Background: Periodontitis affects approximately 7–11% of the global adult population in its severe forms and has been epidemiologically associated with cardiovascular, cardiometabolic, and neurodegenerative diseases. Low-grade chronic inflammation represents the unifying mechanism; however, an integrative framework connecting the oral cavity, the gut, and the brain into a single mechanistic continuum is lacking. Objective: This narrative review, conducted with structured (but non-systematic) elements and PRISMA-2020 style reporting used solely as a transparency tool, synthesizes current evidence on the oral–gut–brain axis. A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar (2000–March 2026), yielding 159 included studies after structured screening and eligibility assessment. The review focuses on: the molecular mechanisms by which periodontal dysbiosis may disrupt intestinal homeostasis and contribute to neuroinflammation; the role of salivary and intestinal biomarkers as monitoring tools for the entire axis; and emerging pharmacological opportunities targeting this tripartite pathway. Results: Periodontal pathogens, particularly Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum, have been detected ectopically in the gut and are associated with reduced tight junction protein expression and altered Firmicutes/Bacteroidetes ratios in preclinical and observational studies. These perturbations have been associated with increased blood–brain barrier (BBB) permeability, microglial activation, and amyloid-beta (Aβ) accumulation, although causal directionality in humans remains to be established. Salivary biomarkers (MMP-8, IL-1β, IL-6, BDNF) and intestinal biomarkers (short-chain fatty acids, calprotectin) reflect systemic inflammatory burden and offer potential for non-invasive screening. Conclusions: The oral–gut–brain axis provides a plausible unifying framework for understanding comorbidity among periodontal, cardiometabolic, and neurodegenerative diseases; however, current evidence is predominantly associative, and mechanistic extrapolation from preclinical models requires validation in longitudinal human studies. Salivary biomarkers may serve as candidate first-line tools for systemic risk assessment, and pharmacological interventions targeting this axis represent promising investigational directions warranting further clinical evaluation.

Background: Berberine, an isoquinoline alkaloid present in Berberis spp., Coptis chinensis and Hydrastis canadensis, is among the most widely consumed metabolic-health supplements, popularized as “nature’s Ozempic”. Concurrent, often undisclosed use with prescription drugs is common in older adults, yet berberine is far from inert. Objective: To synthesize the evidence on berberine as a perpetrator of supplement–drug interactions, propose a four-axis mechanistic taxonomy, with product quality treated separately as a modifier of exposure rather than as a mechanism, and derive a clinically actionable risk-stratification framework. Methods: Structured narrative review, prepared per the SANRA quality criteria; PubMed/MEDLINE, Scopus, Web of Science and Embase were searched up to May 2026. Results: Despite very low systemic exposure (oral bioavailability 0.68% in rats; low ng/mL plasma concentrations in humans), high luminal, enterocytic and hepatic concentrations generate interaction liability, documented in humans for a few pairs and mechanistic for most, along four mechanistic axes: inhibition, and transcriptional induction, of CYP3A4, with CYP2D6/CYP2C9 inhibition that is quasi-irreversible through a metabolite-intermediate complex; transporter modulation (P-glycoprotein, OCT1/OCT2, and MATE1); pharmacodynamic additivity (hypoglycemia, hypotension, and QT prolongation); and microbiome- and gut-barrier-mediated effects, the last of these being a candidate axis rather than a demonstrated one. Product-quality variability is treated separately, as a modifier of exposure. The clinical anchor is increased cyclosporine exposure in renal-transplant recipients (AUC +34.5%; trough 29.3% above control). These elements are integrated into a three-tier risk-stratification framework that combines perpetrator potency, victim-drug vulnerability, and patient vulnerability, with each tier being linked to a defined pharmacy action. Conclusions: In patients on multiple medications, and particularly when berberine is co-administered with drugs of narrow therapeutic index, it should be managed as an active pharmacological perpetrator rather than as an inert supplement. Unstandardized product quality and an unsettled European regulatory framework, under which national limits differ by more than an order of magnitude, further widen the uncertainty around the dose actually delivered. Berberine use should therefore be elicited routinely at medication reconciliation and stratified by mechanism, by victim-drug vulnerability, and by patient risk, with particular attention to metabolic self-medication in the GLP-1 era.

