αO-Conotoxin GeXIVA[1,2] Suppresses In Vivo Tumor Growth of Triple-Negative Breast Cancer by Inhibiting AKT-mTOR, STAT3 and NF-κB Signaling Mediated Proliferation and Inducing Apoptosis.

Breast cancer is one of the leading causes of cancer mortality worldwide, and triple-negative breast cancer (TNBC) is the most problematic subtype. There is an urgent need to develop novel drug candidates for TNBC. Marine toxins are a valuable source for drug discovery. We previously identified αO-conotoxin GeXIVA[1,2] from Conus generalis, which is a selective antagonist of α9 nicotinic acetylcholine receptors (nAChRs). Recent studies indicated that α9 nAChR expression is positively correlated with breast cancer development; thus, α9 nAChR could serve as a therapeutic target for breast cancer. In this study, we aimed to investigate the in vivo antitumor effects of GeXIVA[1,2] on TNBC and to elucidate its underlying anticancer mechanism. Our data showed that GeXIVA[1,2] effectively suppressed 4T1 tumor growth in vivo at a very low dose of 0.1 nmol per mouse. Our results uncovered that the antitumor mechanism of GeXIVA[1,2] simultaneously induced apoptosis and blocked proliferation. Further investigations revealed that GeXIVA[1,2]-induced Caspase-3-dependent apoptosis was achieved through regulating Bax/Bcl-2 balance, and GeXIVA[1,2]-inhibited proliferation was mediated by the downregulation of the AKT-mTOR, STAT3 and NF-κB signaling pathways. Our study provides valuable arguments to demonstrate the potential of GeXIVA[1,2] as a novel marine-derived anticancer drug candidate for the treatment of TNBC.

Emerging anticancer potential and mechanisms of snake venom toxins: A review.

Animal-derived venom, like snake venom, has been proven to be valuable natural resources for the drug development. Previously, snake venom was mainly investigated in its pharmacological activities in regulating coagulation, vasodilation, and cardiovascular function, and several marketed cardiovascular drugs were successfully developed from snake venom. In recent years, snake venom fractions have been demonstrated with anticancer properties of inducing apoptotic and autophagic cell death, restraining proliferation, suppressing angiogenesis, inhibiting cell adhesion and migration, improving immunity, and so on. A number of active anticancer enzymes and peptides have been identified from snake venom toxins, such as L-amino acid oxidases (LAAOs), phospholipase A2 (PLA2), metalloproteinases (MPs), three-finger toxins (3FTxs), serine proteinases (SPs), disintegrins, C-type lectin-like proteins (CTLPs), cell-penetrating peptides, cysteine-rich secretory proteins (CRISPs). In this review, we focus on summarizing these snake venom-derived anticancer components on their anticancer activities and underlying mechanisms. We will also discuss their potential to be developed as anticancer drugs in the future.

Research Progress in Nanofluid-Enhanced Oil Recovery Technology and Mechanism.

Nanofluid-enhanced oil recovery (EOR) technology is an innovative approach to enhancing oil production in oilfields. It entails the dispersion of nanoparticles within a fluid, strategically utilizing the distinctive properties of these nanoparticles (NPs) to engage with reservoir rocks or crude oil, resulting in a significant enhancement of the oil recovery rate. Despite the notable advantages of nanofluid EOR technology over conventional oil recovery methods such as binary and ternary flooding, practical implementations continue to grapple with a range of pressing challenges. These challenges encompass concerns regarding the economic viability, stability, and adaptability of nanomaterials, which pose significant barriers to the widespread adoption of nanofluid EOR technology in the oil field. To tackle these challenges, addressing the current issues may involve selecting simpler and more readily available materials coupled with straightforward material modification techniques. This approach aims to more effectively meet the requirements of large-scale on-site applications. Within this framework, this review systematically explores commonly employed nanofluids in recent years, including inorganic nanofluids, organic nanofluids, and composite nanofluids. It categorizes the research advancements in optimizing modification techniques and provides a comprehensive overview of the mechanisms that underpin nanofluid EOR technology and its practical applications in oilfields. This comprehensive review aims to offer valuable references and serve as a solid foundation for subsequent research endeavors.

