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TAFRO syndrome, first reported in 2010, is a systemic inflammatory disease with a rapid onset and potentially fatal course if not treated promptly and appropriately. The name is derived from the initial letters describing the characteristic symptoms of thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly. It is sometimes considered a special subtype of idiopathic multicentric Castleman disease (iMCD) because lymph node biopsies often reveal the pathology findings seen in iMCD. However, its clinical manifestations and prognoses are not well documented. Since the clinical manifestations and prognoses of TAFRO syndrome differ significantly from those of iMCD, it is recognized as an independent disease concept and considered to partially overlap with the pathology of MCD. The pathogenesis of TAFRO syndrome remains largely unknown. Due to the lack of appropriate treatment, it often presents with multiple organ dysfunction and fatality. In this review, we summarized new findings on the pathogenesis of TAFRO syndrome and discussed current effective therapies and future treatment strategies.

Objectives: Head and neck squamous cell carcinoma (HNSCC) ranks sixth globally, with a 50% five-year survival rate. SAR1A exhibits high expression levels in various tumor types, yet its specific role in HNSCC remains to be clarified. Methods: In vitro assays, such as CCK8, EdU, colony formation, wound-healing, transwell, and Western blotting analyses, as well as in vivo assays, such as tumor xenografts and lung metastasis models, were conducted to evaluate the impacts of SAR1A on HNSCC proliferation, migration, and invasion. Transcriptome sequencing and KEGG enrichment pathway analysis revealed evident alterations in the PI3K/AKT/mTOR(PAM) pathways. LY294002 (a PI3K/AKT inhibitor) was used to investigate the role of the PAM pathway in proliferation, migration, and invasion in HNSCC. Results: Univariate and multivariate Cox regression were conducted to screen SAR1A as a gene prognostic biomarker in HNSCC, and it was validated in the Cancer Genome Atlas (TCGA) database. Functional assays demonstrated that the depletion of SAR1A leads to suppressed proliferation, migration, and invasion of HNSCC cells. This is accompanied by a decrease in the expression of epithelial–mesenchymal transition (EMT)-related markers in HNSCC cell lines. In addition, the diminished capacities of proliferation, migration, and invasion observed in SAR1A knockdown cells were reversed upon the overexpression of SAR1A. Furthermore, RNA-seq and KEGG enrichment analysis demonstrated a significant alteration in the PAM pathway following SAR1A knockdown. LY294002 effectively mitigated the increased proliferation, migration, and invasion induced by SAR1A overexpression. Conclusions: SAR1A facilitates HNSCC proliferation and EMT via the PI3K/AKT/mTOR pathway.

Many researchers are focusing on screening the biological activities of plants owing to their safety and possible pharmacological actions. Consequently, we aimed to explore the antiproliferative and cytotoxic properties of Cycas media methanolic extract on HepG2 cell lines. Moreover, we also explore the antitumor action against the experimentally induced solid Ehrlich carcinoma (SEC) model and investigate the possible involved molecular mechanisms. Also, the antibacterial action of the extract was elucidated. Different concentrations of the extract were incubated with HepG2 to determine cytotoxicity, followed by cell cycle analysis. The in vivo experiment was accomplished by grouping the animals into four different groups (n = 10); normal control, SEC, C. media 100, and C. media 200. The extract was administered at 100 and 200 mg/kg. Tumor volume, tumor inhibition rate, toxicity profile, and antioxidant biomarkers were determined. Moreover, the PI3K/AKT/mTOR signaling pathway was investigated as a possible underlying antitumor mechanism. The tumor control group showed a remarkable upregulation for PI3K, p-AKT, and p-mTOR, along with downregulation for the antioxidant SOD and GPX4, as well as decreased levels of GSH and MDA. C. media extract reversed these parameters to a significant level and the higher dose showed a superior antitumor effect. C. media extract showed antiproliferative effects against HepG2 cells, along with a suppressive action on the PI3K/AKT/mTOR pathway and an antioxidant effect. Additionally, C. media had antibacterial consequences against S. aureus isolates with minimum inhibitory concentrations from 32 to 128 µg/mL. It also caused a noteworthy growth delay as well as a notable reduction in the membrane integrity of S. aureus isolates. These beneficial outcomes suggest C. media to have potential antitumor and antibacterial activities.

