Burning Mouth Syndrome (BMS) and Corneal Neuropathic Pain (CNP) are chronic pain conditions that may present with severe symptoms despite minimal or absent visible tissue pathology. We propose that these disorders may, in at least a subset of patients, be understood within a shared framework of trigeminal small fiber neuropathy (SFN), while acknowledging that both conditions are clinically heterogeneous and may arise through multiple mechanisms. Within this framework, peripheral small-fiber injury or dysfunction affecting different trigeminal branches (V1 in CNP; V2/V3 in BMS) may contribute to persistent nociceptive input, neuroimmune activation, and, in susceptible individuals, central sensitization. We further suggest that corneal confocal microscopy may provide an important translational bridge between ophthalmology and oral medicine, particularly because corneal small-fiber abnormalities have now been reported in both CNP and BMS. We also discuss large-scale brain network changes, including Default Mode Network (DMN) abnormalities, as potential correlates of nociplastic pain, while recognizing that these are not disease-specific findings. Finally, we outline how this hypothesis could be tested through multimodal studies integrating corneal imaging, lingual tissue measures, quantitative sensory testing, and neuroimaging. Rather than redefining disease classification, this hypothesis is intended to stimulate cross-disciplinary mechanistic research and future translational study.
Helicobacter pylori infection has been associated with small intestinal bacterial overgrowth (SIBO), but the mechanisms underlying this relationship remain uncertain. This article aims to propose a phenotype-based dual-pathway hypothesis explaining how H. pylori may contribute to SIBO through distinct but overlapping biological mechanisms. In the preserved-acid pathway, virulence-associated inflammatory signaling may theoretically impair enteric neuromuscular function, migrating motor complex activity and epithelial barrier integrity, although direct human evidence remains limited. In the atrophy–hypochlorhydria pathway, corpus-predominant atrophic gastritis may weaken the gastric acid barrier, increase gastric and proximal small-intestinal microbial burden, and facilitate downstream microbial expansion. A mixed phenotype may arise when partial atrophy, inflammation, proton pump inhibitor exposure, dysmotility and relevant comorbidities coexist. This framework treats chronological age as an imperfect surrogate for gastric phenotype, acid-secretory status, virulence profile, medication exposure and motility reserve. If validated, phenotype-based stratification could improve the design of future studies and support a more individualized evaluation of patients with concomitant H. pylori infection and suspected SIBO.
Menopausal flushing affects 50–85% of women and is characterized by hormonal fluctuations leading to altered thermoregulation. Current management includes lifestyle measures, hormonal and non-hormonal medications. However, existing treatments are limited by adverse effects, contraindications, variable efficacy, and symptom recurrence after discontinuation of treatment. Menopause is accompanied by disturbances in vaginal microbiota, characterized by reduced Lactobacillus abundance and increased microbial diversity. Although no direct evidence currently links these microbiota changes to vasomotor symptoms (VMS), shared upstream drivers particularly estrogen decline and potentially relevant inflammatory pathways provide a rationale for investigating whether vaginal dysbiosis could modulate menopausal symptom expression. However, to date, no studies have evaluated vaginal microbiota transplantation (VMT) as a treatment for menopausal VMS and this pathway remains strictly theoretical. Early evidence suggests that VMT is generally safe and well-tolerated, though long-term safety, cost-effectiveness, accessibility, and sociocultural acceptability remain uncertain. Future well-designed clinical studies are needed to establish its safety, efficacy, and practical applicability in postmenopausal women.