Antidepressants as Autophagy Modulators for Cancer Therapy.

Cancer is a major global public health problem with high morbidity. Depression is known to be a high-frequency complication of cancer diseases that decreases patients' life quality and increases the mortality rate. Therefore, antidepressants are often used as a complementary treatment during cancer therapy. During recent decades, various studies have shown that the combination of antidepressants and anticancer drugs increases treatment efficiency. In recent years, further emerging evidence has suggested that the modulation of autophagy serves as one of the primary anticancer mechanisms for antidepressants to suppress tumor growth. In this review, we introduce the anticancer potential of antidepressants, including tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). In particular, we focus on their autophagy-modulating mechanisms for regulating autophagosome formation and lysosomal degradation. We also discuss the prospect of repurposing antidepressants as anticancer agents. It is promising to repurpose antidepressants for cancer therapy in the future.

Magnolol as a Potential Anticancer Agent: A Proposed Mechanistic Insight.

Cancer is a serious disease with high mortality and morbidity worldwide. Natural products have served as a major source for developing new anticancer drugs during recent decades. Magnolol, a representative natural phenolic lignan isolated from Magnolia officinali, has attracted considerable attention for its anticancer properties in recent years. Accumulating preclinical studies have demonstrated the tremendous therapeutic potential of magnolol via a wide range of pharmacological mechanisms against cancer. In this review, we summarized the latest advances in preclinical studies investigating anticancer properties of magnolol and described the important signaling pathways explaining its underlying mechanisms. Magnolol was capable of inhibiting cancer growth and metastasis against various cancer types. Magnolol exerted anticancer effects through inhibiting proliferation, inducing cell cycle arrest, provoking apoptosis, restraining migration and invasion, and suppressing angiogenesis. Multiple signaling pathways were also involved in the pharmacological actions of magnolol against cancer, such as PI3K/Akt/mTOR signaling, MAPK signaling and NF-κB signaling. Based on this existing evidence summarized in the review, we have conclusively confirmed magnolol had a multi-target anticancer effect against heterogeneous cancer disease. It is promising to develop magnolol as a drug candidate for cancer therapy in the future.

Identification of Differential Expression Genes between Volume and Pressure Overloaded Hearts Based on Bioinformatics Analysis.

Volume overload (VO) and pressure overload (PO) are two common pathophysiological conditions associated with cardiac disease. VO, in particular, often occurs in a number of diseases, and no clinically meaningful molecular marker has yet been established. We intend to find the main differential gene expression using bioinformatics analysis. GSE97363 and GSE52796 are the two gene expression array datasets related with VO and PO, respectively. The LIMMA algorithm was used to identify differentially expressed genes (DEGs) of VO and PO. The DEGs were divided into three groups and subjected to functional enrichment analysis, which comprised GO analysis, KEGG analysis, and the protein-protein interaction (PPI) network. To validate the sequencing data, cardiomyocytes from AR and TAC mouse models were used to extract RNA for qRT-PCR. The three genes with random absolute values of LogFC and indicators of heart failure (natriuretic peptide B, NPPB) were detected: carboxylesterase 1D (CES1D), whirlin (WHRN), and WNK lysine deficient protein kinase 2 (WNK2). The DEGs in VO and PO were determined to be 2761 and 1093, respectively, in this study. Following the intersection, 305 genes were obtained, 255 of which expressed the opposing regulation and 50 of which expressed the same regulation. According to the GO and pathway enrichment studies, DEGs with opposing regulation are mostly common in fatty acid degradation, propanoate metabolism, and other signaling pathways. Finally, we used Cytoscape's three techniques to identify six hub genes by intersecting 255 with the opposite expression and constructing a PPI network. Peroxisome proliferator-activated receptor (PPARα), acyl-CoA dehydrogenase medium chain (ACADM), patatin-like phospholipase domain containing 2 (PNPLA2), isocitrate dehydrogenase 3 (IDH3), heat shock protein family D member 1 (HSPD1), and dihydrolipoamide S-acetyltransferase (DLAT) were identified as six potential genes. Furthermore, we predict that the hub genes PPARα, ACADM, and PNPLA2 regulate VO myocardial changes via fatty acid metabolism and acyl-Coa dehydrogenase activity, and that these genes could be employed as basic biomarkers for VO diagnosis and treatment.