Periodontitis and dental caries remain among the most prevalent chronic diseases, and their local treatment is limited less by the choice of active agent than by the difficulty of sustaining therapeutic concentrations against salivary and crevicular clearance, the mucosal barrier and the biofilm matrix. This narrative review (PubMed/MEDLINE, Scopus, Web of Science; 2010–2026; 118 sources) maps five mechanistic classes—mucoadhesive, in situ gelling, stimuli-responsive, nano-/microparticulate and biomimetic—alongside marketed sustained-release products onto the specific barrier each addresses and onto an explicit translational gradient. The barriers are quantified rather than described: a pocket of ≈0.5 µL perfused at ≈20 µL/h turns over some 40 times hourly, giving an intra-crevicular half-life of about one minute, and the inflamed pocket is neutral-to-alkaline (pH 7.4–8.5), so acid-triggered release is a cariogenic and not a periodontal strategy, whereas alkaline-triggered release remains an open design space. A dose calculation from these figures identifies payload potency and deliverable mass, not carrier retention, as the binding constraint on phytocompound delivery. Because no single class overcomes all barriers, hybrid nano-in-macro architectures are analysed as the structural solution. Measured against a marketed benchmark of ≈0.3 mm additional probing-depth reduction, progress now depends on consolidation rather than on novelty.

Background/Objectives: Polyphenols are dietary constituents and active substances in dosage forms applied locally in the mouth, yet their bioavailability is interpreted almost exclusively in terms of intestinal absorption and colonic microbial metabolism. This review examines the oral cavity as a site of local biotransformation, a compartment that can chemically modify polyphenols before absorption, and asks whether this conversion could be measured as a phenotype. Methods: Narrative synthesis is reported according to SANRA. Four databases were searched from inception to 31 August 2026. Results: Flavonoid glucosides are hydrolysed to aglycones within minutes of contact with saliva; anthocyanins are deglycosylated to cyanidin and converted to protocatechuic acid; epigallocatechin gallate is de-esterified. Local concentrations reach 2–145 μM, two orders of magnitude above plasma. Conversion capacity varied more than twenty-fold among 17 subjects in the only quantitative study. Conclusions: The oral cavity can alter the chemical form of the polyphenols presented to absorption. The orally transformed fraction of an ingested dose is small; a first-pass effect is not demonstrated, and the established consequences are local and qualitative. Oral metabotypes have not been demonstrated; the concept and its operational classification are proposed as hypotheses to be tested in adequately sized cohorts.

Background/Objectives: Periodontitis is sustained by dysbiotic biofilms and dysregulated host responses, providing pharmacological targets for antimicrobial, host-modulating, phytochemical, regenerative, and locally delivered interventions. This scoping review mapped bioactive heterocyclic compounds investigated in periodontitis according to the structural family, pharmacological target, periodontal compartment, therapeutic maturity, selected periodontal–systemic interfaces, and a secondary geriatric cerebrovascular context. Methods: PubMed, Scopus, and the Web of Science Core Collection were searched for the principal review on 30 July 2026. Companion publications were linked at the study level, and design-specific appraisal was applied when sufficient methodological information was available. A separate cerebrovascular extension was searched on 6 August 2026 and analyzed independently of the principal evidence denominator. Results: The principal evidence map comprised 715 independent studies represented by 804 canonical eligible reports. Nitroimidazole-containing regimens formed the largest structural family (283 studies; 39.6%), followed by melatonin and indole-related agents (83; 11.6%), macrolides (77; 10.8%), berberine and isoquinoline-related compounds (29; 4.1%), and quinolones or fluoroquinolones (28; 3.9%). Human clinical evidence was concentrated mainly in established antimicrobial regimens, whereas many host-modulating, phytochemical, regenerative, signaling, and delivery-based approaches remained predominantly translational or preclinical. The detailed clinical subset comprised 48 human studies, including six core comparative studies; heterogeneity in population, regimen, treatment background, follow-up, outcome definition, and analysis unit precluded a clinically meaningful pooled estimate. Prespecified systemic interfaces included diabetes (35 studies), cardiovascular disease (13), and rheumatoid arthritis (2). The separate cerebrovascular component comprised 30 studies addressing the oral health burden, microbial and inflammatory associations, oral care interventions, and treatment safety considerations in older adults with ischemic stroke. Conclusions: The evidence supports compound- and formulation-specific interpretation rather than class-wide therapeutic recommendations. Clinical translation should integrate structural and mechanistic plausibility with periodontal target-site exposure, pharmacokinetic–pharmacodynamic evidence, clinically meaningful benefit, safety, and antimicrobial stewardship. The cerebrovascular evidence supports oral care integration and safety surveillance but does not establish causal periodontal effects on stroke, reperfusion outcomes, or thrombolysis eligibility.