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Decreased expression of mitochondrial frataxin (FXN) causes Friedreich’s ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.

Premature ovarian failure and female infertility are frequent side effects of anticancer therapies, owing to the extreme sensitivity of the ovarian reserve oocytes to the damaging effects of irradiation and chemotherapy on DNA. We report here a robust protective effect of luteinizing hormone (LH) on the primordial follicle pool of prepubertal ovaries against the cisplatin (Cs)-induced apoptosis. In vitro LH treatment of prepubertal ovarian fragments generated anti-apoptotic signals by a subset of ovarian somatic cells expressing LH receptor (LHR) through cAMP/PKA and Akt pathways. Such signals, reducing the oocyte level of pro-apoptotic TAp63 protein and favoring the repair of the Cs-damaged DNA in the oocytes, prevented their apoptosis. Noteworthy, in vivo administration to prepubertal female mice of a single dose of LH together with Cs inhibited the depletion of the primordial follicle reserve caused by the drug and preserved their fertility in reproductive age, preventing significant alteration in the number of pregnancy and of delivered pups. In conclusion, these findings establish a novel ovoprotective role for LH and further support the very attracting prospective to use physiological 'fertoprotective' approaches for preventing premature infertility and risks linked to precocious menopause in young patients who survived cancer after chemotherapy.

There is a growing interest in therapeutically targeting the inflammatory response that underlies age-related chronic diseases including obesity and type 2 diabetes. Through integrative small RNA sequencing, we show the presence of conserved plant miR159a and miR156c in dried nuts having high complementarity with the mammalian TNF receptor superfamily member 1a (Tnfrsf1a) transcript. We detected both miR159a and miR156c in exosome-like nut nanovesicles (NVs) and demonstrated that such NVs reduce Tnfrsf1a protein and dampen TNF-α signaling pathway in adipocytes. Synthetic single-stranded microRNAs (ss-miRs) modified with 2′- O -methyl group function as miR mimics. In plants, this modification naturally occurs on nearly all small RNAs. 2′- O -methylated ss-miR mimics for miR156c and miR159a decreased Tnfrsf1a protein and inflammatory markers in hypertrophic as well as TNF-α-treated adipocytes and macrophages. miR156c and miR159a mimics effectively suppress inflammation in mice, highlighting a potential role of plant miR-based, single-stranded oligonucleotides in treating inflammatory-associated metabolic diseases. Aquilano et al. identify conserved plant miR159a and miR156c in dried nuts and show that these miRNAs target TNF receptor superfamily member 1a to suppress TNF-α-mediated inflammation. This study highlights the potential of plant miR-based oligonucleotides as a therapeutic option to treat metabolic diseases hallmarked by inflammation.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally and are frequently dysregulated in cancer. While most studies focus on individual miRNAs, global patterns and their potential cross-kingdom similarities remain underexplored. This study aims to identify statistically stable human miRNAs in cancer, their key target genes, and analyze sequence complementarity with plant miRNAs to highlight patterns for future research. Experimentally validated human miRNA-gene interactions from miRTarBase were integrated with TCGA expression data across multiple cancers. Using a nonlinear threshold (critical threshold III), 115 underexpressed and 93 overexpressed miRNAs were identified as regulators of 200 genes with the strongest dysregulation. Further, 10,898 plant miRNAs from 127 species were computationally compared to these human miRNAs, and average complementarity scores were calculated to identify plant miRNAs most similar to under- or overexpressed human miRNAs. Statistical parameters such as membership ratios and experiment counts quantified miRNA expression stability. Subsets of human miRNAs exhibited consistent over- or underexpression across cancers, with concordant target gene expression patterns. Several plant miRNAs showed higher complementarity to underexpressed human miRNAs, suggesting reproducible cross-kingdom sequence similarity patterns. Differences in complementarity were modest but systematic, providing a computational framework for prioritizing candidate miRNAs for further study. This work establishes a computational approach integrating human miRNA-gene interactions, cancer expression data, and plant miRNA sequences. It identifies statistically stable miRNAs, key target genes, and cross-kingdom sequence similarities without implying functional or therapeutic activity. The framework can guide future experimental studies in miRNA regulation, comparative genomics, and molecular evolution.

