The paradigm change from reactive medical services to 3PM in ischemic stroke: a holistic approach utilising tear fluid multi-omics, mitochondria as a vital biosensor and AI-based multi-professional data interpretation.

Worldwide stroke is the second leading cause of death and the third leading cause of death and disability combined. The estimated global economic burden by stroke is over US$891 billion per year. Within three decades (1990-2019), the incidence increased by 70%, deaths by 43%, prevalence by 102%, and DALYs by 143%. Of over 100 million people affected by stroke, about 76% are ischemic stroke (IS) patients recorded worldwide. Contextually, ischemic stroke moves into particular focus of multi-professional groups including researchers, healthcare industry, economists, and policy-makers. Risk factors of ischemic stroke demonstrate sufficient space for cost-effective prevention interventions in primary (suboptimal health) and secondary (clinically manifested collateral disorders contributing to stroke risks) care. These risks are interrelated. For example, sedentary lifestyle and toxic environment both cause mitochondrial stress, systemic low-grade inflammation and accelerated ageing; inflammageing is a low-grade inflammation associated with accelerated ageing and poor stroke outcomes. Stress overload, decreased mitochondrial bioenergetics and hypomagnesaemia are associated with systemic vasospasm and ischemic lesions in heart and brain of all age groups including teenagers. Imbalanced dietary patterns poor in folate but rich in red and processed meat, refined grains, and sugary beverages are associated with hyperhomocysteinaemia, systemic inflammation, small vessel disease, and increased IS risks. Ongoing 3PM research towards vulnerable groups in the population promoted by the European Association for Predictive, Preventive and Personalised Medicine (EPMA) demonstrates promising results for the holistic patient-friendly non-invasive approach utilising tear fluid-based health risk assessment, mitochondria as a vital biosensor and AI-based multi-professional data interpretation as reported here by the EPMA expert group. Collected data demonstrate that IS-relevant risks and corresponding molecular pathways are interrelated. For examples, there is an evident overlap between molecular patterns involved in IS and diabetic retinopathy as an early indicator of IS risk in diabetic patients. Just to exemplify some of them such as the 5-aminolevulinic acid/pathway, which are also characteristic for an altered mitophagy patterns, insomnia, stress regulation and modulation of microbiota-gut-brain crosstalk. Further, ceramides are considered mediators of oxidative stress and inflammation in cardiometabolic disease, negatively affecting mitochondrial respiratory chain function and fission/fusion activity, altered sleep-wake behaviour, vascular stiffness and remodelling. Xanthine/pathway regulation is involved in mitochondrial homeostasis and stress-driven anxiety-like behaviour as well as molecular mechanisms of arterial stiffness. In order to assess individual health risks, an application of machine learning (AI tool) is essential for an accurate data interpretation performed by the multiparametric analysis. Aspects presented in the paper include the needs of young populations and elderly, personalised risk assessment in primary and secondary care, cost-efficacy, application of innovative technologies and screening programmes, advanced education measures for professionals and general population-all are essential pillars for the paradigm change from reactive medical services to 3PM in the overall IS management promoted by the EPMA.

Salvia officinalis L. exerts oncostatic effects in rodent and in vitro models of breast carcinoma.