Axonal regeneration in the spinal cord after traumatic injuries presents a challenge for researchers, primarily due to the nature of adult neurons and the inhibitory environment that obstructs neuronal regrowth. Here, we review current knowledge of the intricate network of molecular and cellular mechanisms that hinder axonal regeneration, with a focus on myelin-associated inhibitors (MAIs) and other inhibitory guidance molecules, as well as the pivotal pathways implicated in both inhibiting and facilitating axonal regrowth, such as PKA/AMP, PI3K/Akt/mTOR, and Trk, alongside the regulatory roles of neurotrophins and axonal guidance cues. We also examine current insights into gene therapy, tissue engineering, and pharmacological interventions that show promise in overcoming barriers to axonal regrowth.

Triple-negative breast cancer (TNBC) has a worse prognosis and remains the most challenging breast cancer subtype to treat. This is largely related to the heterogeneity of this disease and the lack of reliable oncological targets. In this review, we discuss the current standard-of-care treatment options for metastatic TNBC, including recent advances with the use of immunotherapy, PARP inhibitors and antibody-drug conjugates. This review also explores new agents and novel combinations arising in the field for the treatment of advanced TNBC.

Due to its intricate heterogeneity, high invasiveness, and poor prognosis, triple-negative breast cancer (TNBC) stands out as the most formidable subtype of breast cancer. At present, chemotherapy remains the prevailing treatment modality for TNBC, primarily due to its lack of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth receptor 2 (HER2). However, clinical chemotherapy for TNBC is marked by its limited efficacy and a pronounced incidence of adverse effects. Consequently, there is a pressing need for novel drugs to treat TNBC. Given the rich repository of diverse natural compounds in traditional Chinese medicine, identifying potential anti-TNBC agents is a viable strategy. This study investigated lasiokaurin (LAS), a natural diterpenoid abundantly present in Isodon plants, revealing its significant anti-TNBC activity both in vitro and in vivo. Notably, LAS treatment induced cell cycle arrest, apoptosis, and DNA damage in TNBC cells, while concurrently inhibiting cell metastasis. In addition, LAS effectively inhibited the activation of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and signal transducer and activator of transcription 3 (STAT3), thus establishing its potential for multitarget therapy against TNBC. Furthermore, LAS demonstrated its ability to reduce tumor growth in a xenograft mouse model without exerting detrimental effects on the body weight or vital organs, confirming its safe applicability for TNBC treatment. Overall, this study shows that LAS is a potent candidate for treating TNBC.

Despite the availability of modern techniques for the treatment of esophageal squamous cell carcinoma (ESCC), tumor recurrence and metastasis are significant challenges in clinical management. Thus, ESCC possesses a poor prognosis and low five-year overall survival rate. Notably, the origin and recurrence of the cancer phenotype are under the control of complex cancer-related signaling pathways. In this review, we provide comprehensive knowledge about long non-coding RNAs (lncRNAs) related to Wnt/β-catenin and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway in ESCC and its implications in hindering the efficacy of chemotherapeutic drugs. We observed that a pool of lncRNAs, such as HERES, TUG1, and UCA1, associated with ESCC, directly or indirectly targets various molecules of the Wnt/β-catenin pathway and facilitates the manifestation of multiple cancer phenotypes, including proliferation, metastasis, relapse, and resistance to anticancer treatment. Additionally, several lncRNAs, such as HCP5 and PTCSC1, modulate PI3K/Akt/mTOR pathways during the ESCC pathogenesis. Furthermore, a few lncRNAs, such as AFAP1-AS1 and LINC01014, block the efficiency of chemotherapeutic drugs, including cisplatin, 5-fluorouracil, paclitaxel, and gefitinib, used for ESCC treatment. Therefore, this review may help in designing a better therapeutic strategy for ESCC patients.

