Fucus vesiculosus and Ascophyllum nodosum Ameliorate Liver Function by Reducing Diet-Induced Steatosis in Rats.

The Asian coastal communities have used the brown seaweeds Fucus vesiculosus and Ascophyllum nodosum since ancient times. Recently, some in vitro and in vivo studies have demonstrated their abilities in reducing risk factors for metabolic syndrome. Here, we analyzed the protective effect of a phytocomplex extracted from these seaweeds on the deposition of fat in the liver after the administration of a high-fat diet (HFD) to rats for five weeks. The administration of F. vesiculosus and A. nodosum led to significant reductions in microvescicular steatosis and plasma biochemical and lipid parameters, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total and conjugated bilirubin, and triglycerides. Furthermore, the postprandial glycemic peak was delayed and significantly reduced (p < 0.01) by the algal extract administration. In conclusion, this extract is effective in reducing microvescicular steatosis and improving glycemic control, thereby lowering the risk of nonalcoholic fatty liver disease, obesity, and diabetes, diseases related to the consumption of fat and sugar-enriched diets.

Serenoa repens and Urtica dioica Fixed Combination: In-Vitro Validation of a Therapy for Benign Prostatic Hyperplasia (BPH).

Benign prostatic hyperplasia (BPH) is an age-related chronic disorder, characterized by the hyperproliferation of prostatic epithelial and stromal cells, which drives prostate enlargement. Since BPH aetiology and progression have been associated with the persistence of an inflammatory stimulus, induced both by Nuclear Factor-kappa B (NF-κB) activation and reactive oxygen species (ROS) production, the inhibition of these pathways could result in a good tool for its clinical treatment. This study aimed to evaluate the antioxidant and anti-inflammatory activity of a combined formulation of Serenoa repens and Urtica dioica (SR/UD) in an in vitro human model of BPH. The results confirmed both the antioxidant and the anti-inflammatory effects of SR/UD. In fact, SR/UD simultaneously reduced ROS production, NF-κB translocation inside the nucleus, and, consequently, interleukin 6 (IL-6) and interleukin 8 (IL-8) production. Furthermore, the effect of SR/UD was also tested in a human androgen-independent prostate cell model, PC3. SR/UD did not show any significant antioxidant and anti-inflammatory effect, but was able to reduce NF-κB translocation. Taken together, these results suggested a promising role of SR/UD in BPH and BPH-linked disorder prevention.

Adipocyte Precursor-Derived NRG1 Promotes Resistance to FGFR Inhibition in Urothelial Carcinoma.

Aberrations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic urothelial cancer (mUC), and blocking the FGF/FGFR signaling axis is used as a targeted therapeutic strategy for treating patients. Erdafitinib is a pan-FGFR inhibitor, which has recently been approved by the FDA for mUC with FGFR2/3 alterations. Although mUC patients show initial response to erdafitinib, acquired resistance rapidly develops. Here, we found that adipocyte precursors promoted resistance to erdafitinib in FGFR-dependent bladder and lung cancer in a paracrine manner. Moreover, neuregulin 1 (NRG1) secreted from adipocyte precursors was a mediator of erdafitinib resistance by activating human epidermal growth factor receptor 3 (ERBB3; also known as HER3) signaling, and knockdown of NRG1 in adipocyte precursors abrogated the conferred paracrine resistance. NRG1 expression was significantly downregulated in terminally differentiated adipocytes compared with their progenitors. Pharmacologic inhibition of the NRG1/HER3 axis using pertuzumab reversed erdafitinib resistance in tumor cells in vitro and prolonged survival of mice bearing bladder cancer xenografts in vivo. Remarkably, data from single-cell RNA sequencing revealed that NRG1 was enriched in platelet-derived growth factor receptor-A (PDGFRA) expressing inflammatory cancer-associated fibroblasts, which is also expressed on adipocyte precursors. Together, this work reveals a paracrine mechanism of anti-FGFR resistance in bladder cancer, and potentially other cancers, that is amenable to inhibition using available targeted therapies. SIGNIFICANCE: Acquired resistance to FGFR inhibition can be rapidly promoted by paracrine activation of the NRG1/HER3 axis mediated by adipocyte precursors and can be overcome by the combination of pertuzumab and erdafitinib treatment. See related commentary by Kolonin and Anastassiou, p. 648.