Introduction: Based on extensive data from oncology research, the use of phytochemicals or plant-based nutraceuticals is considered an innovative tool for cancer management. This research aimed to analyze the oncostatic properties of Salvia officinalis L. [Lamiaceae; Salviae officinalis herba] using animal and in vitro models of breast carcinoma (BC). Methods: The effects of dietary administered S. officinalis in two concentrations (0.1%/SAL 0.1/and 1%/SAL 1/) were assessed in both syngeneic 4T1 mouse and chemically induced rat models of BC. The histopathological and molecular evaluations of rodent carcinoma specimens were performed after the autopsy. Besides, numerous in vitro analyses using two human cancer cell lines were performed. Results and Conclusion: The dominant metabolites found in S. officinalis propylene glycol extract (SPGE) were representatives of phenolics, specifically rosmarinic, protocatechuic, and salicylic acids. Furthermore, the occurrence of triterpenoids ursolic and oleanolic acid was proved in SPGE. In a mouse model, a non-significant tumor volume decrease after S. officinalis treatment was associated with a significant reduction in the mitotic activity index of 4T1 tumors by 37.5% (SAL 0.1) and 31.5% (SAL 1) vs. controls (set as a blank group with not applied salvia in the diet). In addition, salvia at higher doses significantly decreased necrosis/whole tumor area ratio by 46% when compared to control tumor samples. In a rat chemoprevention study, S. officinalis at a higher dose significantly lengthened the latency of tumors by 8.5 days and significantly improved the high/low-grade carcinomas ratio vs. controls in both doses. Analyses of the mechanisms of anticancer activities of S. officinalis included well-validated prognostic, predictive, and diagnostic biomarkers that are applied in both oncology practice and preclinical investigation. Our assessment in vivo revealed numerous significant changes after a comparison of treated vs. untreated cancer cells. In this regard, we found an overexpression in caspase-3, an increased Bax/Bcl-2 ratio, and a decrease in MDA, ALDH1, and EpCam expression. In addition, salvia reduced TGF-ß serum levels in rats (decrease in IL-6 and TNF-α levels were with borderline significance). Evaluation of epigenetic modifications in rat cancer specimens in vivo revealed a decline in the lysine methylations of H3K4m3 and an increase in lysine acetylation in H4K16ac levels in treated groups. Salvia decreased the relative levels of oncogenic miR21 and tumor-suppressive miR145 (miR210, miR22, miR34a, and miR155 were not significantly altered). The methylation of ATM and PTEN promoters was decreased after S. officinalis treatment (PITX2, RASSF1, and TIMP3 promoters were not altered). Analyzing plasma metabolomics profile in tumor-bearing rats, we found reduced levels of ketoacids derived from BCAAs after salvia treatment. In vitro analyses revealed significant anti-cancer effects of SPGE extract in MCF-7 and MDA-MB-231 cell lines (cytotoxicity, caspase-3/-7, Bcl-2, Annexin V/PI, cell cycle, BrdU, and mitochondrial membrane potential). Our study demonstrates the significant chemopreventive and treatment effects of salvia haulm using animal or in vitro BC models.

Significance of flavonoids targeting PI3K/Akt/HIF-1α signaling pathway in therapy-resistant cancer cells - A potential contribution to the predictive, preventive, and personalized medicine.

BACKGROUND: Cancer management faces multiple obstacles, including resistance to current therapeutic approaches. In the face of challenging microenvironments, cancer cells adapt metabolically to maintain their supply of energy and precursor molecules for biosynthesis and thus sustain rapid proliferation and tumor growth. Among the various metabolic adaptations observed in cancer cells, the altered glucose metabolism is the most widely studied. The aberrant glycolytic modification in cancer cells has been associated with rapid cell division, tumor growth, cancer progression, and drug resistance. The higher rates of glycolysis in cancer cells, as a hallmark of cancer progression, is modulated by the transcription factor hypoxia inducible factor 1 alpha (HIF-1α), a downstream target of the PI3K/Akt signaling, the most deregulated pathway in cancer. AIM OF REVIEW: We provide a detailed overview of current, primarily experimental, evidence on the potential effectiveness of flavonoids to combat aberrant glycolysis-induced resistance of cancer cells to conventional and targeted therapies. The manuscript focuses primarily on flavonoids reducing cancer resistance via affecting PI3K/Akt, HIF-1α (as the transcription factor critical for glucose metabolism of cancer cells that is regulated by PI3K/Akt pathway), and key glycolytic mediators downstream of PI3K/Akt/HIF-1α signaling (glucose transporters and key glycolytic enzymes). KEY SCIENTIFIC CONCEPTS OF REVIEW: The working hypothesis of the manuscript proposes HIF-1α - the transcription factor critical for glucose metabolism of cancer cells regulated by PI3K/Akt pathway as an attractive target for application of flavonoids to mitigate cancer resistance. Phytochemicals represent a source of promising substances for cancer management applicable to primary, secondary, and tertiary care. However, accurate patient stratification and individualized patient profiling represent crucial steps in the paradigm shift from reactive to predictive, preventive, and personalized medicine (PPPM / 3PM). The article is focused on targeting molecular patterns by natural substances and provides evidence-based recommendations for the 3PM relevant implementation.

Cell plasticity modulation by flavonoids in resistant breast carcinoma targeting the nuclear factor kappa B signaling.

