The proliferation and metastasis ability of tumors are mediate by the "mutual dialogue" between cells in the tumor microenvironment (TME). Extracellular vesicles (EVs), mainly exosomes and microvesicles, play an important role in achieving intercellular substance transport and information transfer in the TME. Initially considered "garbage dumpsters" and later referred to as "signal boxes", EVs carry "cargo"  that can redirect the function of a recipient cell. Currently, the molecular mechanisms and clinical applications of EVs in head and neck cancers (HNCs) are still at an early stage and need to be further investigate. In this review, we provide insight into the TME of HNCs, classifying and summarizing EVs derived from different cell types and illuminating their complex signaling networks involved in mediating tumor proliferation, invasion and metastasis, vascular angiogenesis and cancer drug resistance. In addition, we highlight the application of EVs in HNCs, underlining the special pathological and physiological environment of HNCs. The application of tumor heterogeneous EVs in saliva and circulating blood diagnostics will provide a new perspective for the early screening, real-time monitoring and prognostic risk assessment of HNCs. Given the concept of precise and individual therapy, nanostructured EVs are equipped with superior characteristics of biocompatibility, low immunogenicity, loadability and modification ability, making these molecules one of the new strategies for HNCs treatment. Head and neck cancers (HNCs) is one of the most common malignant tumors in the world. The head and neck section addresses nonmelanoma skin cancer (NMSCs) of the head and neck as well as those malignancies that arise from the mucosal surfaces of the upper aero-digestive tract (UADT) and salivary glands, thyroid cancers are part of a separate section in the AJCC Cancer Staging Manual, eighth edition . The HNCNumerous epidemiological studies have reached a consensus that tobacco and alcohol consumption, both of which have synergistic effects, are the major risk factors for HNCs. In high-income countries, 71% and 37% of patients with oral cancer died from smoking and alcohol, respectively, compared with 33% and 14% in low- and middle-income countries , 7, 8. AThe treatment of local and early HNCs mainly involves resection with clear 1- to 2-cm margins . In patiIncreasing numbers of studies have demonstrated that the interaction between tumor cells and the tumor microenvironment plays a crucial role in manipulating the tumor immune response, tumor progression and metastasis . The tumEVs are a subcellular structure of phospholipid bilayers membrane-enclosed vesicles. Numerous studies have shown that the cells of virtually all organisms (from prokaryotes to eukaryotes) can release the EVs to extra-environment in an autocrine or paracrine manner . InitialThe extraction methods for EVs have been very mature and commercialized . ClassicExosomes are endosome-derived vesicles with a particle diameter of 30-100 nm (or 150 nm) and are cup- or disc-shaped under electron microscopy , 27, 44.A variety of proteins and molecules are involved in the formation, content assembly and secretion of exosomes. The most explicit mechanism is the endosomal sorting complex required for transport (ESCRT) complex and its associated accessory proteins  , 48. TheThe key protein that regulates the intracellular trafficking of exosomes is the RAB family proteins, which consists of more than 60 GTPases . The divCompared to exosomes, the biogenesis of microvesicles  is relatively simple. These vesicles are formed directly from the budding or shedding of the plasma membrane (PM) and have particle diameters ranging from 50 nm to 10 μm . The bioCompared to the normal state,there is a difference between the population and contents of EVs in the pathological microenvironment . When ceIn summary, the mechanism of EVs produced by different cells and the characteristics of EVs produced under physiological and pathological conditions are different. Based on the specificity anatomy of the head and neck , EVs in the HNCs microenvironment have unique characteristics. Sequencing or proteomic analysis data could show the specificity results of HNCs-derived EVs Table .Table 1STraditionally, tumor cells play a central leading role in the TME. However, in recent decades, studies have revealed that the successful proliferation and metastasis of cancer are inseparable from the "mutual dialogue" between tumor cells and stroma Fig. .Fig. 2HNHeterogenous tumor cells can increase the motility and angiogenic activity of surrounding tumor cells by secreting EVs and creating a premetastatic microenvironment , 68, whiHowever, it is unclear what kind of active molecules in HNC-derived EVs play a role in the regulation of tumor progression. Proteomic analyses revealed that OSCC-derived EVs contain a series of tumor-associated proteins, including TRAP1, EGFR, HSP-90, and MMP-13. These proteins are significantly associated with the clinical stage and prognosis of OSCC patients and may serve as potential biomakers for metastatic phenotype and treatment of OSCC –75. LMP1Noncoding RNAs in HNCs-derived EVs are involved in the regulation of tumor progression , 81. TheDrug resistance is the main reason for the failure of chemotherapy in cancer patients. Interestingly, the exposure of head and neck tumor cells to some chemotherapy drugs  can lead to an imbalance of oncogenic contents in EVs and reduce the anti-proliferation and anti-metastatic effect of chemotherapy drugs , 88. HigTumor cell-derived extracellular vesicles, in addition to their uptake, can also transported to tumor stromal cells in a paracrine manner. Illumination of the mechanism of tumor-derived exosomes in mediating cell-cell communication could definitely provide a new perspective for the development of tumors.Folkman proposed the concept of "tumor growth depends on angiogenesis" as early as the 1970s . Tumor aThe EVs derived from HNC cell can promote the malignant phenotype of tumor cells by delivering exosomal PFKFB3, Shh and other angiogenic proteins and activating the relevant model pathway to induce endothelial proliferation and tube formation , 96. In Cancer-associated fibroblasts (CAFs) are the major stromal cells in the TME . Under pThe effective amplification and metastasis of cancer cannot separated from the immune escape ability of cancer cell or treatment-mediated immune surveillance. Tumor cell-derived EVs are indispensable targets in the complex network of tumor immunity . Tumor cHNC-derived exosomes can prevent the proliferation of T lymphocytes and inhibit their differentiation into Th-1 and Th-17 cell subtypes and promote their conversion to Treg lymphocytes and myeloid-derived suppressor cells (MDSCs) . CompareFig.The transfer of EVs between tumor cells and stroma cells is not unidirectional but rather occurs through dynamic bidirectional and multidirectional complex signal network (TGFβ type II receptor (TβRII) in CAFs-derived exosomes can reactivate the TGF-β signaling pathway in OSCC cells, which is closely related to tumor heterogeneity and tumor progression . The cocThe head and neck are located in the beginning of the digestive and respiratory tract. Distinctive anatomical location makes the malignant tumor originating in this area to the pathogenic microbial environment. In recently decades, the ratio of HPV-positive oropharyngeal cancer (OPC) , 11 and Several studies have verified that HPV-positive cancer cells can dictate the expression levels of tumor genes and proteins in EVs to exert proliferative, anti-apoptotic and anti-senescent effects on surrounding cells , 124. ThEBV can hijack cancer-derived EVs production to regulate cell-to-cell communication and package viral components, such as LMP1 and CD63, which modulate the TME and promote tumor development , 128. EVAs a tool for liquid biopsy, EVs have unique advantages over circulating tumor DNA (ctDNA) and Circulating Tumor Cells (CTCs) , 134. EVCompared with other solid tumors, in addition to substance exchange with circulating body fluids , oral tumors also undergo saliva  erosion and biological effects. In oral tumor microenvironment, tumor-associated biomolecules can enter the saliva through blood circulation or directly through saliva components , 137. SaThe obvious upregulation of circulating EVs population in oral cancer patients positively correlated with IL-6 and TNF-α in tumor tissues. Tumor-derived microparticles can enhance the coagulation function of microparticles free plasma, which may promote venous thrombosis and involved in tumorigenesis . High leThe prognostic evaluation of patients with metastatic tumors, including HNCs, is undoubtedly important for predicting tumor treatment outcomes, reducing recurrence and mortality, and prolonging survival. The inclusion of EVs as a prognostic factor for HNCs may become a trend of near future. Some EV-derived proteins  shown closely related to the survival rate of patients with HNCs , 75, 79.As a natural intercellular information carrier, EVs have great application potential in the field of tumor therapy with its nanolevel molecular structure, unique host fingerprint, and properties of good biocompatibility . CurrentIn summary, EV research is an emerging field that has been rapidly developing and has made some progress. However, the explicit molecular mechanism of EV biogenesis, content loading, intracellular and extracellular transport, and ultimately the regulation of disease progression has not yet explained. EVs are like a "double-edged sword" and have a close relationship with HNCs. On the one hand, EVs, as "alliances" of cancer, can promote the proliferation of cancer cells, assist the escape of cancer cells from the immune system or drug killing, and create a suitable microenvironment for the metastasis of cancer, which plays an important role in the development and progression of cancer. On the other hand, facilitating the occurrence of cancer exposes the existence of cancer and has become an effective means for the diagnosis and treatment of this disease. Currently, there is a debate about the definition of EVs and classification of subtypes and lack of standardization and unification of extraction techniques, which is a tricky issue for studies of EVs. With the advancement of precise and individual treatment, the use of EVs to establish the early screening and diagnosis of head and neck cancers enhance the evaluation of the prognosis and treatment effect, and promote the development of new anti-tumor drugs will be the aims of future exploration.


