The HSP90 inhibitor HVH-2930 exhibits potent efficacy against trastuzumab-resistant HER2-positive breast cancer.

Rationale: Resistance to targeted therapies like trastuzumab remains a critical challenge for HER2-positive breast cancer patients. Despite the progress of several N-terminal HSP90 inhibitors in clinical trials, none have achieved approval for clinical use, primarily due to issues such as induction of the heat shock response (HSR), off-target effects, and unfavorable toxicity profiles. We sought to examine the effects of HVH-2930, a novel C-terminal HSP90 inhibitor, in overcoming trastuzumab resistance. Methods: The effect of HVH-2930 on trastuzumab-sensitive and -resistant cell lines in vitro was evaluated in terms of cell viability, expression of HSP90 client proteins, and impact on cancer stem cells. An in vivo model with trastuzumab-resistant JIMT-1 cells was used to examine the efficacy and toxicity of HVH-2930. Results: HVH-2930 was rationally designed to fit into the ATP-binding pocket interface cavity of the hHSP90 homodimer in the C-terminal domain of HSP90, stabilizing its open conformation and hindering ATP binding. HVH-2930 induces apoptosis without inducing the HSR but by specifically suppressing the HER2 signaling pathway. This occurs with the downregulation of HER2/p95HER2 and disruption of HER2 family member heterodimerization. Attenuation of cancer stem cell (CSC)-like properties was associated with the downregulation of stemness factors such as ALDH1, CD44, Nanog and Oct4. Furthermore, HVH-2930 administration inhibited angiogenesis and tumor growth in trastuzumab-resistant xenograft mice. A synergistic effect was observed when combining HVH-2930 and paclitaxel in JIMT-1 xenografts. Conclusion: Our findings highlight the potent efficacy of HVH-2930 in overcoming trastuzumab resistance in HER2-positive breast cancer. Further investigation is warranted to fully establish its therapeutic potential.

Evaluation of efficacy of Silybum marianum flower extract on the mitigating hair loss in vitro and in vivo.

BACKGROUND: Natural components that can exert a wide range of anti-hair loss activity with fewer side effects are in high demand. The objective of this study was to investigate the anti-hair loss potential of Silybum marianum flower extract (SMFE) in vitro and in vivo. METHODS: The effect of SMFE on dermal papilla cells was evaluated by measuring cell proliferation and VEGF production in hair follicle dermal papilla cells (HFDPCs). In addition, to confirm the effect of SMFE on dermal papilla senescence, SA-ß-gal staining and senescence associated secretory phenotype (SASP) production such as IL-6 was observed in both replicative and hydrogen peroxide (H2 O2 )-induced senescence models. In a clinical study, hair growth was determined by reconstitution analysis after shaving the hair of the clinical subject's scalp and hair area. RESULTS: SMFE increased the proliferation and VEGF production of HFDPCs. It also suppressed cellular senescence of HFDPCs and IL-6 production in replicative senescence and oxidative stress-induced senescence models. The hair density and total hair count at 16 and 24 weeks after using hair shampoo containing SMFE were significantly increased compared with those of the placebo group. CONCLUSION: SMFE has the potential to be used as a natural ingredient for alleviating hair loss.

Fermented black ginseng extract prevents UVB-induced inflammation by regulating the nc886-PKR pathway in human keratinocytes.

BACKGROUND: Continuous exposure of the skin to ultraviolet B (UVB) rays can cause inflammation and photodamage. In previous studies, we observed that the upregulation of nc886, a noncoding RNA (ncRNA), can alleviate UVB-induced inflammation through suppression of the protein kinase RNA (PKR) pathway. We aim to investigate the effect of fermented black ginseng extract (FBGE), which has been shown to increase the expression of nc886, on UVB-induced inflammation in keratinocytes. METHODS: To confirm the cytotoxicity of FBGE, MTT assay was performed, and no significant cytotoxicity was found on human keratinocytes. The efficacies of FBGE were assessed through qPCR, Western blotting, and ELISA analysis which confirmed regulation of UVB-induced inflammation. RESULTS: The analysis results showed that FBGE inhibited the decrease in nc886 expression and the increase in the methylated nc886 caused by UVB. It also prevented the UVB-induced increase of metalloproteinase-9 (MMP-9), metalloproteinase-1 (MMP-1), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α). Additionally, FBGE suppressed the PKR-MAPK pathways activated by UVB. CONCLUSION: These results implicate that FBGE can alleviate UVB-induced inflammation through regulation of the nc886-PKR pathway.