Magnetic Hyperbranched Molecular Materials for Treatment of Oily Sewage Containing Polymer in Oilfield Compound Flooding.

With the continuous improvement in oilfield development and the application of tertiary oil recovery technology, the water content of oilfield-produced fluids has gradually increased, and a large number of oilfield sewage with complex components has also been produced after oil-water separation, and effective treatment is urgently needed. ASP flooding sewage contains alkali, various surfactants, polymers, microemulsion oil droplets, and solid impurities, which are difficult to be effectively treated by traditional water treatment agents and methods. In this study, aminopropyl triethoxysilane (APTES) was used to modify the nano-Fe3O4 coated with tetraethyl silicate (TEOS). The product was used as the ferromagnetic nano-core for the iterative reaction of Michael addition and ester amidation to synthesize a magnetic hyperbranched polyamide amine, and its performance in the treatment of ASP flooding wastewater was evaluated experimentally. For the preparation of APTES-modified Fe3O4@SiO2 (FOSN) product, TEOS was coated over Fe3O4 in an ethanol aqueous solution environment and then APTES was added dropwise. The first-generation branched product (1-FSMN) was obtained by the reaction of FOSN and methyl acrylate graft product (FOSN-M) with ethylenediamine, and the highest yield was 93.7%. The highest yield of the second-generation branched product (2-FSMN) was 91.6%. In this study, a composite flooding wastewater sample from a block in the Bohai oilfield was taken. The suspended solids content was 143 mg/L, the oil content was 921.09 mg/L, the turbidity was 135 NTU, and the zeta potential was -47 mV. The third-generation hyperbranched polymer (3-FSMN) and its quaternary ammonium salt (3-FSMN-Q) performed best in the appropriate dosage range, with the highest oil removal rate of 97%, suspended solid removal rate of 90.3%, turbidity reduction rate of 86.6% and zeta potential reduction rate of 88%. For 3-FSMN and its quaternary ammonium salt, the gravity/magnetic PAC compound treatment experiment was carried out. In the settlement time of only 5 min, 3-FSMN/PAC and 3-FSMN-Q/PAC can achieve the maximum oil removal rate of 87.1% and suspended solids removal rate of 87.3% for polymer containing wastewater from ASP flooding, and 86.3 and 86.0% for 120 mg/L. Its treatment capacity was much better than that of common treatment agent combination (CPAM/PAC).

Samm50 Promotes Hypertrophy by Regulating Pink1-Dependent Mitophagy Signaling in Neonatal Cardiomyocytes.

Pathological cardiac hypertrophy, the adaptive response of the myocardium to various pathological stimuli, is one of the primary predictors and predisposing factors of heart failure. However, its molecular mechanisms underlying pathogenesis remain poorly understood. Here, we studied the function of Samm50 in mitophagy during Ang II-induced cardiomyocyte hypertrophy via lentiviruses mediated knockdown and overexpression of Samm50 protein. We first found that Samm50 is a key positive regulator of cardiac hypertrophy, for western blot and real-time quantitative PCR detection revealed Samm50 was downregulated both in pressure-overload-induced hypertrophic hearts and Ang II-induced cardiomyocyte hypertrophy. Then, Samm50 overexpression exhibits enhanced induction of cardiac hypertrophy marker genes and cell enlargement in primary mouse cardiomyocytes by qPCR and immunofluorescence analysis, respectively. Meanwhile, Samm50 remarkably reduced Ang II-induced autophagy as indicated by decreased mitophagy protein levels and autophagic flux, whereas the opposite phenotype was observed in Samm50 knockdown cardiomyocytes. However, the protective role of Samm50 deficiency against cardiac hypertrophy was abolished by inhibiting mitophagy through Vps34 inhibitor or Pink1 knockdown. Moreover, we further demonstrated that Samm50 interacted with Pink1 and stimulated the accumulation of Parkin on mitochondria to initiate mitophagy by co-immunoprecipitation analysis and immunofluorescence. Thus, these results suggest that Samm50 regulates Pink1-Parkin-mediated mitophagy to promote cardiac hypertrophy, and targeting mitophagy may provide new insights into the treatment of cardiac hypertrophy.