Through real-time acquisition of the visual characteristics of wear debris in lube oil, an on-line visual ferrograph (OLVF) achieves online monitoring of equipment wear in practice. However, since a large number of bubbles can exist in lube oil and appear as a dynamically changing interference shadow in OLVF ferrograms, traditional algorithms may easily misidentify the interference shadow as wear debris, resulting in a large error in the extracted wear debris characteristic. Based on this possibility, a jam-proof uniform discrete curvelet transformation (UDCT)-based method for the binarization of wear debris images was proposed. Through multiscale analysis of the OLVF ferrograms using UDCT and nonlinear transformation of UDCT coefficients, low-frequency suppression and high-frequency denoising of wear debris images were conducted. Then, the Otsu algorithm was used to achieve binarization of wear debris images under strong interference influence. The wear debris in lube oil are closely related to the wear state of the machines. The size and form of the debris can reflect the wear level and reveal the content and temperature rise of the particular material. Therefore, oil debris analysis has become an essential condition monitoring technique that is utilized to diagnose wear and serve as an early warning system. To realize online wear monitoring, many particle detection methods have developed rapidly . The eleOnline visual ferrography (OLVF) is an important image wear detection sensor. Separating ferromagnetic wear debris from lube oil using a high-gradient magnetic field, obtaining ferrograms using an image sensor, and extracting wear debris information, such as size, shape, and concentration, by ferrogram, online visual ferrography (OLVF) achieves online equipment wear monitoring. Compared with online monitoring technology based on inductive sensors, ultrasonic transducers and electrostatic sensors , OLVF caWear debris image processing, as an important prerequisite for equipment wear monitoring, and has been widely studied in recent years. Wu et al.  studied The above methods are mostly proposed for off-line ferrograms, which are not applicable for the processing of OLVF ferrograms. In a complete wear monitoring process, the acquired number of OLVF ferrograms is very large. To facilitate OLVF ferrogram storage, OLVF ferrogram resolution is low, leading to difficulty in the extraction of wear debris characteristics. Meanwhile, to adapt to the online monitoring environment of the industrial site, the OLVF’s optical imaging system is simple and compact in structure such that the optical magnification (approximately 2 times) is considerably smaller than that of the ferroscopy microscope. Under this condition, the detailed information of the debris is limited, which leads to difficulty in extracting the particles’ features. In addition, a large number of bubbles will be generated under the action of valves, oil pumps, and gears during the lube oil cycle. As shown in In recent years, the curvelet transform has been of wide interest to domestic and foreign researchers because of its approximate optimal expression of line singularity features in images. The curvelet transform has been successfully applied to image denoising and fusion and has achieved good results . The curAll window functions are considered to have a As shown in UDCT defines To construct As shown in Then, based on Thus, the expressions for the low-pass window function Similarly, the angle window functions can be constructed asThe square low-pass filter window Suppose The specific structure of the UDCT filter bank is shown in Multiscale and multidirectional decomposition of the OLVF ferrogram was performed using UDCT. Compared with image wavelet decomposition, UDCT not only has vertical, horizontal and diagonal information but also has richer directional information. The OLVF ferrogram was decomposed by UDCT into a low-frequency part and a mid-high-frequency part. UDCT energy is mainly concentrated on the low-frequency coefficient that reflects the overview of the ferrogram. The mid-high-frequency coefficients mainly reflect the multidirectional edge feature information of the wear debris in the ferrogram. After gray processing of the ferrogram, shown in As shown in A nonlinear function was used to process the low-frequency coefficients of the UDCT transform to eliminate the interference shadow information. The nonlinear function  is definHigh-frequency sub-band coefficients reflect the details and edge features of OLVF ferrograms and contain noise. The coefficients for UDCT were adjusted to achieve denoise processing of the OLVF ferrogram. The piecewise nonlinear adjustment function isThe interference shadows are found in the low frequencies, and the processing of low-frequency coefficients is the key. To suppress interference shadows, low-frequency progeny coefficients need to be suppressed. A piecewise nonlinear function was used to process the low-frequency progeny coefficients.The background subtraction method is used to subtract the OLVF spectrum from the background spectrum, and grayscaled to obtain an OLVF spectrum that eliminates background interference;The method of uniform discrete curvelet transform is performed on the OLVF spectrum to obtain a series of high-frequency and low-frequency progeny coefficients;The nonlinear transformation of low-frequency progeny coefficients is segmented, and the low-frequency interference shadow energy is suppressed; then, the high-frequency progeny index is subjected to threshold denoising, with the remaining progeny coefficients unchanged;The progeny coefficients are integrated to perform the inverse discrete curvelet inverse transform to obtain the OLVF spectrum after suppressing the interference shadow;A binarization process is used on the processed spectral slice OLVF with automatic threshold iterative method.The steps of the UDCT-based OLVF spectrum anti-interference binarization algorithm are as follows:The specific algorithm flow is shown in As shown in A gear wear experiment was conducted in a back-to-back setup, shown in Obviously, IPCA has more glitch impulses before 5 h. The reason for this is because at the beginning of the experiment, bubbles are easily generated due to gear agitation because of the viscous lube oil. As the experiment progressed, the temperature of the lube oil increased and the viscosity decreased, and the generated bubbles were reduced, so that the interference of the bubbles on the OLVF spectrum was reduced.Multiscale analysis of OLVF ferrograms was performed using UDCT. Bubbles appear as a low frequency interference shadow in OLVF ferrograms. The proposed anti-interference segmentation method for the OLVF ferrograms was used to suppress the low-frequency coefficients of UDCT to eliminate interference shadow in the ferrograms. A wear debris image with a clear edge can be obtained. Additionally, the method is used in online gear wear monitoring. Additionally, the initial stage IPCA glitch impulses caused by bubbles can be effectively suppressed or eliminated. The proposed method can meet the requirements of OLVF online sampling analysis, which provides more accurate data for the subsequent extraction of wear debris characteristics.


Aging is an inevitable process in the human body that is associated with a multitude of systemic and localized changes. All these conditions have a common pathogenic mechanism characterized by the presence of a low-grade proinflammatory status. Inflammaging refers to all the processes that contribute to the occurrence of various diseases associated with aging such as frailty, atherosclerosis, Alzheimer’s disease, sarcopenia, type 2 diabetes, or osteoarthritis. Inflammaging is systemic, chronic, and asymptomatic. Osteoarthritis and many age-related degenerative joint diseases are correlated with aging mechanisms such as the presence of an inflammatory microenvironment and the impaired link between inflammasomes and autophagy. There is a close relationship between chondrocyte activity and local articular environment changes due to cell senescence, followed by secretion of inflammatory mediators. In addition, systemic inflammaging can lead to cartilage destruction, pain, disability, and an impaired quality of life. The purpose of this review is to summarize the main mechanisms implicated in inflammaging and the connection it has with degenerative joint diseases. It is well known that the aging process is associated with the appearance of various pathologies such as frailty, atherosclerosis, Alzheimer’s disease, sarcopenia, type 2 diabetes, or osteoporosis ,2. All tThe term “inflammaging” was first used in 2000 by Franceschi  and refeArticular cartilage is a thin connective tissue that covers the surfaces of the joints. Cartilage is composed of specialized cells called chondrocytes that produce a large amount of collagenous extracellular matrix, rich in proteoglycan and elastin fibers. Chondrocytes derive from chondroblasts that are trapped in lacunae and mature in chondrocytes. Chondrocyte metabolism responds to both mechanical  and chemical stimuli . Because of the lack of blood vessels and progenitor stem cells, the capacity of self-repair of the articular cartilage is limited .A recently published study has highlighted the changes in articular cartilage in the situation of in vitro monolayer culture. Significant changes in cell phenotype have been observed. Cells modification of the normal shape with a flattened one, altered secretory capacity and synthesis of collagen type X has been noted. Furthermore, a decrease in specific secretion products such as glycoproteins, proteoglycans, or type II collagen was highlighted. All of these changes have been attributed to the “stress responses” induced by cultivation conditions .Aging is responsible for the senescence of chondrocytes and for the specific modifications that appear in the structure of the cartilage  with theAs we know, the incidence of osteoarthritis (OA) increases proportionally with age, but we can’t consider it a direct consequence of aging . The terThe main changes at the articular cartilage level due to the aging process are represented in Moreover, the cartilage suffers from changes in blood flow and, secondarily to this, from the modifications in chondrocyte activity, overall leading to joint cartilage destruction .The mechanisms of inflammaging are not fully understood. However, current data supports its multifactorial etiology, including increased number of proinflammatory cytokines, oxidative stress, immunosenescence, autophagy, or cellular DNA damage, further detailed in Ageing has consequences that lead to changes in the immune system, referred to as immunosenescence, and attributed to evolution on the one hand but also related to a chronic antigenic load that promotes pathologies with an inflammatory common ground, as recent theories describe. Systemic low-grade inflammation is the main pathogenic factor for chronic disorders related to aging, including OA ,17. DataResearch conducted on cultures of articular chondrocytes from older patients highlighted increased levels of IL-7  and IL-1Senescent cells from the articular cartilage have the ability to develop a senescence-associated secretory phenotype, which includes growth factors, chemokine, matrix metalloproteinase (MMP), and a lot of inflammatory cytokines . This inIntrinsic factors in the aging process in association with extrinsic factors such as mechanical overload or different chemical stimuli act on articular cartilage. As a consequence, an inflammatory environment characterized by increased proinflammatory cytokines, chemokine, and activated proteinase occurs locally. All these lead to the aging process of chondrocytes (chondrosenescence), which favors the appearance of degenerative joint modifications .Senescent cells have a particular phenotype characterized by the formation of senescence-associated heterochromatin, by high expression of cyclin-dependent kinase inhibitor (p16INK4a), and senescence-associated β-galactosidase ,31. It hOne study highlighted that telomere length reduction in peripheral leucocytes was correlated with radiological signs of hand OA . In addiData published by Forsyth et al. demonstrated increased secretion of MMP-13 in chondrocytes from older adults compared to young adults . MMP-13 Besides all these data, aging of chondrocytes is also characterized by a decrease in anabolic and proliferative response to cell growth factors such as transforming growth factor-beta (TGF-β), platelet derived growth factor (PDGF), or insulin-like growth factor-I (IGF-I) . In addiThe main changes occurring at the level of aged chondrocytes that are directly involved in the process of degradation of articular cartilage