Suppression of TNBC metastasis by doxazosin, a novel dual inhibitor of c-MET/EGFR.

BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by aggressive growth and a high propensity for recurrence and metastasis. Simultaneous overexpression of c-MET and EGFR in TNBC is associated with worse clinicopathological features and unfavorable outcomes. Although the development of new c-MET inhibitors and the emergence of 3rd-generation EGFR inhibitors represent promising treatment options, the high costs involved limit the accessibility of these drugs. In the present study, we sought to investigate the therapeutic potential of doxazosin (DOXA), a generic drug for benign prostate hyperplasia, in targeting TNBC. METHODS: The effect of DOXA on TNBC cell lines in vitro was evaluated in terms of cell viability, apoptosis, c-MET/EGFR signaling pathway, molecular docking studies and impact on cancer stem cell (CSC)-like properties. An in vivo metastatic model with CSCs was used to evaluate the efficacy of DOXA. RESULTS: DOXA exhibits notable anti-proliferative effects on TNBC cells by inducing apoptosis via caspase activation. Molecular docking studies revealed the direct interaction of DOXA with the tyrosine kinase domains of c-MET and EGFR. Consequently, DOXA disrupts important survival pathways including AKT, MEK/ERK, and JAK/STAT3, while suppressing CSC-like characteristics including CD44high/CD24low subpopulations, aldehyde dehydrogenase 1 (ALDH1) activity and formation of mammospheres. DOXA administration was found to suppress tumor growth, intra- and peri-tumoral angiogenesis and distant metastasis in an orthotopic allograft model with CSC-enriched populations. Furthermore, no toxic effects of DOXA were observed in hepatic or renal function. CONCLUSIONS: Our findings highlight the potential of DOXA as a therapeutic option for metastatic TNBC, warranting further investigation.

Albizia julibrissin Exerts Anti-Obesity Effects by Inducing the Browning of 3T3L1 White Adipocytes.

This study investigated the effects of the Albizia julibrissin Leaf extracts (AJLE) on adipocytes using 3T3-L1 cells. AJLE inhibited adipogenesis by reducing the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding proteins (C/EBPs) that regulate enzymes involved in fat synthesis and storage, and subsequently reduced intracellular lipid droplets, glycerol-3-phosphate dehydrogenase (GPDH), and triglyceride (TG). AJLE also increased the expression of brown adipocyte markers, such as uncoupling protein-1 (UCP-1), PR/SET domain 16 (PRDM16), and bone morphogenetic protein 7 (BMP7) by inducing the differentiation of brown adipocytes, as shown by a decrease in the lipid droplet sizes and increasing mitochondrial mass. AJLE increased the expression of transcription factor A, mitochondrial (TFAM), mitochondrial DNA (mtDNA) copy number, and UCP-1 protein expression, all of which are key factors in regulating mitochondrial biogenesis. AJLE-induced browning was shown to be regulated by the coordination of AMPK, p38, and SIRT1 signaling pathways. The ability of AJLE to inhibit adipogenesis and induce brown adipocyte differentiation may help treat obesity and related diseases.

Ebastine impairs metastatic spread in triple-negative breast cancer by targeting focal adhesion kinase.

We sought to investigate the utility of ebastine (EBA), a second-generation antihistamine with potent anti-metastatic properties, in the context of breast cancer stem cell (BCSC)-suppression in triple-negative breast cancer (TNBC). EBA binds to the tyrosine kinase domain of focal adhesion kinase (FAK), blocking phosphorylation at the Y397 and Y576/577 residues. FAK-mediated JAK2/STAT3 and MEK/ERK signaling was attenuated after EBA challenge in vitro and in vivo. EBA treatment induced apoptosis and a sharp decline in the expression of the BCSC markers ALDH1, CD44 and CD49f, suggesting that EBA targets BCSC-like cell populations while reducing tumor bulk. EBA administration significantly impeded BCSC-enriched tumor burden, angiogenesis and distant metastasis while reducing MMP-2/-9 levels in circulating blood in vivo. Our findings suggest that EBA may represent an effective therapeutic for the simultaneous targeting of JAK2/STAT3 and MEK/ERK for the treatment of molecularly heterogeneous TNBC with divergent profiles. Further investigation of EBA as an anti-metastatic agent for the treatment of TNBC is warranted.