Brown algae comprise up to 2000 species with wide dissemination in temperate zones. A comprehensive untargeted metabolic profiling guided by molecular networking of three uninvestigated Red-Sea-derived brown algae, namely Sirophysalis trinodis, Polycladia myrica, and Turbinaria triquetra, led to the identification of over 115 metabolites categorized as glycerolipids, fatty acids, sterol lipids, sphingolipids, and phospholipids. The three algae exhibited low-to-moderate antioxidant capacity using DPPH and ABTS assays. Preliminary in vitro antiproliferative studies showed that the algal extracts displayed high cytotoxic activity against a panel of cancer cell lines. The most potent activity was recorded against MCF-7 with IC50 values of 51.37 ± 1.19, 63.44 ± 1.13, and 59.70 ± 1.22 µg/mL for S. trinodis, P. myrica, and T. triquetra, respectively. The cytotoxicity of the algae was selective to MCF-7 without showing notable effects on the proliferation of normal human WISH cells. Morphological studies revealed that the algae caused cell shrinkage, increased cellular debris, triggered detachment, cell rounding, and cytoplasmic condensation in MCF-7 cancer cells. Mechanistic investigations using flow cytometry, qPCR, and Western blot showed that the algae induced apoptosis, initiated cell cycle arrest in the sub-G0/G1 phase, and inhibited the proliferation of cancer cells via increasing mRNA and protein expression of p53, while reducing the expression of PI3K, Akt, and mTOR.

Liver ischemia-reperfusion injury (IRI) is a pathophysiological insult that often occurs during liver surgery. Blackberry leaves are known for their anti-inflammatory and antioxidant activities. Aims: To achieve site-specific delivery of blackberry leaves extract (BBE) loaded AgNPs to the hepatocyte in IRI and to verify possible molecular mechanisms. Methods: IRI was induced in male Wister rats. Liver injury, hepatic histology, oxidative stress markers, hepatic expression of apoptosis-related proteins were evaluated. Non-targeted metabolomics for chemical characterization of blackberry leaves extract was performed. Key findings: Pre-treatment with BBE protected against the deterioration caused by I/R, depicted by a significant improvement of liver functions and structure, as well as reduction of oxidative stress with a concomitant increase in antioxidants. Additionally, BBE promoted phosphorylation of antiapoptotic proteins; PI3K, Akt and mTOR, while apoptotic proteins; Bax, Casp-9 and cleaved Casp-3 expressions were decreased. LC-HRMS-based metabolomics identified a range of metabolites, mainly flavonoids and anthocyanins. Upon comprehensive virtual screening and molecular dynamics simulation, the major annotated anthocyanins, cyanidin and pelargonidin glucosides, were suggested to act as PLA2 inhibitors. Significance: BBE can ameliorate hepatic IRI augmented by BBE-AgNPs nano-formulation via suppressing, oxidative stress and apoptosis as well as stimulation of PI3K/Akt/mTOR signaling pathway.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication along with repetitive stereotypic behaviors. Currently, there are no specific biomarkers for diagnostic screening or treatments available for autistic patients. Numerous genetic disorders are associated with high prevalence of ASD, including tuberous sclerosis complex, phosphatase and tensin homolog, and fragile X syndrome. Preclinical investigations in animal models of these diseases have revealed irregularities in the PI3K/Akt/mTOR signaling pathway as well as ASD-related behavioral defects. Reversal of the downstream molecular irregularities, associated with mTOR hyperactivation, improved the behavioral deficits observed in the preclinical investigations. Plant bioactive molecules have shown beneficial pre-clinical evidence in ASD treatment by modulating the PI3K/Akt/mTOR pathway. In this review, we summarize the involvement of the PI3K/Akt/mTOR pathway as well as the genetic alterations of the pathway components and its critical impact on the development of the autism spectrum disorder. Mutations in negative regulators of mTORC1, such as TSC1, TSC2, and PTEN, result in ASD-like phenotypes through the disruption of the mTORC1-mediated signaling. We further discuss the various naturally occurring phytoconstituents that have been identified to be bioactive and modulate the pathway to prevent its disruption and contribute to beneficial therapeutic effects in ASD.