Pithecellobium clypearia: Amelioration Effect on Imiquimod-Induced Psoriasis in Mice Based on a Tissue Metabonomic Analysis.

Pithecellobium clypearia Benth. (accepted name: Archidendron clypearia (Jack) I.C.Nielsen; Mimosaceae), a popular traditional Chinese medicine, has a significant anti-inflammatory effect. The crude water extract of the aerial part of P. clypearia has been clinically applied to treat upper respiratory tract infections, acute gastroenteritis, laryngitis, and pharyngitis. However, the therapeutic mechanism of ethanol fraction of water extract (ESW) of P. clypearia to treat psoriasis should be complemented. The aim of our research was to clarify the protective effects of ESW from P. clypearia against psoriasis-like skin inflammation induced by imiquimod (IMQ) in mice with efficacy indexes and target tissue (spleen and serum) metabolomics. The ingredient of ESW was analyzed by ultrahigh-performance liquid chromatography combined with tandem mass spectrometry (UHPLC-MS/MS) method. The imiquimod-induced psoriatic mouse model was employed to investigate the effect of ESW against psoriasis, where the treatment method was implemented for 6 days both topically (Gel at 5%) and orally (at 2.4 g/kg p.o.). Traditional pharmacodynamic indicators (phenotypic characteristics, psoriasis area and severity index (PASI) score, H&E staining, immunohistochemical staining, the thickness of epidermis, body weight change, and spleen index) were conducted to appraise the efficacy of ESW. Furthermore, a gas chromatography-mass spectrometer (GC-MS) coupled with multivariate analysis was integrated and applied to obtain serum and spleen metabolic profiles for clarifying metabolic regulatory mechanisms of ESW. The current study illustrated that ESW is composed mainly of gallic acid, ethyl gallate, quercitin, 7-O-galloyltricetiflavan, quercetin, and myricetin by UHPLC-MS/MS analysis. ESW could distinctly improve IMQ-induced psoriasis in mouse through reducing PASI score, alleviating tissue damage, restoring spleen index, and inhibiting proliferating cell nuclear antigen (PCNA) expression in psoriasis-like skin tissue. From the metabolomics study, 23 markers with significant changes are involved in eight main pathways in spleen and serum samples, including linoleic acid metabolism and glycine, serine, and threonine metabolism. The current study showed that ESW had obvious antipsoriasis effects on IMQ-induced psoriasis in mice, which might be attributed to regulating the dysfunction of differential biomarkers and related pathways. In summary, ESW of P. clypearia showed a favourable therapeutic effect on IMQ-induced psoriasis, and metabolomics provided insights into the mechanisms of ESW to the treatment of psoriasis.

Serum Metabolomic Profiling Reveals the Amelioration Effect of Methotrexate on Imiquimod-Induced Psoriasis in Mouse.