and in the onset of OA are presented in Specialized studies speak of the existence of a medical interdisciplinary specialty called “geroscience” that examines the link between biological processes in aging and various diseases such as OA . In OA, Low-grade inflammatory status refers to an imbalance between pro- and anti-inflammatory cytokines . The mosThe most important cytokine in age-related disorders seems to be IL-6, being associated with chronic morbidity, mortality, and disability ,46. FurtHigh levels of proinflammatory cytokines including IL-6, IL-1, and TNFα have a crucial role in the aging process by creating an inflammatory environment in most of the organs and body tissues . A studyThe fragility, due to the overproduction of proinflammatory cytokines, associated with physical inactivity, hormonal changes, and diet deficiencies, causes a favorable environment for the appearance of osteopenia and sarcopenia .Data from the literature sustain the role of genetical changes in this susceptibility to inflammaging. The polymorphisms in the promoter C/G 174 on the IL-6 gene is related to immune-inflammatory responses and affect serum IL-6 concentrations . FurtherAlthough it is still unclear, it seems that the shortening process of the telomeres is affected and associated with systemic inflammation in older people. A study which included 1962 participants demonstrated that a shorter telomere length was correlated with an increased level of TNF α and IL-6 . Other sThese three processes are the main mechanisms involved in the pathogenesis of the aging process characterized by a low-grade systemic inflammation. Thus, we can support the view that proinflammatory status characterized by a high titer of proinflammatory cytokines, along with genetic susceptibility, corroborated with the shortening process of the telomeres, lead to the process of inflammaging .Both the progression and debut of OA seems to be linked to cytokines. In the synovial fluid proinflammatory cytokines accumulate together with anti-inflammatory ones forming a combination entitled cytokine network that can modulate the process of degradation of the cartilage matrix ,58.Recent publications, especially proteomic studies of synovial fluid, have identified interleukin-17  to be asOxidative damage through the accumulation of reactive oxygen species (ROS) leads to what is believed to be a remodeling of the immune system to which the body tries to adapt, but in failing to do so, as is the case of elderly patients, predisposition to chronic inflammatory conditions appears .Data sustain the link between oxidative stress, inflammaging, and immunosenescence ,63. MitoThere is a relation between the function of immune cells and the redox state. High levels of antioxidants can decrease the oxidative stress and slow down the aging process ,66. DireThe accumulation of oxygen metabolites could accelerate the process of cellular aging and increase apoptosis by decreasing the adenosine triphosphate (ATP) levels and increasing the porosity of the cellular membranes . Aging of the body is associated with an increase in the oxidative phosphorylation process, which results in the accumulation of oxygen metabolites. Reactive oxygen species include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. All of these have important roles in cell signaling and homeostasis processes. The most important harmful effects of reactive oxygen species on the cell are damage of DNA or RNA, oxidations of polyunsaturated fatty acids in lipids (lipid peroxidation), oxidations of amino acids in proteins, and oxidative deactivation of specific enzymes by oxidation of co-factors.Oxidative stress is also responsible for accelerated apoptosis and cellular damage, which in turn leads to the emergence of various pathologies associated with aging . Due to the avascular characteristic of articular cartilage, synovial fluid, and subchondral bone provide oxygen, nutrients, and antioxidants to chondrocytes by diffusion ,69. Studl-arginine. Endothelial, mitochondrial, and neural NOs are inducible and have a positive role in metabolic processes [Nitric oxide (NO) is synthesized by different NO synthases (NOS) through the oxidation of the guanidino nitrogen of rocesses . It seemrocesses ,75. An irocesses . l-arginine) injected into the knee. After 21 days, the histopathological examination confirmed the positive effect of selective neuronal nitric oxide synthase inhibition on the regeneration of cartilage [A recently published study analyzed the effect of inhibition of selective inducible nitric oxide synthase and neuronal nitric oxide synthase inhibitors on cartilage regeneration. The study included 27 Wistar rats which had saline solution, neuronal nitric oxide synthase inhibitor 7-nitroindazole, inducible nitric oxide synthase inhibitor aminoguanidine, or nitric oxide precursor artilage .Another recent review supports the importance of iNOS in OA development . The autIn OA cases, oxidative stress is not limited to destroying articular cartilage and chondrocytes but also affects the extracellular matrix, especially proteoglycans and collagen fibers. Oxygen reactants can cause structural changes in proteins, can modify their activity, and favor the accumulation of cellular debris, thus inducing and maintaining inflammation ,72. OxidOxidative stress plays an important role in the development of degenerative joint changes, especially in prolonged hypoxia conditions. Reactive oxygen species act both directly on chondrocytes, favoring cell death or hyperproduction of inflammatory factors, as well as on the extracellular matrix, inhibiting its production and accentuating the destruction. The process of osteoarthritis is characterized by the increase of catabolic processes followed by the decrease of the anabolic ones .The definition of cellular senescence refers to the mechanism that leads to an irreversible loss of the proliferation of somatic cells . FurtherSenescent cells have an important role in aging through the secretion of matrix-degrading proteins and proinflammatory cytokines, which is called “senescence-associated secretory phenotype” . The etiology of immunosenescence includes genetic, environmental, and immune factors. The damage of innate immunity refers to monocytes, neutrophils, and natural killer and dendritic cells and is characterized by the reduction of phagocytosis and superoxide production. The damage of acquired immunity includes B and T lymphocytes and determines thymus atrophy, increased proinflammatory cytokines, and autoreactivity . On the other hand, systemic low-grade inflammation can determine stem cell aging through the activation of the signaling pathways  . SenesceThe number of the senescent cells increases during lifetime. This numerical growth is possible through two mechanisms: either production is faster than disposal, or there is an incomplete clearance ,92. The An important role in the process of replicative senescence and age-related diseases belongs to DNA damage response, which is directly related to telomere shortening . DNA damAging is associated with structural and functional changes both in the articular cartilage and other anatomical structures such as the synovial membrane, the subchondral bone, or the periarticular tissues  . The artSenescence-associated secretory phenotype participates in maintaining local and systemic low-grade inflammation and is made of chemokines, growth factors, proinflammatory cytokines, and matrix metalloproteinases . The vasAn important role in the development of cellular senescence is assigned to DNA damage and activation of p38 MAP kinase . In OA cAutophagy is a cellular mechanism which maintains normal function and homeostasis of the cells through removal of abnormal substances via lysomal degradation . This prIn the aging process there is a decrease in the autophagy capacity which determines pronounced proinflammatory responses and mitochondrial damage . LysosomAutophagy defects are associated in the elderly with accumulation of adipose tissue around and within the organs. Many of the adipokines play a proinflammatory role. Leptin, a highly studied adipokine, has endocrine and paracrine roles . Leptin The decrease in autophagy contributes to the inflammation, especially through direct participation in the formation of the proinflammatory state. On the one hand, it stimulates the oxidative stress by mitochondrial damage and, on the other hand, favors the formation of adipokines with an important role in inflammation. A vicious circle is formed, in the center of which there is low grade systemic inflammation, the pillar of subsequent changes associated with various systemic disorders .Autophagy is an important cellular homeostatic mechanism implied in the removal of altered or dysfunctional organelles and macromolecules, being increased by different types of stresses ,107. In Apoptosis represents a programmed cell death , which hMoreover, when apoptosis is affected it leads to the accumulation of dysfunctional cells, reducing the immunological space and thus promoting cancers or infections, which could otherwise be reduced through the correct modulation of the immune system .With aging, studies showed a decrease in the number of chondrocytes in the articular cartilage, this chondrocyte death being closely related to accelerated apoptosis . Data prStudies are talking about an “unusual apoptosis” in chondrocytes because these cells suffer morphological and structural changes such as nucleus fragmentation or chromatin condensation . This paOA is a degenerative disorder characterized by extracellular matrix lesions such as collagen fiber degradation and decreased proteoglycan synthesis. All this affects the attachment of chondrocytes to the extracellular matrix, which leads to the acceleration of apoptosis . MoreoveOther factors involved in the occurrence of OA and apoptosis of chondrocytes are the granzyme B that induces apoptosis with the help of perforin, both being released from granules of cytotoxic cells . MAC (membrane attack complex) also favors the increase of local inflammation and the activation of degrading enzymes such us MMP . Cellular apoptosis is a very well controlled process in the body, having an important role throughout life. Initiation of apoptosis can be made using two pathways. The intrinsic pathway is based on cellular stress and intracellular signals that cause initiation of programmed cell death, while the extrinsic pathway refers to signals received from other cells ,124. BotThe intrinsic pathway may be called the mitochondrial pathway, being closely related to mitochondrial proteins from the intermembrane space . MitochoMitochondrial proteins (SMACs—second mitochondria-derived activator of caspases) can bind IAPs (inhibitors of apoptosis) leading to their deactivation, activation of caspases, and further apoptosis . MoreoveThe extrinsic mechanism of apoptosis is based on the binding of extracellular ligands with different membrane receptors, which results in DISC  formation . This exTNFα is considered to be the major extrinsic mediator of apoptosis. The binding between TNFα and TNFR1 causes caspase activation and initiation of apoptosis . On the Caspases have a central role in apoptosis. They can be divided into two categories: initiator caspases  and effector caspases . Activation of these caspases occurs in the cascade and acts through degradative enzymes. Not all apoptotic processes are dependent on caspase activation; there are also AIF (apoptosis-inducing factor)-controlled pathways .Aging is an inevitable process in the human body which is associated with a multitude of systemic and localized changes. All these conditions have a common pathogenic mechanism characterized by the presence of a low-grade proinflammatory status. As we have previously seen, inflammaging has a multifactorial aetiology including an increased number of proinflammatory cytokines, oxidative stress, immunosenescence, autophagy, or cellular DNA damage. The incidence of OA is steadily increasing, especially among the elderly. The mechanism of articular cartilage degeneration is not necessarily the consequence of aging, but aging is considered to be a risk factor for the occurrence of OA. There is a close relationship between chondrocyte activity and local articular environment changes due to cell senescence followed by secretion of inflammatory mediators. Furthermore, systemic inflammaging can lead to cartilage destruction, pain, disability, and an impaired quality of life. Future research and therapeutic perspectives with respect to longevity should address the pathophysiological mechanisms underlying inflammaging as well as therapy to improve the capacity of the human organism to adapt to damaging agents that increase with age.