Mast cell (MC) plays a central role in intestinal permeability; however, few MC-targeting drugs are currently available for protection of the intestinal barrier in clinical practice. A nonfluorinated Lidocaine analog 2-diethylamino-N-2,5-dimethylphenyl acetamide (JM25-1) displays anti-allergic effect, but its impact on MC remains elusive. In this study, we explored whether JM25-1 has therapeutic potential on intestinal barrier defect through stabilizing MC. JM25-1 alleviated release of β-hexosaminidase and cytokine production of MC. The paracellular permeability was redressed by JM25-1 in intestinal epithelial cell monolayers co-cultured with activated MC. In vivo, JM25-1 diminished intestinal mucosal MC amount and cytokine production, especially downregulating the expression of CRHR1, accompanied by an increase of CRHR2. Protective effects appeared in JM25-1-treated stress rats with a recovery of weight and intestinal barrier integrity. Through network pharmacology analysis, JM25-1 showed a therapeutic possibility for irritable bowel syndrome (IBS) with predictive targeting on PI3K/AKT/mTOR signaling. As expected, JM25-1 reinforced p-PI3K, p-AKT, p-mTOR signaling in MC, while the mTOR inhibitor Rapamycin reversed the action of JM25-1 on the expression of CRHR1 and CRHR2. Moreover, JM25-1 successfully remedied intestinal defect and declined MC and CRHR1 expression in rat colon caused by colonic mucus of IBS patients. Our data implied that JM25-1 possessed therapeutic capacity against intestinal barrier defects by targeting the CRH receptors of MC through PI3K/AKT/mTOR signaling.

The present study is to explore the anticancer effect of loonamycin (LM) in vitro and in vivo, and investigate the underlying mechanism with combined multi-omics. LM exhibited anticancer activity in human triple negative breast cancer cells by promoting cell apoptosis. LM administration inhibited the growth of MDA-MB-468 tumors in a murine xenograft model of breast cancer. Mechanistic studies suggested that LM could inhibit the topoisomerase I in a dose-dependent manner in vitro experiments. Combined with the transcriptomics and proteomic analysis, LM has a significant effect on O-glycan, p53-related signal pathway and EGFR/PI3K/AKT/mTOR signal pathway in enrichment of the KEGG pathway. The GSEA data also suggests that the TNBC cells treated with LM may be regulated by p53, O-glycan and EGFR/PI3K/AKT/mTOR signaling pathway. Taken together, our findings predicted that LM may target p53 and EGFR/PI3K/AKT/mTOR signaling pathway, inhibiting topoisomerase to exhibit its anticancer effect.

Nigrosporins B, an anthraquinone derivative obtained from the secondary metabolites of marine fungus Nigrospora oryzae. In this study, we characterized the distinctive anti-cancer potential of Nigrosporins B in vitro and underlying molecular mechanisms in human cervical cancer Ca Ski cells for the first time. The results of MTT assay showed that Nigrosporins B significantly inhibited the proliferation of multiple tumor cells in a dose-dependent manner, especially for the Ca Ski cells with an IC50 of 1.24 µM. Nigrosporins B exerted an apoptosis induction effect on Ca Ski cells as confirmed by flow cytometry, AO/EB dual fluorescence staining, mitochondrial membrane potential analysis and western blot assay. In addition, Nigrosporins B induced obvious autophagy accompanied with the increase of autophagic vacuoles and the acceleration of autophagic flux as indicated by Cyto-ID staining, mRFP-GFP-LC3 adenovirus transfection and western blot analysis. Interestingly, the combination of Nigrosporins B with the three autophagy inhibitors all significantly enhanced the cytotoxicity of Nigrosporins B on Ca Ski cells, indicating that the autophagy induced by Nigrosporins B might protect Ca Ski cells from death. Furthermore, we found that Nigrosporins B inhibited the phosphorylation of PI3K, AKT, mTOR molecules and increased the protein expression levels of PTEN and p-AMPKα in a dose-dependent manner, suggesting that Nigrosporins B induced apoptosis and protective autophagy through the suppression of the PI3K/AKT/mTOR signaling pathway. Together, these findings revealed the anti-cervical cancer effect of Nigrosporins B and the underlying mechanism of action in Ca Ski cells, it might be as a promising alternative therapeutic agent for human cervical cancer.