Targeting senescence induced by age or chemotherapy with a polyphenol-rich natural extract improves longevity and healthspan in mice.

Accumulating senescent cells within tissues contribute to the progression of aging and age-related diseases. Botanical extracts, rich in phytoconstituents, present a useful resource for discovering therapies that could target senescence and thus improve healthspan. Here, we show that daily oral administration of a standardized extract of Salvia haenkei (Haenkenium (HK)) extended lifespan and healthspan of naturally aged mice. HK treatment inhibited age-induced inflammation, fibrosis and senescence markers across several tissues, as well as increased muscle strength and fur thickness compared with age-matched controls. We also found that HK treatment reduced acutely induced senescence by the chemotherapeutic agent doxorubicin, using p16LUC reporter mice. We profiled the constituent components of HK by mass spectrometry, and identified luteolin-the most concentrated flavonoid in HK-as a senomorphic compound. Mechanistically, by performing surface plasmon resonance and in situ proximity ligation assay, we found that luteolin disrupted the p16-CDK6 interaction. This work demonstrates that administration of HK promotes longevity in mice, possibly by modulating cellular senescence and by disrupting the p16-CDK6 interaction.

Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells.

Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones. Here, we identify the retinoic-acid-receptor (RAR) agonist adapalene as an effective pro-senescence compound in prostate cancer (PCa). Reactivation of RARs triggers a robust senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of adapalene and docetaxel promotes a tumor-suppressive SASP that enhances natural killer (NK) cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of the allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in "immunologically cold" tumors.

CDCP1 expression is frequently increased in aggressive urothelial carcinoma and promotes urothelial tumor progression.

The prognosis of patients with advanced urothelial carcinoma (UC) remains poor and improving treatment continues to be a major medical need. CUB domain containing protein 1 (CDCP1) is a known oncogene in various types of solid cancers and its overexpression is associated with impaired prognosis. However, its role in UC remains undetermined. Here we assessed the clinical relevance of CDCP1 in two cohorts of UC at different stages of the disease. Immunohistochemistry showed that CDCP1 is highly expressed in advanced UC, which significantly correlates with shorter overall survival. Importantly, the basal/squamous UC subtype showed significantly enriched CDCP1 at the mRNA and protein levels. The functional role of CDCP1 overexpression was assessed taking advantage of ex vivo organoids derived from the CDCP1pcLSL/+ transgenic mouse model. Furthermore, CDCP1 knockout UC cell lines were generated using CRISPR/Cas9 technology. Interestingly, CDCP1 overexpression significantly induced the activation of MAPK/ERK pathways in ex vivo organoids and increased their proliferation. Similarly, CDCP1 knockout in UC cell lines reduced their proliferation and migration, concomitant with MAPK/ERK pathway activity reduction. Our results highlight the relevance of CDCP1 in advanced UC and demonstrate its oncogenic role, suggesting that targeting CDCP1 could be a rational therapeutic strategy for the treatment of advanced UC.

Further assessment of Salvia haenkei as an innovative strategy to counteract skin photo-aging and restore the barrier integrity.

Skin is the essential barrier of the human body which performs multiple functions. Endogenous factors, in concert with external assaults, continuously affect skin integrity, leading to distinct structural changes that influence not only the skin appearance but also its various physiological functions. Alterations of the barrier functions lead to an increased risk of developing disease and side reactions, thus the importance of maintaining the integrity of the epidermal barrier and slowing down the skin aging process is evident. Salvia haenkei (SH) has been recently identified as a potential anti-senescence agent; its extract is able to decrease the level of senescent cells by affecting the IL1α release and reducing reactive oxygen species (ROS) generation. In this study, SH extract was tested on human keratinocyte cell line (HaCaT) exposed to stress factors related to premature aging of cells such as free radicals and ultraviolet B radiation. We confirmed that SH acts as scavenger of ROS and found its ability to restore the skin barrier integrity by reinforcing the cytoskeleton structure, sealing the tight junctions and increasing the migration rate of cells. Given these results, this work becomes relevant, identifying Salvia haenkei as a compound useful for anti-aging skin treatment in clinical performance.