Cancer cell plasticity plays a crucial role in tumor initiation, progression, and metastasis and is implicated in the multiple cancer defense mechanisms associated with therapy resistance and therapy evasion. Cancer resistance represents one of the significant obstacles in the clinical management of cancer. Some reversal chemosensitizing agents have been developed to resolve this serious clinical problem, but they have not yet been proven applicable in oncological practice. Activated nuclear factor kappa B (NF-κB) is a frequently observed biomarker in chemoresistant breast cancer (BC). Therefore, it denotes an attractive cellular target to mitigate cancer resistance. We summarize that flavonoids represent an essential class of phytochemicals that act as significant regulators of NF-κB signaling and negatively affect the fundamental cellular processes contributing to acquired cell plasticity and drug resistance. In this regard, flavokawain A, icariin, alpinetin, genistein, wogonin, apigenin, oroxylin A, xanthohumol, EGCG, hesperidin, naringenin, orientin, luteolin, delphinidin, fisetin, norwogonin, curcumin, cardamonin, methyl gallate and catechin-3-O-gallate, ampelopsin, puerarin, hyperoside, baicalein, paratocarpin E, and kaempferol and also synthetic flavonoids such as LFG-500 and 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone have been reported to specifically interfere with the NF-κB pathway with complex signaling consequences in BC cells and could be potentially crucial in re-sensitizing unresponsive BC cases. The targeting NF-κB by above-mentioned flavonoids includes the modification of tumor microenvironment and epithelial-mesenchymal transition, growth factor receptor regulations, and modulations of specific pathways such as PI3K/AKT, MAP kinase/ERK, and Janus kinase/signal transduction in BC cells. Besides that, NF-κB signaling in BC cells modulated by flavonoids has also involved the regulation of ATP-binding cassette transporters, apoptosis, autophagy, cell cycle, and changes in the activity of cancer stem cells, oncogenes, or controlling of gene repair. The evaluation of conventional therapies in combination with plasticity-regulating/sensitizing agents offers new opportunities to make significant progress towards a complete cure for cancer.

Desmoplasia in non-small cell lung carcinomas is associated with low programmed death-ligand 1 expression and the absence of tumor-infiltrating lymphocytes.

Programmed death-ligand 1 (PD-L1) is the most widely utilized predictive marker used to identify non-small cell lung carcinoma (NSCLC) patients most suitable for immunotherapy approaches. The relationship between PD-L1 expression, the presence of CD8+ T cells, and other clinicopathological characteristics of NSCLC patients has not been elucidated yet. In this retrospective study, we immunohistochemically determined PD-L1 expression (using clone 22C3) and CD8+ T cell count (using clone c8/144B) in surgical resection specimens from 698 advanced NSCLC patients. Results of PD-L1 expression and CD8+ T cell count were correlated to various clinicopathological characteristics, including the presence of desmoplasia in NSCLC. Regarding the immunological attributes of the tumor microenvironment, we identified major differences between desmoplastic and non-desmoplastic areas in NSCLC. Tumor areas without desmoplasia were significantly more often PD-L1 positive than tumor cell clusters encased in a dense collagenous stroma (p=0.004). Furthermore, the desmoplastic stroma contained significantly less often an immune cell infiltrate rich in CD8+ T cells (p<0.001). Also, the positivity of PD-L1 significantly correlated with advanced N-stage (p<0.001) and poor differentiation in adenocarcinomas (p=0.032) but not with other clinicopathological characteristics. In conclusion, to our knowledge, this is the first study that points to major differences in terms of immunological attributes between desmoplastic and non-desmoplastic areas in NSCLC. The desmoplastic component, therefore, may represent an immunologically distinct tumor area in which PD-L1 immunohistochemistry and CD8+ T cell count should be evaluated separately.

Heat shock proteins in cancer - Known but always being rediscovered: Their perspectives in cancer immunotherapy.

Heat shock proteins (HSPs) represent cellular chaperones that are classified into several families, including HSP27, HSP40, HSP60, HSP70, and HSP90. The role of HSPs in the cell includes the facilitation of protein folding and maintaining protein structure. Both processes play crucial roles during stress conditions in the cell such as heat shock, degradation, and hypoxia. Moreover, HSPs are important modulators of cellular proliferation and differentiation, and are strongly associated with the molecular orchestration of carcinogenesis. The expression and/or activity of HSPs in cancer cells is generally abnormally high and is associated with increased metastatic potential and activity of cancer stem cells, more pronounced angiogenesis, downregulated apoptosis, and the resistance to anticancer therapy in many patients. Based on the mentioned reasons, HSPs have strong potential as valid diagnostic, prognostic, and therapeutic biomarkers in clinical oncology. In addition, numerous papers describe the role of HSPs as chaperones in the regulation of immune responses inside and outside the cell. Importantly, highly expressed/activated HSPs may be inhibited via immunotherapeutic targets in various types of cancers. The aim of this work is to provide a comprehensive overview of the relationship between HSPs and the tumor cell with the intention of highlighting the potential use of HSPs in personalized cancer management.