Objective: In the rat, the pancreatic islet transplantation model is an established method to induce hepatocellular carcinomas (HCC), due to insulin-mediated metabolic and molecular alterations like increased glycolysis and de novo lipogenesis and the oncogenic AKT/mTOR pathway including upregulation of the transcription factor Carbohydrate-response element-binding protein (ChREBP). ChREBP could therefore represent an essential oncogenic co-factor during hormonally induced hepatocarcinogenesis. Methods: Pancreatic islet transplantation was implemented in diabetic C57Bl/6J (wild type, WT) and ChREBP-knockout (KO) mice for 6 and 12 months. Liver tissue was examined using histology, immunohistochemistry, electron microscopy and Western blot analysis. Finally, we performed NGS-based transcriptome analysis between WT and KO liver tumor tissues. Results: Three hepatocellular carcinomas were detectable after 6 and 12 months in diabetic transplanted WT mice, but only one in a KO mouse after 12 months. Pre-neoplastic clear cell foci (CCF) were also present in liver acini downstream of the islets in WT and KO mice. In KO tumors, glycolysis, de novo lipogenesis and AKT/mTOR signalling were strongly downregulated compared to WT lesions. Extrafocal liver tissue of diabetic, transplanted KO mice revealed less glycogen storage and proliferative activity than WT mice. From transcriptome analysis, we identified a set of transcripts pertaining to metabolic, oncogenic and immunogenic pathways that are differentially expressed between tumors of WT and KO mice. Of 315 metabolism-associated genes, we observed 199 genes that displayed upregulation in the tumor of WT mice, whereas 116 transcripts showed their downregulated expression in KO mice tumor. Conclusions: The pancreatic islet transplantation model is a suitable method to study hormonally induced hepatocarcinogenesis also in mice, allowing combination with gene knockout models. Our data indicate that deletion of ChREBP delays insulin-induced hepatocarcinogenesis, suggesting a combined oncogenic and lipogenic function of ChREBP along AKT/mTOR-mediated proliferation of hepatocytes and induction of hepatocellular carcinoma.

Curcumin and resveratrol are bioactive natural compounds displaying anti-inflammatory, anti-oxidant and anti-cancer properties. In this study, we compared the cytotoxic effects of these molecules and the molecular mechanisms involved against Her-2/neu-positive breast and salivary cancer cell lines. We found that both curcumin and resveratrol were efficient in reducing cancer cell survival and that they differently affected autophagy, ROS and activation of the PI3K/AKT/mTOR pathway. Moreover, we found that resveratrol and curcumin in combination exerted a stronger cytotoxic effect in correlation with the induction of a stronger ER stress and the upregulation of pro-death UPR molecule CHOP. This effect also correlated with the induction of pro-survival autophagy by curcumin and its inhibition by resveratrol. In conclusion, this study unveils new molecular mechanisms underlying the anti-cancer effects of resveratrol, curcumin and their combination, which can help to design new therapeutic strategies based on the use of these polyphenols.