The effect of Salix alba L. bark extract on dark circles in vitro and in vivo.

OBJECTIVE: Dark circles in the infraorbital area are a common cosmetic concern among individuals because they exhibit fatigue and are undesirable across all ages. Of the dark circle etiologies, blood stasis by poor-vascular integrity can cause darkening of the lower eyelid skin, which might be alleviated by reduced endothelial permeability. In this study, we investigated the effects of Salix alba bark extract (SABE) on the synthesis of hyaluronic acid (HA) in fibroblasts and vascular integrity protection from inflammatory cytokine. We also performed a clinical trial investigating the effect of SABE on dark circles. METHODS: To confirm the effect of SABE on HA synthesis in human dermal fibroblasts (HDFs), we performed ELISA and real-time PCR. We investigated the interaction HDF-secreted substance with vascular integrity, and human dermal microvascular endothelial cells (HMEC-1) were treated with conditioned medium (CM) from HDF treated with or without SABE. Subsequently, we conducted a clinical study on 29 subjects by having them apply SABE containing cream for 8 weeks. RESULTS: Salix alba bark extract treatment increased HA synthesis and regulated HMW-HA-related gene expressions in HDF. CM from SABE-treated HDF alleviated endothelial permeability and led to improved vascular integrity in HMEC-1 cells. Treatment with the cream containing 2% SABE for 8 weeks improved the parameters measuring dark circles, skin microcirculation and elasticity. CONCLUSION: Our results showed that SABE could protect against dark circles in vitro, and that topical treatment of SABE improved the clinical indexes of dark circles in a clinical study. Therefore, SABE can be used as an active ingredient for improving dark circles.

OBJECTIF: Les cernes dans la région infra-orbitaire sont un problème cosmétique fréquent chez les patients, car elles témoignent de la fatigue et sont indésirables à tout âge. Parmi les étiologies de cerne, la stase sanguine due à une mauvaise intégrité vasculaire peut entraîner un assombrissement de la peau de la paupière inférieure qui peut être atténué par une réduction de la perméabilité endothéliale. Dans cette étude, nous avons étudié les effets de l'extrait d'écorce de Salix alba sur la synthèse de l'acide hyaluronique (AH) dans les fibroblastes, et la protection de l'intégrité vasculaire contre les cytokines inflammatoires. Nous avons également réalisé une étude clinique portant sur l'effet de l'extrait d'écorce de Salix alba sur les cernes. MÉTHODES: Pour confirmer l'effet de l'extrait d'écorce de Salix alba sur la synthèse de l'AH dans les fibroblastes dermiques humains (Human Dermal Fibroblasts, HDF), nous avons réalisé un test ELISA et un test PCR en temps réel. Nous avons étudié l'interaction entre la substance sécrétée par les HDF et l'intégrité vasculaire, et les cellules endothéliales microvasculaires dermiques humaines (Human Dermal Microvascular Endothelial Cells, HDMEC-1) ont été traitées avec un milieu conditionné pour les HDF traité avec ou sans extrait d'écorce de Salix alba. Par la suite, nous avons mené une étude clinique auprès de 29 sujets en leur demandant d'appliquer une crème à base d'extrait d'écorce de Salix alba pendant 8 semaines. RÉSULTATS: Le traitement par extrait d'écorce de Salix alba a augmenté la synthèse de l'AH et régulé les expressions géniques liées à l'acide hyaluronique à haut poids moléculaire dans les HDF. Les milieux conditionnés pour les HDF traités par extrait d'écorce de Salix alba ont atténué la perméabilité endothéliale et ont permis une amélioration de l'intégrité vasculaire des cellules HMEC-1. Le traitement avec la crème contenant 2% d'extrait d'écorce de Salix alba pendant 8 semaines a amélioré les paramètres de mesure des cernes, la microcirculation cutanée et l'élasticité. CONCLUSION: Nos résultats ont montré que l'extrait d'écorce de Salix alba pouvait protéger contre les cernes in vitro, et que le traitement topique par extrait d'écorce de Salix alba améliorait les indices cliniques des cernes dans une étude clinique. L'extrait d'écorce de Salix alba peut donc être utilisé comme principe actif pour améliorer les cernes.

