed to be the strongest, with the peak values changing to the negative with the peak current signal increasing. Limits of detection (LOD) and quantitation (LOQ) were determined to be 0.0014 µM and 0.004 µM, respectively. [ABSTRACT FROM AUTHOR]

Simple Summary: Different strategies have been explored to counteract immune evasion by shifting the balance in favor of antitumor immune activation, and combination cytotoxic chemotherapies have emerged as potent immune modulators for patients with low programmed death-ligand 1 expression. This study aimed to investigate whether the addition of cyclophosphamide and adriamycin induction therapy prior to nivolumab could enhance the efficacy of immune checkpoint inhibitors in patients previously treated with non-squamous non-small-cell lung cancer with less than 10% programmed death-ligand 1 expression. Patients with a durable response to nivolumab showed higher baseline transferrin receptor protein levels. The predictive role of transferrin receptor protein as a biomarker for immune checkpoint inhibitors in non-squamous non-small-cell lung cancer with low programmed death-ligand 1 expression was validated in an independent cohort. This study aimed to investigate whether cyclophosphamide (C) and adriamycin (A) induction therapy (IT) prior to nivolumab could enhance the efficacy of nivolumab in previously treated patients with non-squamous (NSQ) non-small-cell lung cancer (NSCLC) with less than 10% programmed death-ligand 1 (PD-L1) expression. Twenty-two enrolled patients received four cycles of CA-IT every 3 weeks. Nivolumab was given 360 mg every 3 weeks from the second cycle and 480 mg every 4 weeks after four cycles of CA-IT. The median progression-free survival (PFS) and overall survival (OS) were 2.4 months and 11.6 months, respectively. Fluorescence-activated cell sorting revealed the lowest ratio of myeloid-derived suppressor cells (MDSCs) to CD8+T-cells in the responders. Proteomic analysis identified a consistent upregulation of extracellular matrix-receptor interactions and phagosome pathways in the responders. Among the differentially expressed proteins, the transferrin receptor protein (TFRC) was higher in the responders before treatment (fold change > 1.2). TFRC validation with an independent cohort showed the prognostic significance of either OS or PFS in patients with low PD-L1 expression. In summary, CA-IT did not improve nivolumab efficacy in NSQ-NSCLCs with low PD-L1 expression; however, it induced decreasing MDSC, resulting in a durable response. Higher baseline TFRC levels predicted a favorable response to nivolumab in NSCLC with low PD-L1 expression. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) frequently acquires multidrug resistance (MDR), which is due to poor prognosis. Our previous study indicated that high expression of Survivin and multidrug resistance protein 1 (MDR1) and decreased expression of Bim are associated with MDR in adriamycin- and dexamethasone-resistant cells. However, the fundamental mechanism of MDR in adriamycin- and dexamethasone-resistant MM cells is still unidentified. In this study, we examined the MDR mechanism in adriamycin- and dexamethasone-resistant cells. RPMI8226/ADM, ARH-77/ADM, RPMI8226/DEX, and ARH-77/DEX cells exhibited enhanced nuclear factor κB (NF-κB) p65, Akt, and extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Combination treatment with NF-κB p65, phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinase 1/2 (MEK1/2) inhibitors resensitized to adriamycin and dexamethasone via increased Bim expression. Although treatment with MDR1 or Survivin siRNA did not overcome adriamycin and dexamethasone resistance in RPMI8226/ADM and RPMI8226/DEX cells, administration of Bim siRNA induced adriamycin and dexamethasone resistance in RPMI8226 cells. Moreover, low expression of Bim was related to poor prognosis in MM patients. These results indicate that activation of NF-κB p65, Akt, and ERK1/2 is associated with adriamycin and dexamethasone resistance via decreasing Bim expression, and these signal inhibitor combinations overcome drug resistance in MM. These findings suggest that combination treatment with these inhibitors and adriamycin or dexamethasone may be a promising therapy for adriamycin- and dexamethasone-resistant MM. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is associated with numerous acute and chronic dose-related toxicities including hepatotoxicity. This adverse reaction may limit the use of other chemotherapeutic agents with hepatic excretion, and so, its prevention is an important issue. The aim of this study was to conduct a comprehensive review of in vitro, in vivo and human studies regarding the protective effects of synthetic and naturally-occurring compounds against DOX-induced liver injury. The search was conducted in Embase, PubMed, and Scopus databases using the following keywords: "doxorubicin," "Adriamycin," "hepatotoxicity," "liver injury," "liver damage," and "hepatoprotective," and all articles published in English were included without time restriction. Forty eligible studies to the end of May 2022 finally were reviewed. Our results demonstrated that all of these drugs, except acetylsalicylic acid, had considerable hepatoprotective effects against DOX. In addition, none of the studied compounds attenuated the antitumor efficacy of DOX treatment. Silymairn was the only compound which is assessed in human studies and showed promising preventive and therapeutic effects. Altogether, our results demonstrated that most of compounds with antioxidant, anti-apoptosis, and anti-inflammatory properties are efficacious against DOX-induced hepatotoxicity and may be considered as a potential adjuvant agent for prevention of hepatotoxicity in cancer patients, after fully been assessed in well-designed large clinical trials. [ABSTRACT FROM AUTHOR]

