Dietary polyphenols are garnering attention in the scientific community due to their potential health-beneficial properties and preventative effects against chronic diseases, viz. cardiovascular diseases, diabetes, obesity, and neurodegenerative diseases. Polyphenols are antioxidants that change microbial composition by suppressing pathogenic bacteria and stimulating beneficial bacteria. The interaction of polyphenols with dietary fibers affects their bioaccessibility in the upper and lower parts of the digestive tract. Dietary fibers, polyphenols, their conjugates, and their metabolites modulate microbiome population and diversity. Consuming polyphenol-rich dietary fibers such as pomegranate, cranberry, berries, and tea improves gut health. A complex relationship exists between polyphenol-rich diets and gut microbiota for functioning in human health. In this review, we provide an overview of the interactions of dietary polyphenols, fibers, and gut microbiota, improving the understanding of the functional properties of dietary polyphenols.

Metastatic cancer poses significant clinical challenges, necessitating effective immunotherapies with minimal systemic toxicity. Building on prior research demonstrating the rWTC-MBTA vaccine’s ability to inhibit tumor metastasis and growth, this study focuses on its clinical translation by optimizing vaccine composition, dosing regimens, and freezing techniques. The vaccine formula components included three TLR ligands (LTA, Poly I:C, and Resiquimod) and an anti-CD40 antibody, which were tested in melanoma and triple-negative breast cancer (TNBC) models. The formulations were categorized as rWTC-MBT (Mannan-BAM with LTA, Poly I:C, Resiquimod), rWTC-MBL (LTA), rWTC-MBP (Mannan-BAM with Poly I:C), and rWTC-MBR (Resiquimod). In the melanoma models, all the formulations exhibited efficacy that was comparable to that of the full vaccine, while in the “colder” TNBC models, the formulations with multiple TLR ligands or Resiquimod alone performed the best. Vaccine-induced activation of dendritic cell (DC) subsets, including conventional DCs (cDCs), myeloid DCs (mDCs), and plasmacytoid DCs (pDCs), was accompanied by significant CD80+CD86+ population induction, suggesting robust innate immune stimulation. An initial three-dose schedule followed by booster doses (3-1-1-1 or 3-3-3-3) reduced the metastatic burden effectively. Gradual freezing (DMSO-based preservation) maintained vaccine efficacy, underscoring the importance of intact cell structure. These findings highlight the potential of simplified formulations, optimized dosing, and freezing techniques in developing practical, scalable immunotherapies for metastatic cancers.

Neurodegeneration with brain iron accumulation (NBIA) involves a group of rare neurogenetic disorders often linked with iron overload in the basal nuclei of the brain presenting with spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration. Among NBIA subtypes, beta-propeller-protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45 (WD repeat domain 45). Previously, we demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism, and cell bioenergetics. In addition, antioxidant supplementation partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected. In this work, we explored the possibility of expressing the normal WDR45 allele present in the inactive chromosome X (Xi) of BPAN cells through treatment with epigenetic modulators. The aim of this study was to demonstrate whether biotin, an epigenetic nutrient, was able to restore the expression levels of WDR45 by a mechanism involving Xi reactivation and, consequently, correct BPAN defects. Our study demonstrated that biotin supplementation increases histone biotinylation and allows for the transcription of the WDR45 allele in Xi. Consequently, all physiopathological alterations in BPAN cells were notably corrected. The reactivation of Xi by epigenetic modulators can be a promising approach for the treatment of BPAN and other X-linked diseases.