A dual-action niclosamide-based prodrug that targets cancer stem cells and inhibits TNBC metastasis.

Chemotherapy typically destroys the tumor mass but rarely eradicates the cancer stem cells (CSCs) that can drive metastatic recurrence. A key current challenge is finding ways to eradicate CSCs and suppress their characteristics. Here, we report a prodrug, Nic-A, created by combining a carbonic anhydrase IX (CAIX) inhibitor, acetazolamide, with a signal transducer and transcriptional activator 3 (STAT3) inhibitor, niclosamide. Nic-A was designed to target triple-negative breast cancer (TNBC) CSCs and was found to inhibit both proliferating TNBC cells and CSCs via STAT3 dysregulation and suppression of CSC-like properties. Its use leads to a decrease in aldehyde dehydrogenase 1 activity, CD44high/CD24low stem-like subpopulations, and tumor spheroid-forming ability. TNBC xenograft tumors treated with Nic-A exhibited decreased angiogenesis and tumor growth, as well as decreased Ki-67 expression and increased apoptosis. In addition, distant metastases were suppressed in TNBC allografts derived from a CSC-enriched population. This study thus highlights a potential strategy for addressing CSC-based cancer recurrence.

Epigenetic regulation of SMAD3 by histone methyltransferase SMYD2 promotes lung cancer metastasis.

Epigenetic alterations, especially histone methylation, are key factors in cell migration and invasion in cancer metastasis. However, in lung cancer metastasis, the mechanism by which histone methylation regulates metastasis has not been fully elucidated. Here, we found that the histone methyltransferase SMYD2 is overexpressed in lung cancer and that knockdown of SMYD2 could reduce the rates of cell migration and invasion in lung cancer cell lines via direct downregulation of SMAD3 via SMYD2-mediated epigenetic regulation. Furthermore, using an in vitro epithelial-mesenchymal transition (EMT) system with a Transwell system, we generated highly invasive H1299 (In-H1299) cell lines and observed the suppression of metastatic features by SMYD2 knockdown. Finally, two types of in vivo studies revealed that the formation of metastatic tumors by shSMYD2 was significantly suppressed. Thus, we suggest that SMYD2 is a potential metastasis regulator and that the development of SMYD2-specific inhibitors may help to increase the efficacy of lung cancer treatment.

Tcf7l2 in hepatocytes regulates de novo lipogenesis in diet-induced non-alcoholic fatty liver disease in mice.