The Human Papillomavirus (HPV) is the causative agent of different kinds of tumors, including cervical cancers, non-melanoma skin cancers, anogenital cancers, and head and neck cancers. Despite the vaccination campaigns implemented over the last decades, we are far from eradicating HPV-driven malignancies. Moreover, the lack of targeted therapies to tackle HPV-related tumors exacerbates this problem. Biomarkers for early detection of the pathology and more tailored therapeutic approaches are needed, and a complete understanding of HPV-driven tumorigenesis is essential to reach this goal. In this review, we overview the molecular pathways implicated in HPV infection and carcinogenesis, emphasizing the potential targets for new therapeutic strategies as well as new biomarkers.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by peripheral blood cytopenia and abnormal myeloproliferation, as well as a variable risk of evolution into acute myeloid leukemia (AML). The nucleus is a highly organized organelle with several distinct domains where nuclear inositides localize to mediate essential cellular events. Nuclear inositides play a critical role in the modulation of erythropoiesis or myelopoiesis. Here, we briefly review the nuclear structure, the localization of inositides and their metabolic enzymes in subnuclear compartments, and the molecular aspects of nuclear inositides in MDS.

Hypoxia inducible factor-1α (HIF-1α) is an essential regulator of the cellular response to low oxygen concentrations, activating a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1α is overexpressed in various cancers and therefore represents a considerable chemotherapeutic target. Salternamide A (SA), a novel small molecule that is isolated from a halophilic Streptomyces sp., is a potent cytotoxic agent against a variety of human cancer cell lines. However, the mechanisms by which SA inhibits tumor growth remain to be elucidated. In the present study, we demonstrate that SA efficiently inhibits the hypoxia-induced accumulation of HIF-1α in a time- and concentration-dependent manner in various human cancer cells. In addition, SA suppresses the upstream signaling of HIF-1α, such as PI3K/Akt/mTOR, p42/p44 MAPK, and STAT3 signaling under hypoxic conditions. Furthermore, we found that SA induces cell death by stimulating G2/M cell cycle arrest and apoptosis in human colorectal cancer cells. Taken together, SA was identified as a novel small molecule HIF-1α inhibitor from marine natural products and is potentially a leading candidate in the development of anticancer agents.

Renal injury induced by the chemotherapeutic agent methotrexate (MTX) is a serious adverse effect that has limited its use in the treatment of various clinical conditions. The antioxidant activity of Ginkgo biloba extract (GB) was reported to mitigate renal injury induced by MTX. Our research was conducted to examine the nephroprotective role of GB versus MTX-induced renal injury for the first time through its impact on the regulation of phosphatidylinositol 3-kinase/protein kinase B/ mammalian target of rapamycin (PI3K/Akt/mTOR) signaling together with the renal level of TGF-β mRNA and long non-coding RNA-metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) expression. A group of adult rats was intraperitoneally (ip) injected with MTX 20 mg/kg as a single dose to induce kidney injury (MTX group). The other group of rats was orally administered with GB 60 mg/kg every day for 10 days (GB+ MTX group). The MTX increased the serum creatinine and urea levels, renal TGF-β mRNA and MALAT1 expression, in addition to dysregulation of the PI3K/Akt/mTOR signaling when compared with normal control rats that received saline only (NC group). Moreover, renal damage was reported histopathologically in the MTX group. The GB ameliorated the renal injury induced by MTX and reversed the changes of these biochemical analyses. The involvement of PI3K/Akt/mTOR signaling and downregulation of TGF-β mRNA and MALAT1 renal expressions were firstly reported in the nephroprotective molecular mechanism of GB versus MTX-induced renal injury.

Unlike other breast cancer subtypes, patients with triple negative breast cancer (TNBC) have poor outcomes and no effective targeted therapies, leaving an unmet need for therapeutic targets. Efforts to profile these tumors have revealed the PI3K/AKT/mTOR pathway as a potential target. Activation of this pathway also contributes to resistance to anti-cancer agents, including microtubule-targeting agents. Eribulin is one such microtubule-targeting agent that is beneficial in treating taxane and anthracycline refractory breast cancer. In this study, we compared the effect of eribulin on the PI3K/AKT/mTOR pathway with other microtubule-targeting agents in TNBC. We found that the phosphorylation of AKT was suppressed by eribulin, a microtubule depolymerizing agent, but activated by paclitaxel, a microtubule stabilizing agent. The combination of eribulin and everolimus, an mTOR inhibitor, resulted in an increased reduction of p-S6K1 and p-S6, a synergistic inhibition of cell survival in vitro, and an enhanced suppression of tumor growth in two orthotopic mouse models. These findings provide a preclinical foundation for targeting both the microtubule cytoskeleton and the PI3K/AKT/mTOR pathway in the treatment of refractory TNBC.