Neplanocin A (NPA) is a natural carbocyclic analogue of adenosine that was isolated from Ampullariella regularis, which is known for its antibacterial, antiviral, and anticancer activity. Although the activity of this compound has been demonstrated in many biological models, the mechanism of its anticancer activity is not fully understood. In the current work, we present the comparison of the biological activity of two enantiomers of neplanocin A in the series of cancerous and non-cancerous cell types. In all tested cell lines, the compound with natural stereochemistry, (-)-NPA, was found to be more cytotoxic than its synthetic (+)-NPA derivative; however, sensitivity to neplanocins A varied between cell types. To determine possible reasons for the observed differences in individual cancer cell types, the expression level and effects of individual genes of adenosine-interacting enzymes were analyzed. Bioinformatic analysis of the interaction between (-)-NPA and (+)-NPA with major adenosine-interacting enzymes, such as adenosine kinase (ADK), adenosine deaminases (ADA and ADA2), and S-adenosylhomocysteine hydrolase (SAHH, AHCY), was performed. The molecular docking results revealed differences in the binding energy of the individual enantiomers of neplanocin A with the targets, which sheds new light on the mechanism of action of these adenosine analogues.

Salvia haenkei (SH-Haenkenium®), a native plant of Bolivia, is known as strong inhibitor of senescence and recently exploited in wound healing and for its potential anti-inflammatory properties. Hyaluronan at high and low molecular weight (HCC), explored in diverse cell models, and recently used in clinical practice, showed beneficial effects in dermo aesthetic and regenerative injective treatments. In this research work a novel formulation based on HCC coupled SH was tested for its potentiality in counteracting dermal injury. In vitro wound healing has been used to demonstrate HCC + SH capacity to improve keratinocytes migration respects the sole HCC, supported also by positive modulation of remodeling and integrity biomarkers. In addition, an in vitro dehydration test showed its ability to defend the skin from dryness. Moreover, an in vitro inflammation model (with lipopolysaccharides derived from E. coli) was used to assess molecular fingerprint of the pathological model and compare the cell response after treatments. Inflammatory biomarkers (e.g., KRT6, TLR-4 and NF-κB) and specific cytokines (e.g., IL-6, IL-22, IL-23) proved the effect of HCC + SH, in reducing inflammatory mediators. A more complex model, 3D-FT skin, was used to better resemble an in vivo condition, and confirmed the efficacy of novel formulations to counteract inflammation. All results trigger the interest in the novel formulation based on SH extract and hyaluronan complexes for its potential efficacy as natural anti-inflammatory agent for damaged skin, for its healing and regenerative properties.

Gelsemium has a long history of medicinal use but is also a poisonous plant. Some low-toxicity alkaloids in Gelsemium exhibit anxiolytic, anti-inflammatory, analgesic, and other pharmacological effects; however, certain alkaloids in Gelsemium are highly toxic. Nevertheless, the molecular targets underlying the biological effects of Gelsemium alkaloids remain poorly understood. We employed electrophysiological techniques and molecular modeling to examine the modulatory effects of Gelsemium alkaloids on inhibitory neurotransmitter receptors, as well as to elucidate the mechanisms underlying their molecular interactions. Our findings indicate that low-toxicity alkaloids primarily exert their pharmacological effects through actions on glycine receptors, with the binding site located at the orthosteric site between two α-subunits. Both highly toxic and low-toxicity alkaloids target GABAA receptors, using the β+/α− interface transmembrane structural domains as common binding sites. These results identify the targets through which Gelsemium alkaloids affect the central nervous system and predict the binding modes and key amino acids involved from a computational modeling perspective. However, further experimental validation through mutational studies is necessary to strengthen these findings.

Melanogenesis and melanin deposition are processes essential for the effective immune response of insects to various invaders. Phenoloxidase (PO), produced in specialized cells as an inactive precursor prophenoloxidase (proPO), is the key enzyme for melanin formation. The precursor is activated via limited proteolysis by a dedicated serine proteinase, which is the final element in the cascade of serine proteinases (SPs) that make up the PO system. Melanogenesis provides different cytotoxic molecules active in fighting infections, as well as melanin, which is important for sequestration of invaders. However, since the cytotoxic reactive compounds generated during melanization also pose a threat to host cells, strict control of the PO system is necessary for host self-protection. Different pathogens and parasites influence the PO system and melanization through various strategies, which allow them to survive and develop in the host insect body. In this review, we characterize “the lights and shadows” of PO system activation, indicating, on one hand, its advantages as an efficient and effective mechanism of the insect immune response and, on the other hand, the dangers for the insect host associated with the improper functioning of this system and selected strategies for regulating its activity by entomopathogenic organisms.