AIMS/HYPOTHESIS: Non-alcoholic fatty liver disease (NAFLD) associated with type 2 diabetes may more easily progress towards severe forms of non-alcoholic steatohepatitis (NASH) and cirrhosis. Although the Wnt effector transcription factor 7-like 2 (TCF7L2) is closely associated with type 2 diabetes risk, the role of TCF7L2 in NAFLD development remains unclear. Here, we investigated how changes in TCF7L2 expression in the liver affects hepatic lipid metabolism based on the major risk factors of NAFLD development. METHODS: Tcf7l2 was selectively ablated in the liver of C57BL/6N mice by inducing the albumin (Alb) promoter to recombine Tcf7l2 alleles floxed at exon 5 (liver-specific Tcf7l2-knockout [KO] mice: Alb-Cre;Tcf7l2f/f). Alb-Cre;Tcf7l2f/f and their wild-type (Tcf7l2f/f) littermates were fed a high-fat diet (HFD) or a high-carbohydrate diet (HCD) for 22 weeks to reproduce NAFLD/NASH. Mice were refed a standard chow diet or an HCD to stimulate de novo lipogenesis (DNL) or fed an HFD to provide exogenous fatty acids. We analysed glucose and insulin sensitivity, metabolic respiration, mRNA expression profiles, hepatic triglyceride (TG), hepatic DNL, selected hepatic metabolites, selected plasma metabolites and liver histology. RESULTS: Alb-Cre;Tcf7l2f/f essentially exhibited increased lipogenic genes, but there were no changes in hepatic lipid content in mice fed a normal chow diet. However, following 22 weeks of diet-induced NAFLD/NASH conditions, liver steatosis was exacerbated owing to preferential metabolism of carbohydrate over fat. Indeed, hepatic Tcf7l2 deficiency enhanced liver lipid content in a manner that was dependent on the duration and amount of exposure to carbohydrates, owing to cell-autonomous increases in hepatic DNL. Mechanistically, TCF7L2 regulated the transcriptional activity of Mlxipl (also known as ChREBP) by modulating O-GlcNAcylation and protein content of carbohydrate response element binding protein (ChREBP), and targeted Srebf1 (also called SREBP1) via miRNA (miR)-33-5p in hepatocytes. Eventually, restoring TCF7L2 expression at the physiological level in the liver of Alb-Cre;Tcf7l2f/f mice alleviated liver steatosis without altering body composition under both acute and chronic HCD conditions. CONCLUSIONS/INTERPRETATION: In mice, loss of hepatic Tcf7l2 contributes to liver steatosis by inducing preferential metabolism of carbohydrates via DNL activation. Therefore, TCF7L2 could be a promising regulator of the NAFLD associated with high-carbohydrate diets and diabetes since TCF7L2 deficiency may lead to development of NAFLD by promoting utilisation of excess glucose pools through activating DNL. DATA AVAILABILITY: RNA-sequencing data have been deposited into the NCBI GEO under the accession number GSE162449 ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162449 ).

Assessment of the anti-hair loss potential of Camellia japonica fruit shell extract in vitro.

OBJECTIVE: Hair loss is caused by various factors. Impacts of these factors are often overlapped and intensified. Currently, mitigation of hair loss is being studied by proliferating dermal papilla cells (DPCs) and inhibiting deleterious factors such as dihydrotestosterone (DHT) and oxidative stress on hair growth. Camellia japonica (C. japonica) fruit shell is a discarded part. Its biological activity remains to be elucidated. In this study, we investigated the capacity of C. japonica fruit shell extract (CJFSE) for hair loss mitigation. METHODS: MTT assay, spheroid culture and quantitative RT-PCR were performed to observe the proliferative effect of CJFSE on hair follicle dermal papilla cells (HFDPCs). Effects of CJFSE on DHT-induced hair loss were confirmed by Dkk-1 ELISA, ß-galactosidase (ß-gal) and 5α-reductase activity assay. In addition, effects of CJFSE on oxidative stress were confirmed through DPPH and ROS production assays. RESULTS: CJFSE increased the proliferation and spheroid size of HFDPCs. Expression levels of VEGF-A, Wnt-1, c-Myc and Cyclin D1 were upregulated by CJFSE. CJFSE also suppressed 5α-reductase activity and DHT-induced decrease in cell proliferation, Dkk-1 secretion and ß-gal activity. Moreover, CJFSE showed DPPH scavenging activity and ameliorated hydrogen peroxide-induced ROS production and ß-gal activity. Finally, gallic acid and protocatechuic acid were observed in CJFSE through HPLC analysis. CONCLUSION: CJFSE has the potential to alleviate hair loss by promoting hair cell growth and suppressing effects of DHT and oxidative stress on hair.