BACKGROUND: The imiquimod (IMQ)-induced psoriasis mouse model has been used as a model for pathogenic mechanism research, and methotrexate (MTX) is widely employed to treat various clinical manifestations of psoriasis. We explored the underlying pathogenesis of psoriasis and the treatment mechanism of the conventional drugs from the metabolic perspective of the psoriasis mouse model. METHODS: Male BALB/c mice were smeared IMQ for 7 days to induce treatment-resistant psoriasis and intragastrically administered 1 mg/kg MTX. We evaluated inflammation of psoriasis-like lesions and therapeutic effects of MTX based on histological changes and immunohistochemistry. Based on gas chromatography-mass spectrometer detection of serum samples, a comprehensive metabolomics analysis was carried out to identify alterations of metabolites. RESULTS: It was found that MTX ameliorated psoriatic lesions (representative erythema, scaling, and thickening) by inhibiting proliferation and differentiation of keratinocytes. Using multivariate statistical analysis to process metabolomics data, the results displayed alterations in serum metabolites among mice of the control group, IMQ group, and MTX group. Compared with group, psoriasis mice had the higher level of d-galactose and lower expression of myo-inositol, 9,12-octadecadienoic acid, and cholesterol. In contrast with the model set, serum levels of glycine, pyrrolidone carboxylic acid, d-galactose, and d-mannose were significantly decreased in the MTX group. CONCLUSION: The differential metabolites, reflecting the perturbation in the pathways of inositol phosphate metabolism; galactose metabolism; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; and glutathione metabolism, may lead to the pathogenesis of psoriasis, and they are also related to the pharmacological treatment effect of MTX on psoriasis. This study established the foundation for further research on the mechanism and therapeutic targets of psoriasis.

A refractory case of CDK4-amplified spinal astrocytoma achieving complete response upon treatment with a Palbociclib-based regimen:a case report.

BACKGROUND: Spinal cord astrocytoma is a rare neoplasm, and patients usually recur within months after surgery. There is currently a lack of consensus regarding post-operative treatment. Clinical data on the activity of systemic treatment like chemoradiotherapy and anti-angiogenic agents also remained scant. Next-generation sequencing (NGS) -based genomic profiling thus may help identify potential treatment options for a subset of patients that harbor actionable genetic alterations. CASE PRESENTATION: We reported for the first time a refractory case of grade III spinal cord astrocytoma that underwent two surgeries but eventually progressed following post-operative chemoradiotherapy plus bevacizumab. Hybridization capture-based NGS using a 381-gene panel disclosed cyclin dependent kinase 4 (CDK4) amplification and after receiving a triplet regimen containg palbociclib for 15 months, the patient achieved complete response. CONCLUSIONS: This case demonstrated the importance of genetic profiling and the benefit of a multi-modality treatment strategy in cancer management.

Effect of Chinese Herbal Medicine on the Survival of Colorectal Cancer Patients With Liver-Limited Metastases: A Retrospective Cohort Study, 2008 to 2017.

Background: Colorectal cancer (CRC) remains one of the leading contributors to cancer-related mortality and morbidity worldwide. Traditional Chinese medicines have been widely employed to treat various types of cancer in China. This investigation aims to determine the association between Chinese herbal medicine (CHM) therapy and survival outcomes in CRC patients with liver-limited metastases. Methods: A retrospective cohort study was performed among patients with colorectal liver metastases at the First Affiliated Hospital of Guangzhou University of Chinese Medicine in Guangzhou, China. Data from a series of consecutive patients were collected via an electronic medical record system or telephone follow-up. We defined high exposure as a period of CHM therapy lasting more than 6 months. The primary outcome was overall survival. Results: The study included the data of 191 patients from January 2008 to December 2017; 126 patients (65.97%) met the inclusion criteria of high exposure to CHM. Multivariate analyses revealed that high exposure to CHM was associated with better overall survival (hazard ratio = 0.444, 95% confidence interval = [0.213, 0.926], P = .030). The association was further confirmed by a subgroup exploratory analysis. Conclusion: Long-term CHM therapy is correlated with improved survival outcomes in CRC patients with liver-limited metastases.

[Clinical and pathological study of 47 cases with Alport syndrome].