The effects of Rhus coriaria L. (sumac) and Cinnamomum zeylanicum L. bark on serum cytokine levels in rat mammary carcinogenesis.

The purpose of this study was to assess the potential effects of Rhus coriaria L. (sumac) and of Cinnamomum zeylanicum L. bark on the selected serum cytokines as possible serum tumor markers - interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α) in the rat model of mammary carcinogenesis. R. coriaria and C. zeylanicum bark were used as the chemopreventive-therapeutic agents taken by rats in the powder form in the diet at two different concentrations during the entire period of two experiments carried out separately: lower concentration 1 g/kg - 0.1% and higher concentration 10 g/kg - 1%. The serum levels of cytokines of IL-6, IL-10, and TNF-α were determined using an enzyme-linked immunosorbent assay. In the first experiment treated with R. coriaria, a significant decrease in serum levels of IL-6 and TNF-α was present at higher concentrations compared to the chemoprevention-free control group. R. coriaria at lower concentrations non-significantly reduced the serum levels of IL-6 and TNF-α when compared to controls. A significant decrease in serum levels of TNF-α was present at higher concentrations compared to lower concentrations. The significant effect of R. coriaria on the serum levels of IL-10 was not observed. In the second experiment treated with C. zeylanicum bark, a significant decrease in serum levels of IL-6 was observed in lower and higher concentrations compared to the chemoprevention-free control group. C. zeylanicum bark non-significantly reduced the serum levels of TNF-α and had no effect on the serum levels of IL-10. In conclusion, R. coriaria and C. zeylanicum bark demonstrated significant anti-inflammatory effects by analyzing the selected serum cytokine levels in the rat breast carcinoma model. Observed anti-inflammatory effects of both plant-natural substances were associated with their anticancer activities in rats.

Underexplored reciprocity between genome-wide methylation status and long non-coding RNA expression reflected in breast cancer research: potential impacts for the disease management in the framework of 3P medicine.

Breast cancer (BC) is the most common female malignancy reaching a pandemic scale worldwide. A comprehensive interplay between genetic alterations and shifted epigenetic regions synergistically leads to disease development and progression into metastatic BC. DNA and histones methylations, as the most studied epigenetic modifications, represent frequent and early events in the process of carcinogenesis. To this end, long non-coding RNAs (lncRNAs) are recognized as potent epigenetic modulators in pathomechanisms of BC by contributing to the regulation of DNA, RNA, and histones' methylation. In turn, the methylation status of DNA, RNA, and histones can affect the level of lncRNAs expression demonstrating the reciprocity of mechanisms involved. Furthermore, lncRNAs might undergo methylation in response to actual medical conditions such as tumor development and treated malignancies. The reciprocity between genome-wide methylation status and long non-coding RNA expression levels in BC remains largely unexplored. Since the bio/medical research in the area is, per evidence, strongly fragmented, the relevance of this reciprocity for BC development and progression has not yet been systematically analyzed. Contextually, the article aims at:consolidating the accumulated knowledge on both-the genome-wide methylation status and corresponding lncRNA expression patterns in BC andhighlighting the potential benefits of this consolidated multi-professional approach for advanced BC management. Based on a big data analysis and machine learning for individualized data interpretation, the proposed approach demonstrates a great potential to promote predictive diagnostics and targeted prevention in the cost-effective primary healthcare (sub-optimal health conditions and protection against the health-to-disease transition) as well as advanced treatment algorithms tailored to the individualized patient profiles in secondary BC care (effective protection against metastatic disease). Clinically relevant examples are provided, including mitochondrial health control and epigenetic regulatory mechanisms involved.

Phytochemical-based nanodrugs going beyond the state-of-the-art in cancer management-Targeting cancer stem cells in the framework of predictive, preventive, personalized medicine.

Cancer causes many deaths worldwide each year, especially due to tumor heterogeneity leading to disease progression and treatment failure. Targeted treatment of heterogeneous population of cells - cancer stem cells is still an issue in protecting affected individuals against associated multidrug resistance and disease progression. Nanotherapeutic agents have the potential to go beyond state-of-the-art approaches in overall cancer management. Specially assembled nanoparticles act as carriers for targeted drug delivery. Several nanodrugs have already been approved by the US Food and Drug Administration (FDA) for treating different cancer types. Phytochemicals isolated from plants demonstrate considerable potential for nanomedical applications in oncology thanks to their antioxidant, anti-inflammatory, anti-proliferative, and other health benefits. Phytochemical-based NPs can enhance anticancer therapeutic effects, improve cellular uptake of therapeutic agents, and mitigate the side effects of toxic anticancer treatments. Per evidence, phytochemical-based NPs can specifically target CSCs decreasing risks of tumor relapse and metastatic disease manifestation. Therefore, this review focuses on current outlook of phytochemical-based NPs and their potential targeting CSCs in cancer research studies and their consideration in the framework of predictive, preventive, and personalized medicine (3PM).