OBJECTIF: Divers facteurs sont responsables de la perte de cheveux. Souvent, les conséquences de ces facteurs se superposent et s'intensifient. Actuellement, on étudie comment atténuer la perte de cheveux en faisant proliférer les cellules de la papille dermique (DPC) et en inhibant les facteurs délétères tels que la dihydrotestostérone (DHT) et le stress oxydatif sur la croissance des cheveux. La coque du fruit du Camélia du Japon (Camelia japonica) est habituellement rejetée. Son utilité biologique reste à élucider. Dans cette étude, nous avons étudié la capacité de l'extrait de la coque du fruit du Camélia du Japon (CJFSE) dans la mitigation de la perte de cheveux. MÉTHODES: Un test MTT, une culture de sphéroïdes et une RT-PCR Quantitative ont été effectués pour observer la prolifération de CJFSE sur les cellules de la papille dermique du follicule pileux (HFDPC). Les effets du CJFSE sur la perte de cheveux induite par la DHT ont été confirmés par Dkk-1 ELISA, ß-galactosidase (ß-gal) et 5α-réductase. De plus, les effets du CJFSE sur le stress oxydatif ont été confirmés par des tests de production de DPPH et de ROS. RÉSULTATS: Le CJFSE a augmenté la prolifération et la taille sphéroïde des HFDPC. Les niveaux d'expression de VEGF-A, Wnt-1, c-Myc et cycline D1 ont été régulés de manière efficace par le CJFSE. Le CJFSE a également supprimé l'activité de la 5α-réductase et a induit la réduction de la DHT et de la prolifération cellulaire, ainsi que de la sécrétion de Dkk-1 et de l'activité ß-gal. Le CJFSE a en outre montré une activité de capture du DPPH et amélioré la production de ROS induite par le peroxyde d'hydrogène et l'activité ß-gal. Pour finir, les acides gallique et protocatéchuique ont été observés dans le CJFSE après analyse des HPLC. CONCLUSION: Le CJFSE a le potentiel d'atténuer la perte de cheveux en favorisant la croissance des cellules ciliées et en supprimant les effets de la DHT et du stress oxydatif sur les cheveux.

The EDN1/EDNRA/ß­arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation.

Endothelin receptor A (EDNRA) has been reported to play various crucial physiological roles and has been shown to be associated with the pathology of several diseases, including colorectal cancer (CRC). However, the molecular mechanisms of EDNRA in the development of human CRC have not been fully elucidated to date. In this context, the present study was performed to investigate biological functions and novel downstream signaling pathways affected by EDNRA, during CRC progression. First, using public data repositories, it was observed that the EDRNA expression levels were markedly increased in CRC tissues, as compared to normal tissues. Patients with CRC with an increased EDNRA expression exhibited a significantly decreased survival rate in comparison with those with a lower EDNRA expression. Furthermore, a positive correlation between the levels of EDNRA and its ligand, EDN1, was found in CRC tissues. The ectopic expression of EDNRA or its ligand, EDN1, promoted, whereas the silencing of EDNRA or EDN1 decreased cell proliferation and migration in vitro. To elucidate the signaling pathways involved in the regulation of EDNRA expression in CRC cells, a phosphokinase array analysis was performed, and it was observed that the knockdown of EDNRA substantially suppressed the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in CRC cells. Of note, STAT3 silencing simultaneously decreased EDN1 and EDNRA expression, with the expression of EDN1 and/or EDNRA appearing to be directly regulated by binding STAT3 to their promoter region, according to chromatin immunoprecipitation and promoter assays, ultimately indicating a positive feedback loop in the expression of EDNRA and EDN1. It was also observed that treatment with an EDNRA antagonist (macitentan), alone or in combination with cisplatin, suppressed cell growth and migration ability, and induced cell apoptosis. Collectively, these data suggest a critical role of the EDN1/EDNRA signaling pathway in CRC progression. Thus, the pharmacological intervention of this signaling pathway may prove to be a potential therapeutic approach for patients with CRC.

A synchronized dual drug delivery molecule targeting cancer stem cells in tumor heterogeneity and metastasis.

Cancer stem-like cells (CSCs) represent a key barrier to successful therapy for triple-negative breast cancer (TNBC). CSCs promote the emergence of chemoresistance, triggering relapse and resulting in a poor prognosis. We herein present CDF-TM, a new small molecule-based binary prodrug conjugated with SN-38 and 3,4-difluorobenzylidene curcumin (CDF) that is specifically activated in hypoxic conditions. CDF-TM treatment significantly induced apoptosis in TNBC-derived 3D spheroids, accompanied with caspase-3 activation as well as the attenuation of tumor stemness with evidence of reduction in aldehyde dehydrogenase 1 (ALDH1) activity and the CD44high/CD24low phenotype. An in vivo orthotopic allograft model was used to investigate its effects on tumor growth and metastasis. The dissemination of CSCs from primary allografts was impaired by CDF-TM, along with inhibition of tumor growth via eradication of CSCs and downregulation of multidrug resistance 1 (MDR1). This new small molecule-based binary prodrug offers a novel therapeutic option for metastatic TNBC.