Hao Deng,1,&ast; Yumei Wang,1,&ast; Yue Zhou,1,&ast; Dongliang Zhai,1 Jie Chen,1 Shilei Hao,2 Xiaoliang Chen1 1Department of Nuclear Medicine, Chongqing University Cancer Hospital, Chongqing, 400030, People’s Republic of China; 2Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoliang Chen, Department of Nuclear Medicine, Chongqing University Cancer Hospital, No. 181 HanYu St, Shapingba District, Chongqing, 400030, People’s Republic of China, Tel/Fax +86 023-65079156, Email chenxiaoliang26@163.com Shilei Hao, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, 174 Shazhengjie, Shapingba District, Chongqing, 400030, People’s Republic of China, Tel +86023-135 9463 5765, Email Shilei_hao@cqu.edu.cnBackground: Prostate cancer (PCa) ranks second in the incidence of all malignancies in male worldwide. The presence of multi-organ metastases and tumor heterogeneity often leads to unsatisfactory outcomes of conventional radiotherapy treatments. This study aimed to develop a novel folate-targeted nanohydroxyapatite (nHA) coupling to deliver adriamycin (Doxorubicin, DOX), 32P, and 99mTc simultaneously for the diagnosis and treatment of prostate-specific membrane antigen (PSMA) positive prostate cancer.Methods: The spherical nHA was prepared by the biomimetic method and characterized. Folic acid (FA) was coupled to nHA with polyethylene glycol (PEG), and the grafting ratio of PEG-nHA and FA-PEG-nHA was determined by the thermogravimetric analysis (TGA) method. In addition, 32P, 99mTc, and DOX were loaded on nHA by physisorption. And the labeling rate and stability of radionuclides were measured by a γ-counter. The loading and release of DOX at different pH were determined by the dialysis method. Targeting of FA-PEG-nHA loaded with 99mTc was verified by in vivo SPECT imaging. In vitro anti-tumor effect of 32P/DOX-FA-PEG-nHA was assessed with apoptosis assay. The safety of the nano-drugs was verified by histopathological analysis.Results: The SEM images showed that the synthesized nHA was spherical with uniform particle size (average diameter of about 100nm). The grafting ratio is about 10% for PEG and about 20% for FA. The drug loading and the delayed release of DOX at different pH confirmed its long-term therapeutic ability. The labeling of 32P and 99mTc was stable and the labeling rate was great. SPECT showed that FA-PEG-nHA showed well in vivo tumor targeting and less damage to normal tissues.Conclusion: FA-targeted nHA loaded with 32P, 99mTc, and DOX may be a new diagnostic and therapeutic strategy for targeting PSMA-positive prostate cancer tumors, which may achieve better therapeutic results while circumventing the severe toxic side effects of conventional chemotherapeutic agents.Keywords: prostate cancer, folic acid targeting, nanohydroxyapatite, 99mTc/ 32P, adriamycin