Classical lipoproteins are primarily classified by density, size, lipid composition, and apolipoprotein content, whereas metabolic origin and receptor-mediated routing describe additional biological properties. These variables explain much of lipid transport but do not establish whether supramolecular organization of the lipid interface adds causal information about particle behavior. We hypothesize that classical lipoproteins are apolipoprotein-scaffolded lipid-state particles in which a measurable, perturbable, and persistent lipid-interface state cooperates with a biogenetic scaffold to influence stability, extracellular remodeling, routing, and recipient-cell responses. Within this framework, scaffold-interface coupling represents a restricted mechanistic implementation of extracellular lipid-state transduction within established lipoprotein systems rather than a proposal for a new particle class. Source-state continuity may be material, through direct lipid transfer, or configurational, through source-state-dependent biasing of lipoprotein assembly. Apolipoprotein B (apoB) provides a non-exchangeable scaffold with high continuity, whereas apolipoprotein A-I (apoA-I) forms a more adaptable scaffold that is initiated by ATP-binding cassette transporter A1 (ABCA1)-dependent lipidation and subsequently remodeled by lecithin-cholesterol acyltransferase (LCAT) and plasma factors. The hypothesis predicts that controlled differences in interfacial packing, accessibility, topology, oxidation, or electrostatics will alter protein acquisition, routing, or function after controlling for particle number, size, bulk composition, scaffold abundance, and established receptor pathways. Failure in a specific particle class would narrow the scope of the hypothesis; failure to demonstrate incremental interface-state information across appropriately controlled systems would falsify its core proposition. Its principal limitation is that interfacial dimensions remain difficult to measure or manipulate independently; if supported, it may improve interpretation of dysfunctional lipoproteins.
Dengue remains a major global health challenge, with severe disease driven chiefly by transient endothelial dysfunction and plasma leakage. Although dengue virus (DENV) depends on host lipid metabolism for replication, attempts to exploit this therapeutically have been disappointing. In particular, statins show antiviral and endothelial-protective effects experimentally, but did not improve clinical outcomes in the only randomized controlled clinical trial published to date. We propose that the effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) may help explain this paradox. PCSK9, classically recognised as a regulator of LDL receptor recycling, is increasingly implicated in inflammation, oxidative stress, nitric oxide dysregulation, and endothelial injury. DENV-induced PCSK9 expression has been shown to alter intracellular cholesterol trafficking, enrich endoplasmic reticulum cholesterol, suppress STING-dependent type I interferon responses, and is associated with higher viraemia and plasma leakage. However, evidence for this antiviral arm remains limited, and PCSK9 may also contribute directly to endothelial dysfunction. We hypothesise that PCSK9 acts as a dual mediator in dengue pathogenesis: first, by impairing antiviral interferon signalling and facilitating viral persistence; and second, by amplifying endothelial activation, oxidative stress, reduced nitric oxide bioavailability, glycocalyx injury, and increasing vascular permeability. Statin-induced PCSK9 upregulation may therefore offset the expected antiviral and endothelial benefits of cholesterol synthesis inhibition. This hypothesis generates testable predictions: circulating PCSK9 should correlate more strongly with endothelial injury and plasma leakage markers than with viraemia alone, and PCSK9 inhibition should attenuate vascular dysfunction. If validated, PCSK9 may represent both a biomarker of severe dengue and a novel host-directed therapeutic target. The latter could lead to repurposing currently available PCSK9 inhibitors to treat dengue.
Mutations are commonly studied in human medicine because of their roles in inherited disorders, cancer, and other diseases. However, mutations and the resulting variants may also produce protective, compensatory, restorative, or function-enhancing effects. These effects are not limited to inherited germline variants; they may also arise from postzygotic mosaicism, somatic mutations in particular cell populations, mitochondrial mutations, chromosomal alterations, and changes affecting gene regulation or RNA processing. We define a beneficial mutation as a mutational event whose resulting genetic alteration produces a reproducible net advantage at a specified biological level and under defined cellular, tissue, environmental, and temporal conditions. A mutation may therefore be harmful in one cell type or physiological context but beneficial in another. For example, loss of a normal gene function may damage healthy tissue yet suppress the survival of a cancer cell, while compensatory variants affecting fetal hemoglobin can reduce the severity of sickle cell disease. Other established examples include CCR5-Δ32–associated resistance to HIV infection, APOE3 Christchurch–associated resilience to familial Alzheimer's disease, somatic reversion that restores tissue function in inherited disorders, and programmed somatic hypermutation that improves antibody affinity. These observations suggest that beneficial genetic changes can act at the molecular, cellular, tissue, organ, or whole-person level. Nevertheless, human research has primarily identified mutations through disease phenotypes, whereas alterations that prevent disease, reduce its severity, restore function, or contribute to unusually favorable health-related traits may remain unrecognized or insufficiently characterized. Many such alterations may already exist in genomic and clinical databases but are classified as benign, of uncertain significance, or functionally unknown rather than specifically evaluated for beneficial effects. We propose a broader framework for studying beneficial mutations across germline and somatic compartments through phenotype-first investigation, analysis of resilient individuals and exceptional biological outcomes, re-examination of existing variant databases, longitudinal studies, and functional validation. This approach could complement disease-centered genetics, clarify variable penetrance and spontaneous functional recovery, and identify new mechanisms for prevention, diagnosis, and therapy.