Low-intensity pulsed ultrasound (LIPUS) is a widely used non-invasive approach with therapeutic purposes since it provides physical stimulation with minimal thermal effects. The skin epithelium is the first barrier of the human body that interfaces with LIPUS and is subjected to the highest intensity. Little is known about the impact of LIPUS on the skin surface. This work investigates the biological effects of one-hour exposure to 1 MHz LIPUS on human keratinocytes HaCaT and tumoral SK-MEL-28 skin cells. Specifically, we evaluated the cellular state immediately after LIPUS treatment by analyzing cytogenetic endpoints and the response of cytoskeleton and cell junction proteins. Herein we demonstrate that LIPUS induces genomic damage as shown by an increase of chromosome malsegregation and a consequent decrease of cellular proliferation. The mechanical stimulus produced by LIPUS is also transmitted to the cytoskeletal compartment, inducing the expression and re-organization of junction proteins (i.e., E-cadherin and Desmosomes) and intermediate filaments (i.e., F-actin and Cytokeratins) with impact on cell morphology and cell adhesion. These in vitro results highlight the different outcomes following the cytogenetic damage and the resilience response exerted by the cytoskeleton upon mechanical stress, laying the foundation for future in vivo investigations.

Low temperature stress is one of the major causes of crop yield reduction in agriculture. The alteration of gene expression pattern and the accumulation of stress-related proteins are the main strategies activated by plants under this unfavourable condition. Here we characterize the Arabidopsis thaliana Salt Tolerance Related Protein (STRP). The protein rapidly accumulates under cold treatment, and this effect is not dependent on transcriptional activation of the STRP gene, but on the inhibition of proteasome-mediated degradation. Subcellular localization of STRP was determined by the transient expression of STRP-YFP in A. thaliana protoplasts. STRP is localized into the cytosol, nucleus, and associated to the plasma membrane. Under cold stress, the membrane-associated fraction decreases, while in the cytosol and in the nucleus STRP levels strongly increase. STRP has high similarity with WCI16, a wheat Late Embryogenesis Abundant (LEA)-like protein. Despite no canonical LEA motifs in the STRP sequence are present, physicochemical characterization demonstrated that STRP shares common features with LEA proteins, being a high hydrophilic unstructured protein, highly soluble after boiling and with cryoprotectant activity. To clarify the physiological function of STRP, we characterized the phenotype and the response to low temperature stress of the strp knockout mutant. The mutation causes an equal impairment of plant growth and development both in physiological and cold stress conditions. The strp mutant is more susceptible to oxidative damage respect to the wild type , showing increased lipid peroxidation and altered membrane integrity. Furthermore, the analysis of Abscisic acid (ABA) effects on protein levels demonstrated that the hormone induces the increase of STRP levels, an effect in part ascribable to its ability to activate STRP expression. ABA treatments showed that the strp mutant displays an ABA hyposensitive phenotype in terms of seed germination, root development, stomata closure and in the expression of ABA-responsive genes. In conclusion, our results demonstrate that STRP acts as a multifunctional protein in the response mechanisms to low temperature, suggesting a crucial role for this protein in stress perception and in the translation of extracellular stimuli in an intracellular response.

Chemotherapy often leads to premature death of oocytes, and thus infertility, in young individuals with cancer. Here, Stefania Gonfloni and her colleagues show that chemotherapy-induced activation of the kinase c-Abl is responsible for this oocyte failure and that, in vivo , the c-Abl inhibitor imatinib prevents this effect ( pages 1124–1125 ). Germ cells are sensitive to genotoxins, and ovarian failure and infertility are major side effects of chemotherapy in young patients with cancer. Here we describe the c-Abl–TAp63 pathway activated by chemotherapeutic DNA-damaging drugs in model human cell lines and in mouse oocytes and its role in cell death. In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. Similarly, in oocytes, cisplatin rapidly promotes TAp63 accumulation and eventually cell death. Treatment with the c-Abl kinase inhibitor imatinib counteracts these cisplatin-induced effects. Taken together, these data support a model in which signals initiated by DNA double-strand breaks are detected by c-Abl, which, through its kinase activity, modulates the p63 transcriptional output. Moreover, they suggest a new use for imatinib, aimed at preserving oocytes of the follicle reserve during chemotherapeutic treatments.