Despite aging being by far the greatest risk factor for highly prevalent neurodegenerative disorders, the molecular underpinnings of age-related brain changes are still not well understood, particularly the transition from normal healthy brain aging to neuropathological aging. Aging is an extremely complex, multifactorial process involving the simultaneous interplay of several processes operating at many levels of the functional organization. The buildup of potentially toxic protein aggregates and their spreading through various brain regions has been identified as a major contributor to these pathologies. One of the most striking morphologic changes in neurons during normal aging is the accumulation of lipofuscin (LF) aggregates, as well as, neuromelanin pigments. LF is an autofluorescent lipopigment formed by lipids, metals and misfolded proteins, which is especially abundant in nerve cells, cardiac muscle cells and skin. Within the Central Nervous System (CNS), LF accumulates as aggregates, delineating a specific senescence pattern in both physiological and pathological states, altering neuronal cytoskeleton and cellular trafficking and metabolism, and being associated with neuronal loss, and glial proliferation and activation. Traditionally, the accumulation of LF in the CNS has been considered a secondary consequence of the aging process, being a mere bystander of the pathological buildup associated with different neurodegenerative disorders. Here, we discuss recent evidence suggesting the possibility that LF aggregates may have an active role in neurodegeneration. We argue that LF is a relevant effector of aging that represents a risk factor or driver for neurodegenerative disorders. Despite aging being by far the greatest risk factor for highly prevalent neurodegenerative disorders, the molecular underpinning of age-related brain changes is still not well understood   (2%), and sugar residues  with multiple metabolic origins  degradation by the ubiquitin-proteasome system (UPS); (ii) re-folding and suppression of aggregates by heat shock proteins; and (iii) clearing of abnormal cell contents by lysosome-mediated autophagy (macroautophagy)  generation through the Fenton reaction and further protein oxidation and LF formation  function through the catabolism of gangliosides, and the prevention of their conversion into LF aggregates , are arguably some of the best established findings about the pathophysiological accumulation of LF. However, due to its diverse origin, amalgamated composition, cross-linked nature, autofluorescent properties, and its age-related ubiquitous distribution within the CNS, the role of LF in neurodegeneration is still yet to be elucidated. Moreover, the analysis of a potential pathophysiological role of LF has been hampered by the absence of adequate animal models and their corresponding controls; thus, underscoring the need for simpler system study models.The various mechanisms of production and accumulation of LF discussed within this section depict a complex panorama in which the lysosomes play a central role in lipofuscinogenesis. Thus, the increasing amount of LF deposits during aging in certain post-mitotic tissues, and the massive buildup of LF in disorders associated with lysosomal dysfunction, such as in vitro or in in vivo models. Numerous authors have described different approaches to obtain LF from diverse biological sources. For example, several methods have been established to produce N-retinylidene-N-retinylethanolamine (A2E), which is one of the principal fluorescent components of LF from retinal pigmented epithelial cells . Mutations in these genes are associated with several distinct NCL disorders, which share several common features, including inflammation, lysosomal LF deposits, and lipid abnormalities, but have different age at onset, clinical phenotypes, and progression rates . NCLs are a group of rare neurodegenerative disorders characterized by intracellular (and at a minor extent extracellular) accumulation of a fluorescent lipopigment called “ceroid lipofuscin”  gene  gene  gene  is a degenerative disorder of the RPE of the central retina, which represents the most important cause of vision loss in the elderly. It has a multifactorial etiopathology and is characterized by the presence of deposits of lysosomal origin, such as LF, melanolipofuscin, and melanosomes  are associated with frontotemporal degeneration with TDP-43-positive inclusions (FTD-TDP). FTD is highly heterogeneous in its clinical presentation, age at onset and duration of the disease even within the same families, suggesting the mediation of additional modifying genes. Strikingly, while the deletion c.813_816del (rs63749877) in the GRN gene in heterozygosis is also associated with FTD, the same mutation when presented in homozygosis causes adult-onset NCL, revealing a remarkable link between neurodegeneration and lipofuscinogenesis  gene normalizes lysosomal activity and rescues FTD-related behavioral abnormalities and retinal degeneration, without showing a decrease in LF accumulation  appear to be directly involved in the selective degeneration of dopaminergic neurons in the SNC , Wellings and collaborators found a strong inverse correlation between NPNFP intensity and LF autofluorescence, suggesting that these changes contribute to degeneration of postural reflexes observed in PD  attack lipids, proteins and other susceptible groups, either locally or far from their origin, because they are diffusible and can migrate and act at a distance. Consequently, lipid peroxidation end-products , are produced and their distribution could be either restricted to a specific tissue or tissue domains or be systemically distributed. For instance, in brains from AD patients, the lipid peroxidation product malondialdehyde, an important component of the phospholipid bilayer membranes of neurons, is significantly increased  are less frequently affected by LF accumulation. The polyanionic character of PNs appears to contribute to reducing local oxidative potential in the neuronal microenvironment by scavenging and binding redox-active iron , related to the expansion of CAG triplet repeats, resulting in an extended polyglutamine stretch (polyQ) within the huntingtin protein, which becomes unstable, gradually damaging neuronal cells  is an inherited disorder caused by an autosomal dominant mutation in the Huntingtin gene  has been found to colocalize with LF aggregates in the extracellular space   did not show efficacy to halt the growth rate of geographic atrophy (GA) in AMD, but patients seemed to tolerate it well. A phase IIa clinical trial with Emixustat (NCT01002950) showed a biological effect in GA in AMD patients. A Phase II/III study (NCT01802866) has been completed, but no results are yet available  of different neurodegenerative diseases. Thus, we argue that LF plays a transversal function on both cellular senescence and across neurodegeneration. Provided that LF increasingly accumulates with age, and assuming the hypothesis that LF is a risk factor for different neurodegenerative disorders, one may expect higher incidences of neurodegenerative disorders with the increased levels of the risk factor (in this case LF). However, although age is also one of the strongest risk factors for late-onset neurodegenerative disorders, the normalized incidence of each entity (perhaps with the exception of AD) peaks at certain age range, from which it starts to decay. This apparent disagreement between a continuously increasing buildup of LF deposits as a risk factor and the variable age-specific peak incidence of diverse neurodegenerative disorders  (de Pedro-Cuesta et al., In line with the work from Giaccone and collaborators that discussed the potential pathogenic role of LF in AD (Giaccone et al., All authors participated in the conception and aims of the review. AM-G, AK, and OC participated in the literature search, and analysis of references, participated in the experimental acquisition of images for Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


One of the most important scientific discoveries of recent years was the disclosure that the intestinal microflora takes part in bidirectional communication between the gut and the brain. Scientists suggest that human gut microflora may even act as the “second brain” and be responsible for neurodegenerative disorders like Alzheimer’s disease (AD). Although human-associated microbial communities are generally stable, they can be altered by common human actions and experiences. Enteric bacteria, commensal, and pathogenic microorganisms, may have a major impact on immune system, brain development, and behavior, as they are able to produce several neurotransmitters and neuromodulators like serotonin, kynurenine, catecholamine, etc., as well as amyloids. However, brain destructive mechanisms, that can lead to dementia and AD, start with the intestinal microbiome dysbiosis, development of local and systemic inflammation, and dysregulation of the gut-brain axis. Increased permeability of the gut epithelial barrier results in invasion of different bacteria, viruses, and their neuroactive products that support neuroinflammatory reactions in the brain. It seems that, inflammatory-infectious hypothesis of AD, with the great role of the gut microbiome, starts to gently push into the shadow the amyloid cascade hypothesis that has dominated for decades. It is strongly postulated that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. This is promising area for therapeutic intervention. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention, alter microbial partners and their products including amyloid protein, will probably become a new treatment for AD. Alzheimer’s disease (AD) is the most common form of dementia in older adults. It is a major public health problem, and the incidence and prevalence are expected to achieve epidemic proportions in the next few decades if no intervention aimed to prevent or reduce the disease progress is developed.In early 90’s, the amyloid cascade hypothesis has been the main hypothesis about the AD pathophysiology AD . CurrentThere are many doubts and controversies about amyloid cascade hypothesis, and it is more and more likely it may fail due to rising documented studies showing no correlation between Aβ deposits and clinical manifestation of the disease , 10. ManMore recently, there is an increasing interest to evaluate the role of the gut microbiome in the AD pathogenesis and the induction of neuroinflammatory changes. A recent advance in studies of AD etiology suggests that dysbiosis of microbiota  during life may lead to systemic inflammatory response and influence the immune response of microglia. Moreover, with time, the gut and the BBB permeability increases, and the vicious circle of neuronal destruction begins to work.Lederberg and McCray for the first time in 2001 provided a new specific definition of the term “microbiome,” and its current usage describes the ecological community of commensal, symbiotic, and pathogenic microorganisms sharing human body space . The ter2) between the host, environmental factors, and antigens in the human body [The human gastrointestinal (GI) tract harbors a most abundant population of microorganisms. The reason is that the GI represents one of the largest interfaces  [P. gingivalis-administration in mice, and the proportion of phylum Firmicutes was significantly higher. It seems that changes in the gut microbiota composition switched the gut immune profile to Th17 dominance [P. gingivalis in mouse model induced change of bacterial composition in the ileal microflora [P. gingivalis caused inflammatory response in the liver through the increase expression of pro-inflammatory cytokines TNF-α, IL-6, as well as Fitm2 and Plin2 -associated with lipid droplet formation. The last important may support the thesis that periodontitis affects NAFLD . Komazaki et al. [Aggregatibacter actinomycetemcomitans antibody titers correlated positively with visceral fat in NAFLD patients. Mouse treated with A. actinomycetemcomitans developed impaired glucose tolerance and insulin resistance. Studies showed that periodontitis may induce systemic low-grade inflammation. Experimental periodontitis in obese rats resulted with an increased gene expression of TNF-alpha and CRP in liver and increased levels of IL-6 and CRP in adipose tissue [Gut microbiota alterations can result from exposure to mentioned above lifestyle-related or environmental factors, but also to pathogens. The greatest potential to cause microbial dysbiosis has an enteric pathogens. However, gut microbiome is related to oral cavity flora, both in diversity and in composition. It is noticed that the swallowed saliva of patients with periodontitis may contain great amount of bacteria (up to 10ria/day) . Thus, rria/day) . In healria/day) . Periodoria/day) , 46 as wria/day) . Thus, pria/day) , 49. Perominance . Swallowcroflora , 51, endcroflora  noted thi et al.  showed te tissue . Thus, ie tissue .Intestinal microflora, which contains up to 95% of all human microbiome bacteria, forms the microbiome-gut axis that provides two-way communication through cytokine, immunological, hormonal, and neuronal signals –57. Sincbutyrate affects cholinergic neurons of the gut nervous system, causing increased motility, whereas propionate seems to decrease motility and increases secretions. Acetate can cross the blood-brain barrier and signals satiety to the brain. Additionally, it affects microglia and also decreases permeability in the BBB [In particular, the role of the intestinal microbiome in the metabolism of tryptophan is relatively well documented, and some studies showed that dysregulation of serotonin and kynurenic pathways was documented in various neurodegenerative disorders, also in AD . Dysregu the BBB –69. Buty the BBB . In addi the BBB . Butyrat the BBB . It was  the BBB . In mice the BBB , 73. Alt the BBB . Adminis the BBB  and redu the BBB . UndoubtA wide variety of microbiome-resident bacteria and fungi generate significant quantities of LPS, amyloids, and various microbial exudates , 77, 78.Clostridium defficile with very good clinical effects [Aging is associated with marked changes in human microbiome, and age-related changes in gut microbiota composition involve a reduction of microbial biodiversity, with a higher abundance of Proteobacteria together with decreased number of Bifidobacteria species, and significantly lowered SCFAs production –85. Age- effects . Also, s effects . Fecal t effects , 87. It The role of microbes in both aging and the onset and progression of the AD has been emerging in recent years. Studies on animals showed that modifications of gut microbiota induced by oral bacteriotherapy reflect changes in genes involved in inflammatory and neural plasticity processes with a positive impact on neural functions . ImproveOn the other hand, it is suggested that the intestinal nematodes and their secreted individual immune modulatory molecules may be considered as a defined therapeutic strategy. Successful infection by gastrointestinal nematodes results from their ability to survive within their hosts for long periods and causes chronic infection through regulation of the host immune responses, physiology, and behavior . In longTregs) that actively contribute to a shift in gut microbiota [Caenorhabditis elegans [Heligmosmoides polygyrus can prevent Bacteriodes vulgatus outgrowth and protect mice against intestinal inflammation by restoring goblet cell numbers in Nod2−/− mice [B. vulgatus results from the type 2 immune response that leads to the expansion of intestinal bacteria Clostridiales species [Intestinal nematodes reside in an extraordinary environment with commensal intestinal microbiota, where any disturbances result in the dysregulation of the immune system, thus leading to the development of chronic inflammatory disorders of the intestinal tract and even the CNS. Intestinal nematodes and host commensal flora, gut bacteria, sharing the same environmental niche evolved together . It is qcrobiota . It is p elegans . The las elegans  provides−/− mice . The hel species . Based o species , but not species . The intCurrently, presented methods can be considered as a real prospect of slowing down the development of Alzheimer’s type neurodegeneration Fig. .Fig. 2GuThe lack of effective treatment for Alzheimer’s disease stems mainly from the incomplete understanding of AD causes. Currently, there are several hypotheses which try to explain the early molecular mechanisms of AD pathogenesis. The current pathophysiological approach is based on a number of common known mechanisms of neurodegeneration, including accumulation of abnormal proteins tau an ABeta, mitochondrial dysfunction, oxidative stress, impaired insulin signaling, calcium homeostasis dysregulation, imbalance of neurotransmitters, early synaptic disconnection, late apoptotic cell death, and especially neuroinflammation in CNS with dysfunction of microglia, the brain resident macrophages. AD pathophysiology problem have long term considered as the diseases only of CNS without important influence of the periphery.Meanwhile, the rapidly growing number of scientific reports highlights the important role of peripheral infections and intestinal bacterial flora in the physiological function of the microbiome-intestine-brain axis. Microbiome controls the basic aspects of CNS, immunity, and behavior in health and disease. Changes in the amount and composition of the microbiome (dysbiosis) can be linked to disorders of the immune, endocrine, and nervous system, including mood changes, depression, increased susceptibility to stressors, and autistic behaviors. Abnormalities in the composition of the intestinal microbiome have also been found in many neurodegenerative diseases, including Alzheimer’s neurodegeneration. Dysbiotic intestinal microbiome, often accompanied by fungi and parasitic worms, jointly produces and releases onto the surface of the intestinal mucosa a multi-component mixture of secretion substances and microbial metabolic products containing a large group of compounds significantly increasing the innate immune function, elevating production of cytokines and inflammatory mediators. These compounds further increase the permeability of the intestinal mucosa and the permeability of the blood-brain barrier, significantly intensify inflammatory reactions, and induce amyloid aggregation. Decreased tightness of the intestinal mucosa and increased permeability of blood-brain barriers in the elderly, as well as dysbiosis of the intestinal microbiome, facilitate the entry of a large amount of bacterial amyloid and LPS into the circulatory system and CNS, where they activate innate resistance receptors: TLR and RAGE. Cooperation and cross-reactivation of RAGE and TLR receptors maintain a neuropathogenic inflammatory cycle in neurodegenerative diseases, including AD and other neuropathological disorders with the amyloidogenic component.It is more likely that infections, infectious agents, and their toxic products may be a trigger factor for neurodegenerative processes, mainly through disruption of functioning of the immune system, which is associated with excessive synthesis and accumulation of Aβ, hyperphosphorylation of tau protein, and induction of chronic inflammation in the brain. Chronic peripheral infections and dysbiotic intestinal microflora may lead to many pathological changes in different tissues, also distant from the source of infection. Initially, the body is able to resist of this alterations; however, during aging, the regenerative capacity and ability to restrict infections decrease, leading to predominate of neurodegenerative processes and clinical manifestations of dementia. This confirms that pathological changes in the brain may start and follow many years before symptoms of the disease appear.Early human studies suggested that altering microbiota with beneficial bacteria or probiotics can lead to changes in brain function including cognitive functions. Recently, identification of gastrointestinal microorganisms using metagenomics and metabolomics methods increased ability to examine more subtle interactions between host and microbiome. The gut provides the largest physical interface between the environment (including the microbiome) and self. This bidirectional information flow between the microbiota and the brain suggests that the brain development, function, mood, and cognition may be influenced by our gastrointestinal contents. We should underline that microbiota with major component as bacteria can induce autoimmune and widespread neuroinflammation disorders with aging such AD. Our experiences and review of literature allow us to pay attention to the other relatively less- until recently -operated field of possible pathology which serious and perhaps predominant influence on the development of pathophysiological changes in the brain of AD patients.According to our opinion, in the near future, better understanding of the bidirectional communication between the brain and microbiota, host-microbe-helminth interactions, and determining the role of specific probiotic bacteria will allow the development of functional diets and the use of intestinal microbiome to improve the results of pharmacological therapy of many diseases. It is expected that these pathways will be especially harnessed to provide novel method to enhance health and treat AD. There is no doubt that in patients with AD, attempts to restore the intestinal microbiome to a composition reminiscent of that found in healthy adult humans will significantly slow down the progression of neurodegeneration by lowering the level of inflammatory reactions and/or amyloidogenesis.In conclusion, the new strategies seem to focus on examining the potential neuroprotective activity of disease-modifying drugs in the presymptomatic stages of AD, with the help of biomarkers that predict disease progression before development of overt dementia.