Therapy-resistant breast cancer in focus: Clinically relevant mitigation by flavonoids targeting cancer stem cells.

Significant limitations of the reactive medical approach in breast cancer management are clearly reflected by alarming statistics recorded worldwide. According to the WHO updates, breast malignancies become the leading cancer type. Further, the portion of premenopausal breast cancer cases is permanently increasing and demonstrates particularly aggressive patterns and poor outcomes exemplified by young patients with triple-negative breast cancer that lacks targeted therapy. Accumulating studies suggest the crucial role of stem cells in tumour biology, high metastatic activity, and therapy resistance of aggressive breast cancer. Therefore, targeting breast cancer stem cells is a promising treatment approach in secondary and tertiary breast cancer care. To this end, naturally occurring substances demonstrate high potential to target cancer stem cells which, however, require in-depth analysis to identify effective anti-cancer agents for cost-effective breast cancer management. The current article highlights the properties of flavonoids particularly relevant for targeting breast cancer stem cells to mitigate therapy resistance. The proposed approach is conformed with the principles of 3P medicine by applying predictive diagnostics, patient stratification and treatments tailored to the individualised patient profile. Expected impacts are very high, namely, to overcome limitations of reactive medical services improving individual outcomes and the healthcare economy in breast cancer management. Relevant clinical applications are exemplified in the paper.

Diabetic retinopathy as the leading cause of blindness and early predictor of cascading complications-risks and mitigation.

Proliferative diabetic retinopathy (PDR) the sequel of diabetic retinopathy (DR), a frequent complication of diabetes mellitus (DM), is the leading cause of blindness in the working-age population. The current screening process for the DR risk is not sufficiently effective such that often the disease is undetected until irreversible damage occurs. Diabetes-associated small vessel disease and neuroretinal changes create a vicious cycle resulting in the conversion of DR into PDR with characteristic ocular attributes including excessive mitochondrial and retinal cell damage, chronic inflammation, neovascularisation, and reduced visual field. PDR is considered an independent predictor of other severe diabetic complications such as ischemic stroke. A "domino effect" is highly characteristic for the cascading DM complications in which DR is an early indicator of impaired molecular and visual signaling. Mitochondrial health control is clinically relevant in DR management, and multi-omic tear fluid analysis can be instrumental for DR prognosis and PDR prediction. Altered metabolic pathways and bioenergetics, microvascular deficits and small vessel disease, chronic inflammation, and excessive tissue remodelling are in focus of this article as evidence-based targets for a predictive approach to develop diagnosis and treatment algorithms tailored to the individual for a cost-effective early prevention by implementing the paradigm shift from reactive medicine to predictive, preventive, and personalized medicine (PPPM) in primary and secondary DR care management.

Potential Treatment Options for Neuroblastoma with Polyphenols through Anti-Proliferative and Apoptotic Mechanisms.

Neuroblastoma (NB) is an extracranial tumor of the peripheral nervous system arising from neural crest cells. It is the most common malignancy in infants and the most common extracranial solid tumor in children. The current treatment for high-risk NB involves chemotherapy and surgical resection followed by high-dose chemotherapy with autologous stem-cell rescue and radiation treatment. However, those with high-risk NB are susceptible to relapse and the long-term side effects of standard chemotherapy. Polyphenols, including the sub-class of flavonoids, contain more than one aromatic ring with hydroxyl groups. The literature demonstrates their utility in inducing the apoptosis of neuroblastoma cells, mostly in vitro and some in vivo. This review explores the use of various polyphenols outlined in primary studies, underlines the pathways involved in apoptotic activity, and discusses the dosage and delivery of these polyphenols. Primary studies were obtained from multiple databases with search the terms "neuroblastoma", "flavonoid", and "apoptosis". The in vitro studies showed that polyphenols exert an apoptotic effect on several NB cell lines. These polyphenols include apigenin, genistein, didymin, rutin, quercetin, curcumin, resveratrol, butein, bisphenols, and various plant extracts. The mechanisms of the therapeutic effects include calpain-dependent pathways, receptor-mediated apoptosis, and, notably, and most frequently, mitochondrial apoptosis pathways, including the mitochondrial proteins Bax and Bcl-2. Overall, polyphenols demonstrate potency in decreasing NB proliferation and inducing apoptosis, indicating significant potential for further in vivo research.