Fracture and dementia share a complex and close association. Epidemiological studies have found that the risk of dementia increases by 28% to 41% after fracture occurrence. Psychological studies attribute this phenomenon to low mood and restricted social interaction in patients after a fracture. Molecular biology studies propose that fracture-induced release of inflammatory factors activates NLRP3 in the brain, which serves as a potential driver of dementia. However, these existing views have certain limitations. We propose that exosomes carrying RANKL secreted by osteoblasts after fracture mediate the development of post-fracture dementia and affect patients' emotional status. This hypothesis holds that RANKL-containing exosomes are proposed to cross the BBB, potentially aided by their lipid bilayer composition. Simultaneously, they mediate the onset of depressive-like symptoms by activating the NF-κB signalling pathway. It reconciles the fragmentation of previous hypotheses to a certain extent and provides a new direction for the prevention of post-fracture dementia.
Expansion of primary chondrocytes in two-dimensional monolayer culture causes progressive dedifferentiation and limits cartilage tissue engineering. A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) is primarily known as a secreted aggrecanase, but its intracellular role under cellular stress remains unclear. We propose that expansion-induced mechanical and oxidative stress redistributes ADAMTS4 to intracellular ribonucleoprotein complexes, where it suppresses HMOX1 post-transcriptionally. RNA sequencing after ADAMTS4 silencing, intracellular RNA immunoprecipitation sequencing, and interactome analysis collectively support an association between ADAMTS4 and HMOX1 RNA. ADAMTS4 may contact HMOX1 RNA directly as an unconventional RNA-binding protein or indirectly through canonical RNA-binding proteins, thereby weakening the Nrf2/HO-1 cytoprotective axis and accelerating dedifferentiation. This model links extracellular matrix remodeling to intracellular RNA regulation and suggests a dual function for ADAMTS4. If validated, it may provide new strategies for preserving the chondrocyte phenotype during expansion.
Vitamin D3 is conventionally viewed as a secosteroid prohormone generated by ultraviolet B radiation and converted into metabolites that regulate calcium homeostasis, epithelial function and immunity. This article proposes a testable hypothesis: vitamin D3 or vitamin D-associated molecular assemblies may participate in mechanically, chemically or oxidatively induced photophysical processes during immune activation. The term “solar-derived photophysical reservoir” does not imply storage of intact ultraviolet photons. It refers to the possibility that photochemical formation may leave energy represented indirectly in molecular structure, chemical free energy, conformational or metastable states, or later molecular organization, thereby influencing subsequent energy conversion. The proposal draws on independently established observations: vitamin D3 arises through ultraviolet photochemistry; vitamin D receptor signaling promotes antimicrobial pathways; vitamin D compounds exhibit ordered solid-state conformations, polymorphs and cocrystals; molecular crystals can show triboluminescence; and oxidatively stressed cells emit ultraweak photons. No direct evidence links these observations into a vitamin D3-dependent photophysical antimicrobial mechanism, and several mechanistic steps remain untested. Because biological ultraweak photon emission is far weaker than externally applied ultraviolet or photodynamic therapy, local redox modulation is more plausible than direct pathogen photodamage unless substantial confinement or amplification is demonstrated. The hypothesis does not replace established vitamin D receptor signaling. It can be tested through vitamin D mechanoluminescence assays, immune-cell photon counting, spectroscopy, bacterial killing models, optical attenuation and vitamin D receptor-independent controls. If supported, it would broaden vitamin D biology from endocrine signaling alone to a possible interface between sunlight-derived molecular structure, local energy conversion and innate antimicrobial defense.