Vaginal health is an essential component of active and healthy aging in women at midlife and beyond. As a consequence of hormonal deprivation and senescence, the anatomy and function of urogenital tissues are significantly affected and vulvovaginal atrophy (VVA) may occur. In a high proportion of postmenopausal women, progressive and chronic VVA symptoms have a strong impact on sexual function and quality of life. The new definition of genitourinary syndrome of menopause (GSM) comprises genital symptoms , sexual symptoms  and urinary symptoms . Many variables  influence the clinical impact VVA/GSM symptoms and attitudes of elderly women to consult for receiving effective treatments. Psychosocial factors play a critical role in sexual functioning, but the integrity of the urogenital system is as well important affecting many domains of postmenopausal women's health, including sexual function. Several international surveys have extensively documented the need to improve VVA/GSM management because of the strong impact on women's daily life and on couple's intimacy. Health care providers (HCPs) need to be proactive in the early recognition of VVA/GSM in order to preserve urogenital and sexual longevity, by using hormonal and non-hormonal strategies. The clinical diagnosis is based on genital examination to identify objective signs and on the use of subjective scales to rate most bothersome symptoms (MBS), especially vaginal dryness. Recent studies point to the importance of addressing VVA/GSM as a potential early marker of poor general health in analogy with vasomotor symptoms. Therefore, a standard of VVA/GSM care in elderly women is desirable to enhance physical, emotional and mental well-being. Women live longer than men all around the world  and in dThe present narrative review points to the importance of addressing the chronic condition of vulvovaginal atrophy (VVA)/genitourinary syndrome of menopause (GSM) in the context of promoting urogenital and sexual longevity in women at midlife and beyond. It merely reflects the expert opinion of the authors by analyzing the amount of available evidence (1990–2019) in this complex field of research. Therapeutic strategies to effectively manage sexual symptoms associated with VVA/GSM have been reviewed extensively elsewhere –12 and, Among the multitude of menopausal complaints, vasomotor symptoms (hot flushes and cold or night sweats) and vaginal dryness have clearly shown a strong relationship with low estrogens during and after the menopausal transition . Up to 8Urogenital aging is an old problem, newly recognized, which can be highly prevented upon early recognition of signs and symptoms . VaginalBasic counseling is the first step in the management of postmenopausal sexual dysfunctions  and a stIn recent years, VVA has a new name, genitourinary syndrome of menopause (GSM), to underline the multitude of genital, sexual and urinary symptoms associated with the anatomical and functional changes of vulvo-vaginal tissues occurring with menopause and aging . A termiVVA is strictly related to estrogen deficiency and is an integral part of GSM . HoweverHormonal fluctuations driving the female reproductive life cycle highly modulate the functional anatomy of the uro-genital and pelvic tract. Early data showed that untreated postmenopausal women displaying <50 pg/ml of circulating estradiol suffer more from symptoms associated with VVA . A histoThe neurovascular and neuromuscular substrates of the pelvic area are also impaired because the vulva, as well as the pelvic floor and the urinary tract, manifest similar anatomical and functional changes –66. In pClinical interviews and rating scales to score the most bothersome symptoms (MBS)  are usefIn both clinical and research settings, subjective assessment (the MBS approach) and objective assessments of VVA  should be combined according to a recent systematic literature search . Even thNotwithstanding these findings, HCPs may pose very simple questions to facilitate an open conversation on urogenital health and to record the variety of vaginal, vulvar and urinary symptoms. Visual vaginal, vulvar and pelvic assessment by HCPs is a useful measure for diagnosing VVA/GSM and assessing response to treatment. Moreover, it may help HCPs to identify women at risk of vaginal dryness and dyspareunia, and allow them to proactively engage in conversations about sexual health . Figure Women with breast cancer and other gynecological malignancies are at very high risk of VVA and associated symptoms. Indeed, endocrine chemotherapy, surgery and/or radiation may induce profound changes at urogenital levels which have to be timely recognized in the oncologic care , 77. MorIn the last decade, many international surveys attempted to clarify the impact of VVA/GSM on sexual function and QoL  indicatiCultural aspects are strongly related to the interpretation of results from surveys on VVA/GSM and explain differences in reporting bothersome symptoms and consequences associated with them. For example, women reporting VVA in Southern Europe stopped having sex in 18 % of the cases , in NortThe EVES study collected very accurate information in a clinical population of EU  postmenopausal women aged 45–75 years reporting at least one subjective VVA symptom and objectively diagnosed with VVA during gynecological examination. Women scored 19 potentially VVA-related complaints on a 4-point severity scale  and filled in both the EuroQol questionnaire (EQ-5D-3L)  and the The chronic nature of VVA/GSM indicates that effective treatments should preferably be prescribed at the onset of the symptoms and signs of atrophic changes of the vagina, early before severe pictures of the condition occur, and should be continued over time in order to maintain their benefits . The the2 laser, the non-ablative vaginal Erbium YAG laser (VEL) and energy-based devices are increasingly used to alleviate VVA/GSM symptoms with promising results and a good safety profile  which are useful to reduce friction during sexual activity, whereas moisturizers are longer acting than lubricants and may exert a trophic effect . Pelvic  profile .Urogenital and sexual longevity is an integral part of healthy aging in postmenopausal women and their partners. The severity of VVA/GSM and the type of prevailing symptoms are mostly influenced by the multitude of clinical phenotypes of postmenopausal women depending on a wide range of biopsychosocial variables which are difficult to estimate in large scale trials. It is known that women loose less years of sexually active life because of poor health than men . This daThe management of VVA/GSM is increasingly important in light of the feminilization of aging. Postmenopausal women are becoming aware that preserving urogenital and sexual longevity is a major step in gender equality and healthy living. HCPs should address the issue in daily clinical practice with the aim to prevent the long-term health consequences associated with estrogen deprivation . Early rRN: conception and design. EM, LC, LT, AI, EB, SM, and DB: acquisition, analysis, and interpretation of data. CC and BG: drafting the article. RN and BG: revising for intellectual content. RN, EM, LC, SM, LT, AI, DB, CC, and BG: final approval.During the past 2 years, RN had a financial relationship  with Bayer HealthCare, Endoceutics, Exceltis, Gedeon Richter, MSD, Novo Nordisk, Palatin, Pfizer, Shionogi, Teva, and Theramex. These companies have no involvement with the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Accessory ossicles are supernumerary and inconstant structures that are notcaused by fractures. Derived from unfused ossification centers, accessoryossicles were first described by Vesalius in 1543. For centuries, they werebelieved to be asymptomatic. However, with advances in radiology techniques,many have been associated with painful syndromes. Although the originaldescriptions date from the sixteenth century, the subject is little discussedand, in some cases, controversial. The objective of this study was to describethe radiological aspects of a series of accessory ossicles and to review theevolution of their various descriptions, in order to revive discussion of thesubject. They arederived from unfused ossification centers, which can form free ossicles, sesamoid ossicles (imbeddedin a tendon), or bipartite ossicles . Although accessory ossicles werefirst described by Vesalius in 1543, the subject attracted little attention until recently,because, prior to the advent of radiology, there was a lack of knowledge withrespect to their clinical implications. There is now greater interest in the area,due to reports of pain syndromes related to these ossicles.Accessory ossicles are inconstant, independent, and considered well formed bones, notarising from fractures or other diseases, although they are equally susceptible toboth conditionsThe purpose of this study was to highlight a series of cases of accessory orbipartite ossicles that were of clinical importance, either because they provokedsymptoms or because their differential diagnoses were important. Data related to thecases were obtained from the archives of one of the authors.,2.The accessory ossicle adjacent to the base of the fifth metatarsal is known as osvesalianum pedis . It was ,3. Although it is typically considered an asymptomatic incidentalfinding, there have been reports of pain syndromes.The incidence of the os vesalianum pedis ranges from 0.1% to 0.4%, although computedtomography (CT) or magnetic resonance imaging (MRI) might be necessary for theaccurate diagnosis of the finding.The os vesalianum pedis should be distinguished from the os peroneum, the apophysisof the fifth metatarsal, Iselin's disease, avulsion fracture of the tuberosity,Jones and stress fracture of the fifth metatarsal. Identification of a joint withthe cuboid can guide the diagnosis, because it suggests os vesalianumpedis,3,6.The os peroneum is a sesamoid bone within the peroneus longus tendon, adjacent to thecalcaneocuboid joint , and is relativelycommon, with an incidence of 9-26%,3 and can be seen on X-rays in individuals 9-11 yearsof age, before it fuses with the bone axis at 12-16 years of age.The apophysis of the fifth metatarsal is parallel to the long axis of the metatarsaldiaphysis.Iselin's disease consists of self-limiting apophysitis caused by traction of the baseof the fifth metatarsal, resulting from repeated microtrauma. An X-ray of the footcan show enlargement or fragmentation of the osteochondral joint, and MRI can showbone edema.Avulsion fracture of the tuberosity of the fifth metatarsal results from forcedinversion of the foot. The increased tension on the peroneus brevis tendon in themovement causes apophysis detachment and the trace of the fracture is transverse atthe base of the fifth metatarsal, all ofthe cases being attributed to forced inversion and plantar flexion of thefoot.The Jones fracture was described in 1902, in a report of six cases (including that ofthe author), as a fracture transverse to the long axis of the fifth metatarsalapproximately 2 cm from its base, between the insertions of the peroneus brevis andperoneus tertius tendons. Poor irrigation of the metadiaphyseal regionusually impairs the healing of these fractures, which can delay or prevent theconsolidation of the