Flavonoids attenuate cancer metabolism by modulating Lipid metabolism, amino acids, ketone bodies and redox state mediated by Nrf2.

Metabolic reprogramming of cancer cells is a common hallmark of malignant transformation. The preference for aerobic glycolysis over oxidative phosphorylation in tumors is a well-studied phenomenon known as the Warburg effect. Importantly, metabolic transformation of cancer cells also involves alterations in signaling cascades contributing to lipid metabolism, amino acid flux and synthesis, and utilization of ketone bodies. Also, redox regulation interacts with metabolic reprogramming during malignant transformation. Flavonoids, widely distributed phytochemicals in plants, exert various beneficial effects on human health through modulating molecular cascades altered in the pathological cancer phenotype. Recent evidence has identified numerous flavonoids as modulators of critical components of cancer metabolism and associated pathways interacting with metabolic cascades such as redox balance. Flavonoids affect lipid metabolism by regulating fatty acid synthase, redox balance by modulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activity, or amino acid flux and synthesis by phosphoglycerate mutase 1. Here, we discuss recent preclinical evidence evaluating the impact of flavonoids on cancer metabolism, focusing on lipid and amino acid metabolic cascades, redox balance, and ketone bodies.

Curcumin, calebin A and chemosensitization: How are they linked to colorectal cancer?

Colorectal cancer (CRC) is one of the leading malignant diseases worldwide with a high rate of metastasis and poor prognosis. Treatment options include surgery, which is usually followed by chemotherapy in advanced CRC. With treatment, cancer cells could become resistant to classical cytostatic drugs such as 5-fluorouracil (5-FU), oxaliplatin, cisplatin, and irinotecan, resulting in chemotherapeutic failure. For this reason, there is a high demand for health-preserving re-sensitization mechanisms including the complementary use of natural plant compounds. Calebin A and curcumin, two polyphenolic turmeric ingredients derived from the Asian Curcuma longa plant, demonstrate versatile anti-inflammatory and cancer-reducing abilities, including CRC-combating capacity. After an insight into their epigenetics-modifying holistic health-promoting effects, this review compares functional anti-CRC mechanisms of multi-targeting turmeric-derived compounds with mono-target classical chemotherapeutic agents. Furthermore, the reversal of resistance to chemotherapeutic drugs was presented by focusing on calebin A's and curcumin's capabilities to chemosensitize or re-sensitize CRC cells to 5-FU, oxaliplatin, cisplatin, and irinotecan. Both polyphenols enhance the receptiveness of CRC cells to standard cytostatic drugs converting them from chemoresistant into non-chemoresistant CRC cells by modulating inflammation, proliferation, cell cycle, cancer stem cells, and apoptotic signaling. Therefore, calebin A and curcumin can be tested for their ability to overcome cancer chemoresistance in preclinical and clinical trials. The future perspective of involving turmeric-ingredients curcumin or calebin A as an additive treatment to chemotherapy for patients with advanced metastasized CRC is explained.

Programmed death ligand-1 expression and its association with the degree of differentiation and the presence of necrosis in non-small cell lung carcinoma.

The mechanisms underlying the expression of programmed death ligand-1 (PD-L1) in non-small cell lung carcinoma (NSCLC) are not yet fully clarified. In this study, surgical resections of 730 lung cancer patients with diagnosed NSCLC were analyzed. Results of PD-L1 immunohistochemistry (using clone 22C3) were correlated with clinicopathological variables including the degree of tumor differentiation and the presence of confluent areas of coagulative necrosis. PD-L1 immunohistochemistry was analyzed in tumor cells, whereas PD-L1 positivity was defined as membranous staining in ≥ 1 of tumor cells. A significantly higher proportion of PD-L1 positive cases was noted in poorly differentiated (grade 3) adenocarcinomas compared to better differentiated (grade 1 and grade 2) subtypes (63.8 % vs. 28.7 %; p < 0.001). Contrary to this, better differentiated (keratinizing) and less differentiated (non-keratinizing) squamous cell carcinoma subtypes were found to have a similar proportion of PD-L1 positive cases (51.4 % vs. 55.8 %; p = 0.570). High levels of PD-L1 expression significantly correlated with the presence of necrosis in NSCLC: seventy-nine of 109 NSCLC cases with the presence of necrosis were PD-L1 positive compared to 256 out of 621 NSCLC without necrosis (72.5 % vs. 41.2 %; p < 0.001). High PD-L1 expression was not positively correlated with age, gender, and advanced T stage but a significant association between PD-L1 positivity and higher N stage was observed (p < 0.001) in NSCLC patients. In conclusion, the proportion of PD-L1 positive cases is higher only in poorly differentiated NSCLC of the adenocarcinoma type. A significantly higher overall rate of PD-L1 positive cases was noted in NSCLC with the presence of necrosis. Further investigation is suggested to elucidate the intricated interconnections between the plethora of hypoxic biomarkers and immunological factors in different types and subtypes of NSCLC.