Colorectal cancer (CRC) is the third most common cancer and is associated with a poor prognosis. The mutation profile and related involved pathways of CRC have been, in broad terms, analyzed. The main current therapeutic approaches have been comprehensively reviewed here, and future possible therapeu-tic options and related technologies have been perspectively presented. The complex scenario represented by the multiple-level resistance mechanism in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAF V600E, is discussed. Examples of engineered therapeutic approaches from the literature along with a drug combination tested in clinical trials are discussed. The encouraging results observed with the latter combination (the BEACON clinical trial), totally free from chemotherapy, prompted the authors to imagine a future possible nanotechnology-assisted therapeutic approach for bypassing multiple-level resistance mechanisms, hopefully allowing, in principle, a complete biological cancer remission.

Recurrent pregnancy loss (RPL) of unknown genesis is a complex condition with multifactorial origins, including genetic, hormonal, and immunological factors. However, the specific mechanisms underlying endocervical cell proliferation disorders in women with RPL remain inadequately understood, particularly concerning the role of microbiota and viral infections. The aim of this study was to investigate the mechanisms of endocervical cell proliferation disorders in women with RPL of unknown genesis by examining microbiota, human papillomavirus (HPV) typing, and the expression levels of key molecular biological markers, including p16/Ki-67, BCL-2, miR-145, and miR-34a. A prospective observational comparative study was executed on women with RPL and healthy pregnant controls with full ethical approval. Samples were collected for HPV typing and immunocytochemical analysis to evaluate the expression of p16, Ki-67, BCL-2, and the anti-oncogenic microRNAs (miR-145 and miR-34a). The expression of mRNA for the progesterone receptor (PGR-A) was also assessed, alongside local immune status markers, including proinflammatory T-lymphocytes (Th17/Th1) and regulatory CD4+ Tregs. Overexpression of p16, Ki-67, and BCL-2 was observed in 52.5% of women with RPL who had an ASC-US/LSIL cytogram, with the average double expression of p16/Ki-67 being three times higher than in the healthy pregnant group. A significant decrease in PGR-A mRNA expression in the endocervix of women with RPL was noted, accompanied by a dysregulated local immune status characterized by an increased prevalence of Th17/Th1 cells and a reduction in regulatory CD4+ Tregs. Additionally, the expression of miR-145 and miR-34a in the endocervix and endometrium of women with RPL significantly differed from the physiological pregnancy group, particularly in the context of high-risk HPV infection. The findings describe that disorders of endocervical cell proliferation in women with RPL of unknown genesis are associated with overexpression of specific molecular markers, impaired immune regulation, and altered microRNA profiles. These alterations may contribute to the pathophysiology of RPL, highlighting the need for further research into targeted interventions that could improve reproductive outcomes in affected individuals.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with heterogeneous clinical presentation. Diagnosing ASD is complex, and the criteria for diagnosis, as well as the term ASD, have changed during the last decades. Diagnosis is made based on observation and accomplishment of specific diagnostic criteria, while a particular biomarker of ASD does not yet exist. However, studies universally report a disequilibrium in membrane lipid content, pointing to a unique neurolipid signature of ASD. This review sheds light on the possible role of cholesterol and gangliosides, complex membrane glycosphingolipids, in the development of ASD. In addition to maintaining membrane integrity, neuronal signaling, and synaptic plasticity, these lipids play a role in neurotransmitter release and calcium signaling. Evidence linking ASD to lipidome changes includes low cholesterol levels, unusual ganglioside levels, and unique metabolic profiles. ASD symptoms may be mitigated with therapeutic interventions targeting the lipid composition of membranes. However, restoring membrane equilibrium in the central nervous system remains a challenge. This review underscores the need for comprehensive research into lipid metabolism to uncover practical insights into ASD etiology and treatment as lipidomics emerges as a major area in ASD research.