Abstract Purpose Adriamycin is a novel chemotherapeutic agent of great benefit for treating breast cancer. However, adriamycin ‐resistance remains a major obstacle. The vital Glutathione transferase P1 (GSTPi) inhibitor 6‐(7‐nitro‐2,1,3‐benzoxadiazol‐4‐ylthio) hexanol (NBDHEX) has recently shown antitumor activity in various cancers. In this study, we analyzed the effect of NBDHEX and adriamycin combination against breast cancer in vitro and in vivo. Methods CCK‐8 assay was performed to test cell viability. The location and expression level of GSTpi was determined by immunofluorescence and Western blot in cells and immunohistochemistry staining in tissues. The enzyme activity test was applied to detect the effect of NBDHEX on the activity of GSTpi. The apoptosis related proteins' expression was tested using Western blot. The phosphorylation sites of GSTpi were detected by mass spectrometry. Antitumor effects of single treatment or co‐administration of adriamycin and NBDHEX were evaluated in nude mice. Results NBDHEX treatment inhibited GSTpi enzyme activity and co‐administration of adriamycin and NBDHEX promoted apoptosis of adriamycin‐resistance breast cancer cell. Moreover, drug combination of NBDHEX and adriamycin significantly enhanced tumor growth inhibition compared with single agent. Conclusion NBDHEX serves as a good candidate for combination with adriamycin, offering new insights for breast cancer treatment.

Yongquan Chen, Yecheng Deng, Linghua Chen, Ziyao Huang, Yi Yan, Zhaoqi Huang Department of Cardiology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Zhaoqi Huang, Department of Cardiology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510150, People’s Republic of China, Email zhaoqihuang2007@163.comIntroduction: Adriamycin (ADR) is commonly used in tumor chemotherapy, but its nonreversible cardiotoxicity severely hampers its clinical application. Ferroptosis is an implicated cause of ADR-induced injury. However, the underlying molecular mechanisms remain poorly understood. This study explored whether ferroptosis is a pivotal pathogenic pathway underlying ADR-induced cardiotoxicity and the possible molecular mechanisms involved.Methods: In vivo and in vitro experimental models were used to study the mechanism of ADR-mediated ferroptosis. Ferroptosis levels were examined in mice and human/rat cardiomyocytes. Mechanistically, the expression levels of SLC7A11 and related miRNAs were examined. Bioinformatics prediction and luciferase reporter assays were used to verify the potential interaction between miR-16-5p and SLC7A11. The biological functions and interaction of SLC7A11 and miR-16-5p were investigated in vivo and in vitro.Results: Our study observed that ADR treatment significantly increased ferroptosis levels in vivo and in vitro. Ferroptosis-related pharmacological interventions further confirmed these results. Our data displayed that the SLC7A11 level was significantly decreased in cardiac tissues and cells, while an increased expression level of miR-16-5p was observed. Moreover, upregulation of SLC7A1 and inhibition of miR-16-5p attenuated ADR-induced cardiomyocyte ferroptosis injury. Interactive rescue experiments showed that the protective effects of miR-16-5p inhibition on ADR-induced cardiomyocyte injury were blocked by SLC7A11 knockdown.Discussion: Based on these findings, targeting miR-16-5p could partially reverse the ADR-induced cardiotoxicity by rescuing the SLC7A11 to attenuate ferroptosis. This study presents a pre-clinical basis to identify miR-16-5p/SLC7A11 as a potential treatment target for ADR-induced cardiotoxicity.Keywords: adriamycin, cardiomyocytes, ferroptosis, SLC7A11, miR-16-5p