Flavonoids' Dual Benefits in Gastrointestinal Cancer and Diabetes: A Potential Treatment on the Horizon?

Diabetes and gastrointestinal cancers (GI) are global health conditions with a massive burden on patients' lives worldwide. The development of both conditions is influenced by several factors, such as diet, genetics, environment, and infection, which shows a potential link between them. Flavonoids are naturally occurring phenolic compounds present in fruits and vegetables. Once ingested, unabsorbed flavonoids reaching the colon undergo enzymatic modification by the gut microbiome to facilitate absorption and produce ring fission products. The metabolized flavonoids exert antidiabetic and anti-GI cancer properties, targeting major impaired pathways such as apoptosis and cellular proliferation in both conditions, suggesting the potentially dual effects of flavonoids on diabetes and GI cancers. This review summarizes the current knowledge on the impact of flavonoids on diabetes and GI cancers in four significant pathways. It also addresses the synergistic effects of selected flavonoids on both conditions. While this is an intriguing approach, more studies are required to better understand the mechanism of how flavonoids can influence the same impaired pathways with different outcomes depending on the disease.

Insights into Antiviral Properties and Molecular Mechanisms of Non-Flavonoid Polyphenols against Human Herpesviruses.

Herpesviruses are one of the most contagious DNA viruses that threaten human health, causing severe diseases, including, but not limited to, certain types of cancer and neurological complications. The overuse and misuse of anti-herpesvirus drugs are key factors leading to drug resistance. Therefore, targeting human herpesviruses with natural products is an attractive form of therapy, as it might improve treatment efficacy in therapy-resistant herpesviruses. Plant polyphenols are major players in the health arena as they possess diverse bioactivities. Hence, in this article, we comprehensively summarize the recent advances that have been attained in employing plant non-flavonoid polyphenols, such as phenolic acids, tannins and their derivatives, stilbenes and their derivatives, lignans, neolignans, xanthones, anthraquinones and their derivatives, curcuminoids, coumarins, furanocoumarins, and other polyphenols (phloroglucinol) as promising anti-herpesvirus drugs against various types of herpesvirus such as alpha-herpesviruses (herpes simplex virus type 1 and 2 and varicella-zoster virus), beta-herpesviruses (human cytomegalovirus), and gamma-herpesviruses (Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus). The molecular mechanisms of non-flavonoid polyphenols against the reviewed herpesviruses are also documented.

Pre-pregnancy check-up of maternal vascular status and associated phenotype is crucial for the health of mother and offspring.