ß-Escin overcomes trastuzumab resistance in HER2-positive breast cancer by targeting cancer stem-like features.

BACKGROUND: The emergence of de novo or intrinsic trastuzumab resistance is exceedingly high in breast cancer that is HER2 positive and correlates with an abundant cancer stem cell (CSC)-like population. We sought to examine the capacity of ß-escin, an anti-inflammatory drug, to address trastuzumab resistance in HER2-positive breast cancer cells. METHODS: The effect of ß-escin on trastuzumab-resistant and -sensitive cell lines in vitro was evaluated for apoptosis, expression of HER2 family members, and impact on CSC-like properties. An in vivo model of trastuzumab-resistant JIMT-1 was used to examine the efficacy and toxicity of ß-escin. RESULTS: ß-escin induced mitochondrial-mediated apoptosis accompanied by reactive oxygen species (ROS) production and increased active p18Bax fragmentation, leading to caspase-3/-7 activation. Attenuation of CSC-related features by ß-escin challenge was accompanied by marked reductions in CD44high/CD24low stem-like cells and aldehyde dehydrogenase 1 (ALDH1) activity as well as hindrance of mammosphere formation. ß-escin administration also significantly retarded tumor growth and angiogenesis in a trastuzumab-resistant JIMT-1 xenograft model via downregulation of CSC-associated markers and intracellular domain HER2. Importantly, ß-escin selectively inhibited malignant cells and was less toxic to normal mammary cells, and no toxic effects were found in liver and kidney function in animals. CONCLUSIONS: Taken together, our findings highlight ß-escin as a promising candidate for the treatment of trastuzumab-resistant HER2-positive breast cancers.

A novel HSP90 inhibitor SL-145 suppresses metastatic triple-negative breast cancer without triggering the heat shock response.

Despite recent advances, there remains a significant unmet need for the development of new targeted therapies for triple-negative breast cancer (TNBC). Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction of the heat shock response (HSR) and off-target effects leading to toxicity. SL-145 is a novel, rationally-designed C-terminal HSP90 inhibitor that induces apoptosis in TNBC cells via the suppression of oncogenic AKT, MEK/ERK, and JAK2/STAT3 signaling and does not trigger the HSR, in contrast to other inhibitors. In an orthotopic allograft model incorporating breast cancer stem cell-enriched TNBC tumors, SL-145 potently suppressed tumor growth, angiogenesis, and metastases concomitant with dysregulation of the JAK2/STAT3 signaling pathway. Our findings highlight the potential of SL-145 in suppressing metastatic TNBC independent of the HSR.

Isatis tinctoria L. Leaf Extract Inhibits Replicative Senescence in Dermal Fibroblasts by Regulating mTOR-NF-κB-SASP Signaling.

Senescent fibroblasts progressively deteriorate the functional properties of skin tissue. Senescent cells secrete senescence-associated secretory phenotype (SASP) factor, which causes the aging of surrounding non-senescent cells and accelerates aging in the individuals. Recent findings suggested the senomorphic targeting of the SASP regulation as a new generation of effective therapeutics. We investigated whether Isatis tinctoria L. leaf extract (ITE) inhibited senescence biomarkers p53, p21CDKN1A, and p16INK4A gene expression, and SASP secretions by inhibiting cellular senescence in the replicative senescent human dermal fibroblast (RS-HDF). ITE has been demonstrated to inhibit the secretion of SASP factors in several senomorphic types by regulating the MAPK/NF-κB pathway via its inhibitory effect on mTOR. ITE suppressed the inflammatory response by inhibiting mTOR, MAPK, and IκBα phosphorylation, and blocking the nuclear translocation of NF-κB. In addition, we observed that autophagy pathway was related to inhibitory effect of ITE on cellular senescence. From these results, we concluded that ITE can prevent and restore senescence by blocking the activation and secretion of senescence-related factors generated from RS-HDFs through mTOR-NF-κB regulation.

Immune-enhancing effect of water-soluble beta-glucan derived from enzymatic hydrolysis of yeast glucan.