fragments.Therefore, the sequelae of such fractures can be confused with a diagnosis with osvesalianum pedis.A stress fracture evolves from microfractures to complete fracture, on average, 1.5cm from the proximal diaphysis of the fifth metatarsal.The earliest reports of divided scaphoid were published in 1877 and 1895 by Gruberand Pfitzner. Although the authors dissected 3007 and 1450 specimens, theyidentified a divided scaphoid in only 4 (0.13%) and 9 (0.62%) of the cases,respectively. Fracture was the main hypothesis to explain the division, although ahypothesis of non-fusion of the radial and ulnar ossification centers of thescaphoid, forming a bipartite scaphoid , has als. However, that theory has been questioned. Louis etal. reviewed 17,439wrist X-rays (5365 were in children between 54 and 150 months of age) and foundmultiple scaphoid ossification centers in three cases (~0.01%), all in children.Despite the lack of follow-up of those three cases, the authors concluded that theputative multiple ossification centers likely coalesce to form a single scaphoid inadults.In 1906, Dwight reported a case of congenital bipartite scaphoid and was able toconfirm the non-fusion hypothesis reported the caseof a young girl with two scaphoid ossification centers, one on each side, andsubsequent evolution (between 8 and 17 years of age) to symptomatic bilateralbipartite scaphoid. The differential diagnosis would be a scaphoid fracture,although that is uncommon in children and, when it occurs, the division of thefragments is typically in the distal third. The authors concluded that, althoughextremely uncommon, one of the causes of division could be congenital unfusedossification centers (bipartite scaphoid).Recent evidence supporting the non-fusion hypothesis was published in 1990, whenDoman et al.. Althoughone of the pillars of diagnosis is the absence of degenerative changes, there havebeen reports of cases of symptomatic bipartite scaphoid with osteoarthritis in itscomponents,14,15. Therefore, the diagnosis of a divided scaphoid can bechallenging, especially when the patient is symptomatic, because it could representa bipartite scaphoid with degenerative changes or a fractured scaphoid withpseudoarthrosis.The diagnostic criteria described by Bunnell are currently accepted: absence of ahistory of trauma; presence of bilateral scaphoid division; equal size and densityof both scaphoid ossicles; the absence of degenerative changes in both scaphoidcomponents or another site in the wrist; and rounded, regular margins of bothscaphoid components,17. Theposterior process of the talus contains two tuberosities, the medial and thelateral, divided by the sulcus of the flexor hallucis longus tendon. The os trigonum articulates, viaa synchondrosis, with one of the tuberosities of the posterior process of the talus,can articulate with the calcaneus, and rarely, can occur in duplicate, one ostrigonum being seen in each tuberosity,17,19. It was first described by Rosenmüller in1804, being classifiedas an accessory ossicle by Gruber in 1864 and Stieda in 1869. However, in 1882,Shepherd concluded that it was the result of fracture of the posterior process ofthe talus. Although Shepherd'serror was corrected in that same year by Turner, the incorrect term "Shepherd's fracture" can still befound in the literature.The os trigonum  and 4 is. Both bonyappendages may cause talar compression syndrome or posterior ankle impingementsyndrome, especially in individuals who perform repeated plantar flexion of thefoot,23. This syndrome occurs in dancers and soccerplayers, because, by maintaining the pointe anddemi-pointe ballet positions or by kicking the ball, they compress the adjacent structures, such as the posterior talar,intermalleolar, and tibiofibular ligaments or the flexor hallucis longus tendonitself.The same ossification center that forms the os trigonum, when merged with theposterior process of the talus, can create a more prominent tuberosity known asStieda's process; however, softtissues are better studied on MRI. Excision of the os trigonum or Stieda's process is usuallysufficient to reduce pain.The posterior ankle impingement syndrome includes pain in the posterolateral aspectof the ankle that worsens upon vigorous plantar flexion. Lateral ankle X-rays canshow the os trigonum and Stieda's process, and an additional incidence in plantarflexion may be useful to identify the impact of the bony protuberance on thetibia. Given theincidence of findings in the tuberosities of the posterior process of the talus,talar compression syndrome and posterior ankle impingement syndrome should beconsidered in patients with ankle pain.The differential diagnosis of talar compression syndrome includes tenosynovitis orrupture of the flexor hallucis longus tendon, tenosynovitis of the peroneus tendonsin the lateral portion of the ankle, and tendonitis of the calcanealtendon. The divided acromion was first described by the Roman surgeonGaleno between the second and third centuries, and in 1863 Gruber described 3 cases among 100 dissectedcadavers, attributing the division to unfused epiphyses and referred to theaccessory ossicle as os acromiale,27.Os acromiale  and 6 is. Shortly thereafter, anatomists, such as Gray andCunningham, adopted the hypothesis of unfused epiphyses but did not rule out thehypothesis of fractures in some cases.Despite the results obtained by Gruber, Struthers et al., in 1896, dissected 14cadavers and attributed the division of the acromion to fractures that, with theconstant movement of the scapula against the clavicle, did not consolidate andformed a joint between the two portions of the acromion:bilaterality; rounded borders and constant thickness of the cleavage line betweenthe ossicle and the remainder of the uniform acromion; and position of the ossicleat or higher than the rest of the acromion.To mitigate the discussion and end the divergence, Liberson, in 1937, reported 25cases of os acromiale identified on shoulder X-rays and proposed three criteria todistinguish between those resulting from fracture and those representing osacromiale. Similar findings from a series of eight cases byMudge et al. in 1984 confirmed the hypothesis of rupture of the rotator cuff relatedto os acromiale.Neer, in 1972, reported 50 cases of shoulder impingement syndrome that underwentacromioplasty. In some cases, os acromiale was identified during surgery and wasimplicated as one of the causes of rotator cuff rupture,31, such as edema or calcificationin the supraspinatus tendon. Osteophytosis of the margins of os acromiale indicatesinstability that can result in impingement syndrome.Although os acromiale can be identified on axillary X-rays, CT or MRI can benecessary in order to visualize degenerative changes of the ossicle or indicationsof rotator cuff injury.The identification of os acromiale is crucial in the context of shoulder impingementsyndrome, because the presence of the accessory ossicle can alter the surgicalapproach. In 1932, Bugart evaluated 1452wrist X-rays and identified an os hamuli proprium in 1 (0.06%), whereas Chow et al.identified it in 42 (1.3%) of 3218 wrist X-rays evaluated between 1989 and2002,34.The os hamuli proprium, or bipartite hamulus , is a ra,35. The tensile forces that result in a fractured hamatecomplicate its fusion and favor pseudoarthrosis. Therefore, an unfused fracture of the hamulus is the maindifferential diagnosis of os hamuli proprium.The hook of the hamate is an important landmark in the wrist, because it is thelateral and distal delimiter of Guyon's canal, which contains the fat and ulnarartery, nerve, and veins. Its other delimiters are the pisiform bone ; the volar carpal ligament (anteriorly); and the pisohamate andtranscarpal ligaments (posteriorly). The hamulus serves as a pulley for the flexorpollicis profundus tendon and insertion site of the ulnar border of the transversecarpal ligament, the pisohamate ligament, and the flexor digiti minimi brevis andopponens pollicis muscles. Hamate hook fracture can occur in athletes engaged insports that require palmar gripping of a racket, club, or bat , as well as in cyclists and jackhammer operators. Neuropathy ofthe ulnar nerve was thought to be associated with hamate hook fracture, until 1981,when Greene et al. reported a case of bipartite hamulus associated with ulnar tunnelsyndrome. The presenceof os hamuli proprium might also be associated with carpal tunnel syndrome, giventhat Chow et al., in 2005, found that 95.2% of individuals with bipartite hamulusalso had carpal tunnel syndrome.Pain and paresthesia in the hypothenar eminence with irradiation to the fourth andfifth fingers may be caused by compression of the ulnar nerve at the level ofGuyon's canal. This clinical entity was designated ulnar tunnel syndrome by Dupontet al., in 1965. A carpal tunnel view X-ray can identify separation of thehamulus from the hamate, although CT might be indicated to distinguish betweenfracture and bipartite hamulus, which will present a well-defined regularmargin, and MRI mightbe indicated to assess the involvement of the ulnar nerve.The differential diagnosis of pain in the hypothenar eminence includes the following:fracture or dislocation of the pisiform bone; pyramidal osteochondral fracture;hamate hook fracture; carpal ulnar flexor tendonitis; tenosynovitis of the flexorpollicis tendon; osteoarthritis of the piso-pyramidal joint; ulnar tunnel syndrome;hypothenar hammer syndrome; hand-arm vibration syndrome; ganglion cyst; schwannoma;hemangioma; lipoma; and osteoid osteoma.Investigation can begin with X-rays, which can reveal, for example, os hamuliproprium, although other methods might be needed to clarify the diagnosis.Pain in the hypothenar eminence is a common complaint and has a broad differentialdiagnosis and was foundto correspond to a sesamoid in the posterior tibial tendon, which inserts into theposterior portion of the navicular tubercle. Von Luschka, in 1858, reported avariation of Bauhin's description in a 17-year-old individual. The adolescentpresented an ossicle in the posterior region of the navicular tubercle, albeitarticulated and surrounded by a joint capsule. The third alteration was described in 1914 by Geist, whofound 14 feet with accessory navicular bones among 100 X-rays. Among these 14 feet,the authors found some (the exact number was not reported) in which the ossicle hadfused to the navicular bone, forming a more prominent tuberosity.The navicular bone can present three different alterations that are consideredaccessory: the first, described by Bauhin in 1605, was designated os tibialeexternum: type 1, when rounded, measuringbetween 2 and 6 mm and located inside the posterior tibial tendon ; type2  had a type 1 accessory navicularbone.,41.An accessory navicular bone can be identified and classified on foot X-rays, althoughMRI can be necessary in symptomatic cases to identify signs of bone edema andchanges in the adjacent soft tissue, such as the synchondrosis and of the posteriortibial tendon. Adivided patella at the superolateral angle was first reported in 1883 by Gruber, whodesignated the condition bipartite patella. Other cases were reported and thedivision was attributed to fracture, until 1921, when Todd and McCally suggestedthat the patella could originate from more than one ossification center and