Homocysteine (Hcy) metabolism is crucial for regulating methionine availability, protein homeostasis, and DNA-methylation presenting, therefore, key pathways in post-genomic and epigenetic regulation mechanisms. Consequently, impaired Hcy metabolism leading to elevated concentrations of Hcy in the blood plasma (hyperhomocysteinemia) is linked to the overproduction of free radicals, induced oxidative stress, mitochondrial impairments, systemic inflammation and increased risks of eye disorders, coronary artery diseases, atherosclerosis, myocardial infarction, ischemic stroke, thrombotic events, cancer development and progression, osteoporosis, neurodegenerative disorders, pregnancy complications, delayed healing processes, and poor COVID-19 outcomes, among others. This review focuses on the homocysteine metabolism impairments relevant for various pathological conditions. Innovative strategies in the framework of 3P medicine consider Hcy metabolic pathways as the specific target for in vitro diagnostics, predictive medical approaches, cost-effective preventive measures, and optimized treatments tailored to the individualized patient profiles in primary, secondary, and tertiary care.

Breast cancer incidence is actually the highest one among all cancers. Overall breast cancer management is associated with challenges considering risk assessment and predictive diagnostics, targeted prevention of metastatic disease, appropriate treatment options, and cost-effectiveness of approaches applied. Accumulated research evidence indicates promising anti-cancer effects of phytochemicals protecting cells against malignant transformation, inhibiting carcinogenesis and metastatic spread, supporting immune system and increasing effectiveness of conventional anti-cancer therapies, among others. Molecular and sub-/cellular mechanisms are highly complex affecting several pathways considered potent targets for advanced diagnostics and cost-effective treatments. Demonstrated anti-cancer affects, therefore, are clinically relevant for improving individual outcomes and might be applicable to the primary (protection against initial cancer development), secondary (protection against potential metastatic disease development), and tertiary (towards cascading complications) care. However, a detailed data analysis is essential to adapt treatment algorithms to individuals’ and patients’ needs. Consequently, advanced concepts of patient stratification, predictive diagnostics, targeted prevention, and treatments tailored to the individualized patient profile are instrumental for the cost-effective application of natural anti-cancer substances to improve overall breast cancer management benefiting affected individuals and the society at large.

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.

Inflammation is an essential pillar of the immune defense. On the other hand, chronic inflammation is considered a hallmark of cancer initiation and progression. Chronic inflammation demonstrates a potential to induce complex changes at molecular, cellular, and organ levels including but not restricted to the stagnation and impairment of healing processes, uncontrolled production of aggressive ROS/RNS, triggered DNA mutations and damage, compromised efficacy of the DNA repair machinery, significantly upregulated cytokine/chemokine release and associated patho-physiologic protein synthesis, activated signaling pathways involved in carcinogenesis and tumor progression, abnormal tissue remodeling, and created pre-metastatic niches, among others. The anti-inflammatory activities of flavonoids demonstrate clinically relevant potential as preventive and therapeutic agents to improve individual outcomes in diseases linked to the low-grade systemic and chronic inflammation, including cancers. To this end, flavonoids are potent modulators of pro-inflammatory gene expression being, therefore, of great interest as agents selectively suppressing molecular targets within pro-inflammatory pathways. This paper provides in-depth analysis of anti-inflammatory properties of flavonoids, highlights corresponding mechanisms and targeted molecular pathways, and proposes potential treatment models for multi-level cancer prevention in the framework of predictive, preventive, and personalized medicine (PPPM / 3PM). To this end, individualized profiling and patient stratification are essential for implementing targeted anti-inflammatory approaches. Most prominent examples are presented for the proposed application of flavonoid-conducted anti-inflammatory treatments in overall cancer management.

Mitochondria are the “gatekeeper” in a wide range of cellular functions, signaling events, cell homeostasis, proliferation, and apoptosis. Consequently, mitochondrial injury is linked to systemic effects compromising multi-organ functionality. Although mitochondrial stress is common for many pathomechanisms, individual outcomes differ significantly comprising a spectrum of associated pathologies and their severity grade. Consequently, a highly ambitious task in the paradigm shift from reactive to predictive, preventive, and personalized medicine (PPPM/3PM) is to distinguish between individual disease predisposition and progression under circumstances, resulting in compromised mitochondrial health followed by mitigating measures tailored to the individualized patient profile. For the successful implementation of PPPM concepts, robust parameters are essential to quantify mitochondrial health sustainability. The current article analyses added value of Mitochondrial Health Index (MHI) and Bioenergetic Health Index (BHI) as potential systems to quantify mitochondrial health relevant for the disease development and its severity grade. Based on the pathomechanisms related to the compromised mitochondrial health and in the context of primary, secondary, and tertiary care, a broad spectrum of conditions can significantly benefit from robust quantification systems using MHI/BHI as a prototype to be further improved. Following health conditions can benefit from that: planned pregnancies (improved outcomes for mother and offspring health), suboptimal health conditions with reversible health damage, suboptimal life-style patterns and metabolic syndrome(s) predisposition, multi-factorial stress conditions, genotoxic environment, ischemic stroke of unclear aetiology, phenotypic predisposition to aggressive cancer subtypes, pathologies associated with premature aging and neuro/degeneration, acute infectious diseases such as COVID-19 pandemics, among others.