Abstract: Cardiovascular disease remains the leading cause of disease burden globally with far-reaching consequences including enormous socio-economic burden to healthcare and society at large. Cardiovascular health is decisive for reproductive function, healthy pregnancy and postpartum. During pregnancy, maternal cardiovascular system is exposed to highly increased haemodynamic stress that significantly impacts health status of the mother and offspring. Resulting from sub-optimal maternal health conditions overlooked in pre-pregnancy time, progressive abnormalities can be expected during pregnancy and postpartum. Contextually, there are two main concepts to follow in the framework of predictive, preventive and personalised medicine, namely to develop:1. advanced screening of sub-optimal health conditions in young populations to predict and prevent individual health risks prior to planned pregnancies2. in-depth companion diagnostics during pregnancy to predict and prevent long-lasting postpartum health risks of the mother and offspring.Data collected in the current study demonstrate group-specific complications to health of the mother and offspring and clinical relevance of the related phenotyping in pre-pregnant mothers. Diagnostic approach proposed in this study revealed its great clinical utility demonstrating important synergies between cardiovascular maladaptation and connective tissue dysfunction. Co-diagnosed pre-pregnancy low BMI of the mother, connective tissue dysfunction, increased stiffness of peripheral vessels and decreased blood pressure are considered a highly specific maternal phenotype useful for innovative screening programmes in young populations to predict and prevent severe risks to health of the mother and offspring. This crucial discovery brings together systemic effects characteristic, for example, for individuals with Flammer syndrome predisposed to the phenotype-specific primary vascular dysregulation, pregnancy-associated risks, normal tension glaucoma, ischemic stroke at young age, impaired wound healing and associated disorders. Proposed maternal phenotyping is crucial to predict and effectively protect both the mother and offspring against health-to-disease transition. Pre-pregnancy check-up focused on sub-optimal health and utilising here described phenotypes is pivotal for advanced health policy. Plain English abstract: Cardiovascular health is decisive for reproductive function and healthy pregnancy. During pregnancy, maternal cardiovascular system may demonstrate health-to-disease transition relevant for the affected mother and offspring. Overlooked in pre-pregnancy time, progressive abnormalities can be expected during pregnancy and lifelong. Here we co-diagnosed maternal pre-pregnancy low bodyweight with systemic effects which may increase risks of pregnancy, eye and heart disorders and ischemic stroke at young age, amongst others. Innovative screening  programmes focused on sub-optimal health in young populations to predict and to mitigate individual health risks prior to pregnancy is an essential innovation for health policy proposed.

Antithrombotic and antiplatelet effects of plant-derived compounds: a great utility potential for primary, secondary, and tertiary care in the framework of 3P medicine.

Thromboembolism is the third leading vascular disease, with a high annual incidence of 1 to 2 cases per 1000 individuals within the general population. The broader term venous thromboembolism generally refers to deep vein thrombosis, pulmonary embolism, and/or a combination of both. Therefore, thromboembolism can affect both - the central and peripheral veins. Arterial thromboembolism causes systemic ischemia by disturbing blood flow and oxygen supply to organs, tissues, and cells causing, therefore, apoptosis and/or necrosis in the affected tissues. Currently applied antithrombotic drugs used, e.g. to protect affected individuals against ischemic stroke, demonstrate significant limitations. For example, platelet inhibitors possess only moderate efficacy. On the other hand, thrombolytics and anticoagulants significantly increase hemorrhage. Contextually, new approaches are extensively under consideration to develop next-generation antithrombotics with improved efficacy and more personalized and targeted application. To this end, phytochemicals show potent antithrombotic efficacy demonstrated in numerous in vitro, ex vivo, and in vivo models as well as in clinical evaluations conducted on healthy individuals and persons at high risk of thrombotic events, such as pregnant women (primary care), cancer, and COVID-19-affected patients (secondary and tertiary care). Here, we hypothesized that specific antithrombotic and antiplatelet effects of plant-derived compounds might be of great clinical utility in primary, secondary, and tertiary care. To increase the efficacy, precise patient stratification based on predictive diagnostics is essential for targeted protection and treatments tailored to the person in the framework of 3P medicine. Contextually, this paper aims at critical review toward the involvement of specific classes of phytochemicals in antiplatelet and anticoagulation adapted to clinical needs. The paper exemplifies selected plant-derived drugs, plant extracts, and whole plant foods/herbs demonstrating their specific antithrombotic, antiplatelet, and fibrinolytic activities relevant for primary, secondary, and tertiary care. One of the examples considered is antithrombotic and antiplatelet protection specifically relevant for COVID-19-affected patient groups.

Flavonoids exert potential in the management of hypertensive disorders in pregnancy.

Hypertensive disorders in pregnancy represent severe complications of pregnancy, which, if not treated, can result in serious health consequences for the mother and the child. Flavonoids are bioactive secondary metabolites commonly found in fruits, vegetables, green tea, whole grains, and medicinal plants. Flavonoids exert potent protective efficacy in experimental models of hypertensive disorders in pregnancy, especially preeclampsia, demonstrated through their capacity to modulate inflammatory responses, oxidative stress, and vascular dysfunction. In addition to their potential as therapeutics, flavonoids or flavonoid-rich food could be helpful to decrease the risk of hypertensive disorders in pregnancy when included in the diet pattern before and during pregnancy. However, the clinical evaluation of the potential capacity of flavonoids in hypertensive disorders in pregnancy is insufficient. Due to promising results from experimental studies, we highlight the need for the evaluation of flavonoids also in an appropriate clinical setting, which can be, together with proper preventive strategies, helpful in the overall management of hypertensive disorders in pregnancy.