Immunostimulants play an important role in the treatment of immunodeficiency. Macrophages are the first line in our immune defense system and play a critical role in the immune response. Therefore, finding new and better substances to induce an immune response by activating macrophages is an attractive research topic, especially in the fields of immunopharmacology and cancer prevention. Keratinocytes actively crosstalk with immune cells during wound repair, so enhancing the function of keratinocytes is also an important part of improving immunity. Beta-glucans are naturally occurring polysaccharides, consisting of d-glucose monomers linked by beta-glycosidic bonds. Several studies have investigated the immunomodulatory effects of beta-glucan, such as its anti-inflammatory and antibacterial properties. However, the use of yeast cell wall glucan has been limited because it is not soluble in water. In this study, we produced low-molecular-weight water-soluble yeast glucan (WSY glucan) and confirmed various aspects of its immune-enhancing effect. The structure of the beta-(1→3) and (1→6) bonds of WSY glucan were confirmed by nuclear magnetic resonance spectroscopy (1H-NMR) analysis. Our results showed that treatment with WSY glucan significantly and dose-dependently induced the production of inflammatory mediators (prostaglandin E2 (PGE2) and nitric oxide (NO)) and pro-inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-6) in macrophages. In addition, WSY glucan treatment showed changes in the morphological structure of the macrophages and promoted phagocytic activity of the macrophages and wound healing in keratinocytes. Based on these results, WSY glucan is considered as a potential candidate for the treatment of diseases related to the weakening of the immune system without the limitation of insolubility.

Effect of Cirsium japonicum Flower Extract on Skin Aging Induced by Glycation.

Advanced glycation end products (AGEs) have recently been increasingly discussed as one factor of skin aging. In this study, we investigated the effects of Cirsium japonicum flower (CFE) extract on glycation in relation to skin aging and skin elasticity. Moreover, we learned the main active constituent of CFE that has effects against glycation. To demonstrate the effects of CFE on glycation, we carried out an in vitro glycation study, 3-dimensional culture, and clinical study. As a result, CFE inhibited formation of AGEs in both bovine serum albumin (BSA)/glucose glycation system and aldehyde-derived glycation system. Moreover, CFE reduced Nε-(carboxymethyl), lysine (CML), and carbonylated proteins that increased by glycation. Furthermore, CFE broke crosslinks of collagen-AGEs and inhibited the increase of matrix metalloproteinase-1 (MMP-1) gene expression by AGEs. In the 3D culture condition, CFE restored the reduction of collagen gel contraction by glycation. Moreover, apigenin was detected as the main active constituent in CFE that has anti-glycation effects. In the clinical study, we confirmed that CFE has effects on skin wrinkles and skin elasticity. Our findings suggest that CFE can be used as a cosmetic or cosmeceutical ingredient for improving skin elasticity and wrinkles. Regulation of AGEs can be an interesting target for anti-aging.

The Alleviating Effect of Lagerstroemia indica Flower Extract on Stretch Marks through Regulation of Mast Cells.

Striae distensae (SD) or stretch marks are common linear scars of atrophic skin with disintegrating extracellular matrix (ECM) structures. Although fibroblasts contribute to the construction of ECM structure in SD, some studies have reported that mast cell degranulation causes the disruption of ECM in early SD lesions. Lagerstroemia indica flower (LIF) has traditionally been used in India as a diuretic. However, little is known about the effect and molecular action of Lagerstroemia indica flower extract (LIFE) on alleviating SD. This study evaluated the effects of LIFE on mast cell degranulation and the synthesis of ECM components in fibroblasts. LIFE inhibits the adhesion of rat basophilic leukemia (RBL) cells, RBL-2H3 on fibronectin (FN) and the expression of integrin, a receptor for FN, thereby reducing focal adhesion kinase (FAK) phosphorylation. In addition, LIFE attenuated the allergen-induced granules and cytokine interleukin 3 (IL-3) through the adhesion with FN. Moreover, the conditioned medium (CM) of activated mast cells decreases the synthesis of ECM components, and LIFE restores the abnormal expressions induced by activated mast cells. These results demonstrate that LIFE suppresses FN-induced mast cell activation and promotes the synthesis of ECM components in fibroblast, which indicates that LIFE may be a useful cosmetic agent for SD treatment.