Current methods for the authentication of essential oils focus on analyzing their chemical composition. This study describes the use of nanofluidic protein post-translational modification (PTM) profiling to differentiate essential oils by analyzing their biochemical effects. Protein PTM profiling was used to measure the effects of four essential oils, copaiba, mandarin, Melissa, and turmeric, on the phosphorylation of MEK1, MEK2, and ERK1/2 in the MAPK signaling pathway; Akt and 4EBP1 in the pI3K/Akt/mTOR signaling pathway; and STAT3 in the JAK/STAT signaling pathway in cultured HepG2 cells. The gain or loss of the phosphorylation of these proteins served as direct read-outs for the positive or negative regulatory effects of essential oils on their respective signaling pathways. Furthermore, protein PTM profiling and GC-MS were employed side-by-side to assess the quality of the essential oils. In general, protein PTM profiling data concurred with GC-MS data on the identification of adulterated mandarin, Melissa, and turmeric essential oils. Most interestingly, protein PTM profiling data identified the differences in biochemical effects between copaiba essential oils, which were indistinguishable with GC-MS data on their chemical composition. Taken together, nanofluidic protein PTM profiling represents a robust method for the assessment of the quality and therapeutic potential of essential oils.

The epithelial–mesenchymal transition (EMT) is a phenomenon that facilitates epithelial cells to acquire invasive potential to induce the initiation the metastatic spread of tumor cells. Here, we determined if brassinin (BSN) can affect the EMT process and deciphered its anti-cancer effects. BSN attenuated the levels of EMT linked genes and suppressed transforming growth factor beta (TGF-β)-mediated regulation of diverse mesenchymal markers. Additionally, BSN did increase the expression of various epithelial marker proteins in lung cancer cells. TGF-β-induced morphological changes and induction of invasive ability of tumor cells was also found to be abrogated by BSN treatment. Finally, BSN not only suppressed constitutive, but also inducible phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) phosphorylation in tumor cells.

Background: The antitumor activity of CLE-10 (4-epi-isoinuviscolide), a sesquiterpene lactone compound, isolated from Carpesium abrotanoides L. has rarely been reported. The aim of this study is to investigate the antitumor activity of CLE-10 and give a greater explanation of its underlying mechanisms. Methods: The cytotoxicity of CLE-10 was evaluated using MTT assay. Autophagy was detected by the formation of mRFP-GFP-LC3 fluorescence puncta and observed using transmission electron microscopy, while flow cytometry was employed to detect apoptosis. The protein expressions were detected through Western blotting. Results: CLE-10 induced pro-death autophagy and apoptosis in MDA-MB-231 cells by increasing the protein expression of LC3-II, p-ULK1, Bax, and Bad, as well as downregulating p-PI3K, p-Akt, p-mTOR, p62, LC3-I, Bcl-2, and Bcl-xl. CLE-10 that was pretreated with 3-methyladenine (3-MA) or chloroquine (CQ) weakened the upregulation of the protein expression of p-ULK1, or the downregulation of p62, p-mTOR, and decreased the level of cytotoxicity against MDA-MB-231 cells. Meanwhile, rapamycin enhanced the effect of CLE-10 on the expression of autophagy-related protein and its cytotoxicity, with the IC50 value of CLE-10 decreasing from 4.07 µM to 2.38 µM. Conclusion: CLE-10 induced pro-death autophagy and apoptosis in MDA-MB-231 cells by upregulating the protein expressions of LC3-II, p-ULK1, Bax, and Bad and downregulating p-PI3K, p-Akt, p-mTOR, p62, Bcl-2, and Bcl-xl.