Rosemary (Rosmarinus officinalis L.) has been used since ancient times in traditional medicine, while nowadays various rosemary formulations are increasingly exploited by alternative medicine to cure or prevent a wide range of health disorders. Rosemary's bioproperties have prompted scientific investigation, which allowed us to ascertain antioxidant, anti-inflammatory, cytostatic, and cytotoxic activities of crude extracts or of pure components. Although there is a growing body of experimental work, information about rosemary's anticancer properties, such as chemoprotective or anti-proliferative effects on cancer cells, is very poor, especially concerning the mechanism of action. Melanoma is a skin tumor whose diffusion is rapidly increasing in the world and whose malignancy is reinforced by its high resistance to cytotoxic agents; hence the availability of new cytotoxic drugs would be very helpful to improve melanoma prognosis. Here we report on the effect of a rosemary hydroalcoholic extract on the viability of the human melanoma A375 cell line. Main components of rosemary extract were identified by liquid chromatography coupled to tandem mass spectrometry (LC/ESI-MS/MS) and the effect of the crude extract or of pure components on the proliferation of cancer cells was tested by MTT and Trypan blue assays. The effect on cell cycle was investigated by using flow cytometry, and the alteration of the cellular redox state was evaluated by intracellular ROS levels and protein carbonylation analysis. Furthermore, in order to get information about the molecular mechanisms of cytotoxicity, a comparative proteomic investigation was performed.

Diet and nutrition are important factors in the promotion and maintenance of good health throughout the entire life course. A plant-based diet may be able to prevent and treat chronic diseases such as diabetes, heart disease and hypertension, obesity, chronic inflammation and cancer. Phytonutrient rich foods are found in traditional African diet which is mostly vegetarian, and most of these food plants are often used for medicinal purposes. This review focuses on a peculiar plant Moringa oleifera, called the “Miracle Tree”, considered to be one of nature’s healthiest and most nutritious foods. Countless studies describe the benefits of Moringa leaves, pods, seeds and flowers. Its well-documented role in prevention and treatment of chronic diseases is hypothesized here as a result of possible of cross-kingdom regulation by exogenous vegetal microRNAs and synergistic action of plant bioactive components on endogenous human microRNA regulation. The potential health impact of phytocomplexes from African dietary plants within the context of cross-kingdom and endogenous microRNA regulation on health improvement and the overall economic well-being of the continent is estimated to be enormous.

Ellagic acid (EA) is a polyphenolic compound that can be found as a naturally occurring hydrolysis product of ellagitannins in pomegranates, berries, grapes, green tea and nuts. Previous studies have reported the antitumor properties of EA mainly using in vitro models. No data are available about EA influence on bladder cancer cell invasion of the extracellular matrix triggered by vascular endothelial growth factor-A (VEGF-A), an angiogenic factor associated with disease progression and recurrence, and tumor growth in vivo. In this study, we have investigated EA activity against four different human bladder cancer cell lines (i.e., T24, UM-UC-3, 5637 and HT-1376) by in vitro proliferation tests (measuring metabolic and foci forming activity), invasion and chemotactic assays in response to VEGF-A and in vivo preclinical models in nude mice. Results indicate that EA exerts anti-proliferative effects as a single agent and enhances the antitumor activity of mitomycin C, which is commonly used for the treatment of bladder cancer. EA also inhibits tumor invasion and chemotaxis, specifically induced by VEGF-A, and reduces VEGFR-2 expression. Moreover, EA down-regulates the expression of programmed cell death ligand 1 (PD-L1), an immune checkpoint involved in immune escape. EA in vitro activity was confirmed by the results of in vivo studies showing a significant reduction of the growth rate, infiltrative behavior and tumor-associated angiogenesis of human bladder cancer xenografts. In conclusion, these results suggest that EA may have a potential role as an adjunct therapy for bladder cancer.