OBJECTIVE: To analyze the clinical and pathological features of children with Alport syndrome (AS). METHODS: A series of 47 patients with AS from unrelated families hospitalized from Jan. 1990 to Jan. 2007 were involved in this study. The clinical and histopathological data were collected and analyzed. RESULTS: Of the 47 cases, 32 were male and 15 female, M/F: 2.1:1. The patient's age ranged from 15 months to 13 years, mean 9 years. Thirty-nine of the 47 cases had positive family history, X-linked dominant inheritance AS was diagnosed in 37 cases, autosomal recessive inheritance AS in 2 cases. Gross hematuria or microscopic hematuria were found in 59.3% of the cases as the first manifestations, while 29.8% showed edema or proteinuria. The major clinical manifestations were isolated hematuria (23.4%), hematuria and proteinuria (36.2%), nephrotic syndrome (29.8%), and renal failure (10.6%). Hematuria and proteinuria existed in all the cases, while only 7 to 13 years children had nephrotic syndrome and renal failure. Of the 47 patients, 33 (70.2%) showed mesangial proliferative glomerulonephritis (MsPGN) under the light microscope, 13 (27.6%) focal segmental glomerulosclerosis (FSGS), 1 (2.1%) membrane proliferative glomerulonephritis (MPGN). For immunofluorescence, there was IgM (40.4%) as the dominant deposition in 19 patients, IgA in 9 (19.1%), IgG in 9 (19.1%), and 10 (21.4%) were negative. Thirty-nine cases showed typical glomerular basement membrane (GBM) pathological changes under electron microscope, while thin basement membrane in 8 cases; 46 showed abnormal skin and/or renal alpha-chain distribution. CONCLUSION: For Alport syndrome, number of male patients was higher than that of female patients. There was a significant difference among different age groups. Hematuria might be present throughout the course, while urine protein increases gradually. MsPGN was the dominant pathological change. The GBM pathological changes in younger children is not typical, so the immunofluorescence test of alpha-chain in collagen IV should be used as an important diagnostic method.

[Cyclosporin A treatment of 83 children with nephrotic syndrome of different pathological types].

OBJECTIVE: To evaluate the efficacy of cyclosporin A (CyA) therapy in 83 children with nephrotic syndrome of different pathological types. METHODS: Eighty-three children enrolled in this study were all hospitalized children with idiopathic nephrotic syndrome, aged 3 to 14 yrs (average 8.3 yrs) and included 52 males and 31 females. There were 35 cases with steroid-dependent, 17 with steroid resistant and 26 with frequent relapses. CyA was given to each patient with dosage of 5 mg/(kg.d) during the corticosteroid was diminished. The renwal biopsy was performed in all patients before the administration of CyA. The duration of CyA therapy lasted for about 3 to 6 months. The plasma concentration of CyA was monitored. RESULTS: Eighty-three children with nephrotic syndrome of different pathological types were treated with CyA, including 42 cases of minimal change nephrotic syndrome (MCNS), 31 cases of mesangioproliferative glomerulonephritis (MsPGN), 5 cases of membranoproliferative glomerulonephritis (MPGN) and 4 cases of focal segmental glomerular sclerosis (FSGS). All the 83 patients tolerated well to the CyA treatment. Forty-five cases got complete remission, 23 partial remission, 15 cases no change after one month treatment with CyA in the hospital. The overall response rate was 82%. Patients with different renal pathological types showed different responses. Among them, MCNS and MsPGN exhibited the best response rates of 86% and 84%, respectively; MPGN cases showed a lower response rate and FSGS cases showed the lowest rate. The response time was 7 to 45 days. The blood concentration of CyA was monitored for 1 week and 2 weeks after the drug was given. The effective drug concentration was maintained at 100 to 200 microg/L, and the course lasted for 3 to 6 months. During the follow-up of 83 cases, in 17 of 68 cases the disease relapsed when therapy was tapered or discontinued. The relapse rate was 25%. The results indicated that CyA would be effective to the relapsed cases. The serum creatinine increased temporarily after administration of CyA in 5 cases, N-acetyl-beta-D-glucosaminidase (NAG) in 8 cases and eventually reached the normal range after the adjustment of dosage. The side effects included anorexia, nausea, vomiting and so on. CONCLUSION: CyA is one of the effective substitutes for the treatment of nephrotic syndrome, especially for the cases with MCNS and MsPGN. And CyA could control refractory nephrotic syndrome effectively and rapidly. The clinical effect was related to the blood concentration of CyA and pathological types.