Hamacanthins, bis (indole) alkaloids, are found in a few marine sponges, including Spongosorites sp. Hamacanthins have been shown to possess cytotoxic, antibacterial and antifungal activities. However, the precise mechanism for the biological activities of hamacanthins has not yet been elucidated. In the present study, the anti-angiogenic effects of 6″-debromohamacanthin A (DBHA), an active component of isolated hamacanthins, were evaluated in cultured human umbilical vascular endothelial cells (HUVEC) and endothelial-like cells differentiated from mouse embryonic stem (mES) cells. DBHA significantly inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation, migration and tube formation in the HUVEC. DBHA also suppressed the capillary-like structure formation and the expression of platelet endothelial cell adhesion molecule (PECAM), an endothelial biomarker, in mES cell-derived endothelial-like cells. To further understand the precise molecular mechanism of action, VEGF-mediated signaling pathways were analyzed in HUVEC cells and mES cell-derived endothelial-like cells. DBHA suppressed the VEGF-induced expression of MAPKs (p38, ERK and SAPK/JNK) and the PI3K/AKT/mTOR signaling pathway. In addition, DBHA inhibited microvessel sprouting in mES/EB-derived embryoid bodies. In an ex vivo model, DBHA also suppressed the microvessel sprouting of mouse aortic rings. The findings suggest for the first time that DBHA inhibits angiogenesis by targeting the vascular endothelial growth factor receptor 2 (VEGFR2)-mediated PI3K/AKT/mTOR signaling pathway in endothelial cells.

ViceninII is a naturally flavonoid glycoside extracted from Dendrobium officinale, a precious Chinese traditional herb, has been proven to be valuable for cancer treatment. Transforming growth factor-β1 (TGF-β1), promotes the induction of epithelial–mesenchymal transition (EMT), a process involved in the metastasis of cells that leads to enhanced migration and invasion. However, there is no previously evidence that ViceninII has an inhibitory effect on cancer metastasis, specifically on the TGF-β1-induced EMT process in lung adenocarcinoma cells. In this experiment, we used UV, ESIMS, and NMR to identify the structure of ViceninII.A549 and H1299 cells were treated with TGF-β1 in the absence and presence of ViceninII, and subsequent migration and invasion were measured by wound-healing and transwell assays. The protein localization and expressions were detected by immunofluorescence and Western blotting. The results indicated that TGF-β1 induced spindle-shaped changes, increased migration and invasion, and upregulated or downregulated the relative expression of EMT biomarkers. Meanwhile, these alterations were significantly inhibited when co-treated with ViceninII and inhibitors LY294002 and SB431542. In conclusion, ViceninII inhibited TGF-β1-induced EMT via the deactivation of TGF-β/Smad and PI3K/Akt/mTOR signaling pathways.This is the first time that the anti-metastatic effects of ViceninII have been demonstrated, and their molecular mechanisms provided.

For the past several decades, cancer patients in the U.S. have chosen the use of natural products as an alternative or complimentary medicine approach to treat or improve their quality of life via reduction or prevention of the side effects during or after cancer treatment. The genus Ganoderma includes about 80 species of mushrooms, of which several have been used for centuries in traditional Asian medicine for their medicinal properties, including anticancer and immunoregulatory effects. Numerous bioactive compounds seem to be responsible for their healing effects. Among the approximately 400 compounds produced by Ganoderma spp., triterpenes, peptidoglycans and polysaccharides are the major physiologically-active constituents. Ganoderma anticancer effects are attributed to its efficacy in reducing cancer cell survival and growth, as well as by its chemosensitizing role. In vitro and in vivo studies have been conducted in various cancer cells and animal models; however, in this review, we focus on Ganoderma’s efficacy on breast cancers. Evidence shows that some species of Ganoderma have great potential as a natural therapeutic for breast cancer. Nevertheless, further studies are needed to investigate their potential in the clinical setting and to translate our basic scientific findings into therapeutic interventions for cancer patients.