Abstract Background Glomerular damage is a common clinical indicator of nephrotic syndrome. High-dose hormone treatment often leads to hormone resistance in patients. How to avoid resistance and improve the efficiency of hormone therapy draws much attention to clinicians. Methods Adriamycin (ADR) was used to induce nephropathy model in SD rats. The rats were treated with dexamethasone (DEX), icariin (ICA), and DEX + ICA combination therapy. The changes in urinary protein (UP), urea nitrogen (BUN), and serum creatinine (SCR) contents in rats were detected by enzyme-linked immunosorbent assay (ELISA), and the degree of pathological injury and the expression level of podocin were detected by HE staining and immunohistochemistry, to test the success of the model and the therapeutic effects of three different ways. The effect of treatments on podocytes autophagy was evaluated via transfection of mRFP-GFP-LC3 tandem adenovirus in vitro. Results The contents of UP, SCR, and BUN were significantly increased, the glomerulus was seriously damaged, and the expression of Nephrosis2 (NPHS2) was significantly decreased in the ADR-induced nephrotic syndrome rat model compared to that of the control group. DEX, ICA, and the DEX + ICA combined treatment significantly alleviated these above changes induced by ADR. The combined treatment of DEX + ICA exhibited better outcome than single treatment. The combined treatment also restored the podocyte autophagy, increased the expression of microtubule-associated protein light-chain 3II (LC3II), and reduced the expression of p62 in vitro. The combined treatment protects podocytes by mediating the PI3K/AKT/mTOR (rapamycin complex) signaling pathway. Conclusion ICA enhances the therapeutic effect of DEX on the nephrotic syndrome.

BackgroundRecently, attention has been paid to the protective properties of active ingredients in Salvia miltiorrhiza (AISM) against organ toxicity induced by chemotherapy drugs. Purpose of the present systematic review is to evaluate the chemoprotective effects and mechanisms of AISM on in vitro and in vivo models of doxorubicin-induced cardiotoxicity (DIC).MethodsAccording to the PRISMA guideline, the current systematic review was conducted in the Web of Science, PubMed, Embase, and the Cochrane Library to collect all relevant in vitro and in vivo studies on “the role of AISM on DIC” published up until May 2023. The SYRCLE's tool was used to identify potential risk of bias.ResultsTwenty-two eligible articles were included in this systematic review. Eleven types of active ingredients in Salvia miltiorrhiza were used for DIC, which have the following effects: improvement of physical signs and biochemical indicators, reduction of cardiac function damage caused by DIC, protection of heart tissue structure, enhancement of myocardial cell viability, prevention of cardiomyocyte apoptosis, increase of the chemosensitivity of cancer cells to Doxorubicin, etc. The cardioprotective mechanism of AISM involves inhibiting apoptosis, attenuating oxidative stress, suppressing endoplasmic reticulum (ER) stress, decreasing inflammation, improving mitochondrial structure and function, affecting cellular autophagy and calcium homeostasis. The quality scores of included studies ranged from 4 to 7 points (a total of 10 points), according to SYRCLE's risk of bias tool.ConclusionThis systematic review demonstrated that AISM have chemoprotective effects on DIC in vivo and in vitro models through several main mechanisms such as anti-apoptosis, antioxidant effects, anti-ER stress, and anti-inflammatory.

Background: Recently the carcinogenic and toxic effects of some heavy metals such as chromium (Cr), and lead (Pb) through the mechanism of oxidative stress have been reported. Due to the various consequences of chemotherapeutic treatments on body hemostasis, the present study aimed to evaluate the effect of Adriamycin 60 mg/m2 and Cytoxan 600 mg/m2 (AC) chemotherapy on the serum levels of Cr, Pb, and the percent a-diphenyl-ß-picrylhydrazyl (DPPH) inhibition. Methods: This study was performed on 50 patients with breast cancer at two separate sampling times, the first at the initiation of chemotherapy and the last at the end of three courses of the AC chemotherapy treatment. Serum levels of Cr and Pb were measured using atomic absorption spectrophotometry. The percent DPPH inhibition (% I) and also the effect of age and stage of the disease on the mentioned variables were evaluated. Statistical comparison of the obtained results before and after chemotherapy was performed using paired sample t-test. Intra-group evaluation of age and disease stages was done using an independent sample t-test. Results: A significant decrease was observed in the percent DPPH inhibition after 3 courses of chemotherapy (p<0.001). Cr and also Pb were significantly higher in patients with breast cancer after AC chemotherapy (p<0.001). Conclusion: According to the results, AC chemotherapy in patients with breast cancer is associated with higher levels of Cr and Pb, which can eventually lead to worsened oxidative stress status in affected patients. However, it seems that these changes do not necessarily depend on age and the stage of the disease. [ABSTRACT FROM AUTHOR]