that adivided patella could be caused by an anomaly of fusion of those centers.The patella is considered a sesamoid that works like a pulley, facilitating theextension of the knee reported a caseof bilateral divided patella identified during the autopsy of a 63-year-old man.Upon histological analysis of the fragments of the patella, the patellar capsule andthe cartilage between the fragments were found to be intact, with no evidence of thefibrosis that would have suggested a previous fracture. On the basis of thatfinding, the author proposed that the acquired cause (fracture) and the congenitalcause could be differentiated through histological analysis of the fragments. In afractured patella, there is discontinuity of the patellar capsule and cartilagebetween the fragments, whereas both are intact in a bipartite patella.In 1935, George,45. In 1943, Saupe proposed a classification of types ofbipartite patella according to the location of the accessory fragment: type I , and is bilateral in approximately 50% of cases: type I , when it.The bipartite patella was believed to be an asymptomatic anatomical variation until1977, when Weaver, reported 21 symptomatic cases, all with Saupe type III bipartitepatella. The majority of cases were young athletes with knee pain during or afterintense exercise, with no other probable cause and with improvement of symptomsafter excision of the accessory fragment. The cause of the pain was attributed toabnormal mobility of the synchondrosis between fragments found duringsurgery.An accessory fragment can usually be identified on X-rays, in anteroposterior andaxial patellar views, or on CT; however, MRI is necessary in order to clarify thediagnosis, because it can show edema in the accessory fragment and in the margins ofthe synchondrosis, between the fragments, in symptomatic patients,47. Thispathophysiology resembles the findings of Osgood-Schlatter disease-traction injuryin the tibial tuberosity at the patellar tendon insertion, which can causefragmentation of the affected tibial portion-and Sinding-Larsen-Johansson disease-inthe lower pole of the patella, at the level of the patellar tendon insertion, whichcan cause fragmentation of the affected patellar portion, a differential diagnosisfor type I bipartite patella-48. Therefore, the cause ofbipartite patella has not yet been fully clarified.Despite the fact that the congenital ossification center non-fusion hypothesis iswell established in the literature, there are reports of putative bipartite patellaein adults with knee pain in whom previous X-rays had shown normal patellae.According to Lawson, that suggests that the accessory fragment responsible for painactually represents chronic chondro-osseous disruption rather than the degenerativechanges of a congenital synchondrosis:Sinding-Larsen-Johansson disease, Osgood-Schlatter disease, jumper's knee (patellartendonitis), and patella sleeve fracture (avulsion fracture of the lower patellapole).The differential diagnosis of symptomatic bipartite patella includes thefollowing. That isprobably attributable to the low frequency of the type, which accounts for 5% ofreported cases, and an overlapwith Sinding-Larsen-Johansson syndrome, because both conditions affect mainly youngmen who practice physical activity, present knee pain, and have a fragment in theinferior aspect of the patella. Probably, the only way to distinguish between the two conditionswould be by evaluating previous examinations: a previously divided patellaindicating bipartite patella and a previously normal patella indicatingSinding-Larsen-Johansson. There are those who argue that there is no separateossification center in the lower patella and that cases of supposedly type Ibipartite patella are in fact sequelae of Sinding-Larsen-Johansson disease or itsasymptomatic form,50.The majority of reported cases of symptomatic bipartite patella occur in Saupe typesII and III. The only reports of symptomatic type I bipartite patella are the fourcases described by Okuno et al., in which there was traumatic separation of thebipartite patella


The extensive application of engineered nanomaterial (ENM) in various fields increases the possibilities of human exposure, thus imposing a huge risk of nanotoxicity. Hence, there is an urgent need for a detailed risk assessment of these ENMs in response to their toxicological profiling, predominantly in biomedical and biosensor settings. Numerous “toxico-omics” studies have been conducted on ENMs, however, a specific “risk assessment paradigm” dealing with the epigenetic modulations in humans owing to the exposure of these modern-day toxicants has not been defined yet. This review aims to address the critical aspects that are currently preventing the formation of a suitable risk assessment approach for/against ENM exposure and pointing out those researches, which may help to develop and implement effective guidance for nano-risk assessment. Literature relating to physicochemical characterization and toxicological behavior of ENMs were analyzed, and exposure assessment strategies were explored in order to extrapolate opportunities, challenges, and criticisms in the establishment of a baseline for the risk assessment paradigm of ENMs exposure. Various challenges, such as uncertainty in the relation of the physicochemical properties and ENM toxicity, the complexity of the dose-response relationships resulting in difficulty in its extrapolation and measurement of ENM exposure levels emerged as issues in the establishment of a traditional risk assessment. Such an appropriate risk assessment approach will provide adequate estimates of ENM exposure risks and will serve as a guideline for appropriate risk communication and management strategies aiming for the protection and the safety of humans. The environment surrounding us has a plethora of natural and manmade toxicants. These toxicants have gained access to almost every aspect of our life such as air, water, food, homes, workplaces, and belongings. It is very difficult to detoxify and eliminate toxicants after their entry into the human body, leading to the development of different syndromic symptoms. The exposure to these toxicants causes severe illness, diseases, and disability or death. Some of the common environmental toxicants are chemical compounds such as pesticides, heavy metals, plastics, and hydrocarbons. Many of these chemical compounds possess carcinogenic properties and, due to their common use in our society, are unavoidable. The jumbled chaos and rapid industrialization have profound effects on the augmentation of the air, water, and soil pollution. One of the rapidly emerging research areas in the twenty-first century is nanotechnology. Due to the advent and advancement of the nanoscience and technologies many engineered nanomaterials (ENMs) have been given access to our lives. ENMs have a broad spectrum of applications in various fields, such as in the fields of nanotheranostics and personalized medicine (the field of delivering a suitable drug to the right subjects at a precise time). The use of personalized medicine for cancer therapy is one of the promising areas in nanotheranostics  involved in cellular uptake and intracellular trafficking of ENMs is essential for evaluating the biomedical function, bio-distribution, toxicity, and therapeutic efficacy  group and neutral hydroxyl (–OH) groups help in reducing toxicity, enhancing stability and improving cellular internalization , PEGylated gold nanorods, and nanospheres, ranging in a size of 200–2,100 nm are efficiently uptaken by phagocytes by adsorption of opsonins such as immunoglobulin, laminin, fibronectin, or complement proteins to the surface of ENMs , Herceptin-coated gold, Carbon Nanotubes (CNTs), Silica Nanotubes (SNTs), polystyrene, carboxylated polystyrene, alginate–chitosan, carboxylated quantum dots, and almost all lipid-based ENMs internalize via Clathrin-mediated endocytosis , D, L-polylactide, poly(ethylene glycol-co-lactide), Silica-based (SiOAmine labeled polystyrene (60 nm), alginate-chitosan (157 nm), silica 60 nm), and polystyrene NP (40 nm) utilize this mode of internalization , carboxylated polystyrene (40 and 200 nm) and lipid ENMs (60 nm) are translocated through this mode  is the correlation between the physicochemical characteristics of ENMs with their biological activities. This allows the prediction and modification of the activity of ENM by manipulation of the molecular structure. The functional or chemical groups responsible for evoking the biological effect can be determined through the analysis of SAR. The SAR approach can also be used to model the potential hazards of ENMs and predict the potential risks specific to ENMs based on specific structural and compositional features  DNA methylation, (ii) modification of histones, and (iii) regulation of non-coding RNAs (ncRNAs) that alter DNA accessibility and chromatin structure, thereby modulating the gene expression pattern . These pde novo methylation and maintenance of the DNA are a family of DNA Methyl Transferases (DNMTs) of which DNMT1 is predominantly responsible for maintaining CpG methylation by adding methyl groups to the non-methylated daughter strand formed during replication, while enzymes like DNMT3a and DNMT3b are required during embryogenesis for methylation  bind to the methylated DNA to repress the transcription . PTMs can guide the state of chromatin  and eventually the expression of genes  and the long ncRNAs (>200 nucleotides). The three major classes of short non-coding RNAs are microRNAs (miRNAs), short interfering RNAs (siRNAs), and piwi-interacting RNAs (piRNAs). Generally, ncRNAs function to regulate gene expression at the transcriptional and post-transcriptional level by inducing heterochromatin formation, histone modification, DNA methylation targeting, and gene silencing  and long non-coding RNAs (lncRNAs). The persistence of these changes through the process of cell division would ensure the alteration of heritable gene expression pattern  is a well-studied epigenetic signaling tool that cells use to lock the genes in the silenced state. Researchers have learned a great deal about DNA methylation, including how and where it occurs. It has also been discovered that methylation of DNA is an important component in numerous cellular processes, including embryonic development, genomic imprinting, inactivation of X-chromosome, and maintenance of chromosome stability. Hypermethylation of promoter regions (CpG islands) silences the DNA repair, cell cycle, and apoptosis pathways genes, whereas hypomethylation of a CpG dinucleotide in the global genome activates gene expressions  and 5-hmC  with occupational exposure to multi-wall carbon nanotubes (MWCNT) and unexposed controls (n = 43) from the same workplace in the blood cells have shown changes in the DNA methylation  resulted in both hypomethylation of GPX gene and hypermethylation of ATM, CDK, and GSR genes in the lung tissues , which play a crucial part in the regulation of gene expression through their dynamic interactions with DNA, RNA, and proteins leading to various epigenetic modifications  alleviation of miRNA-21 and miRNA-30a expression. It was also observed that after every 2 h miR-155 is upregulated, but is subsequently degraded following longer times of exposure  in NIH/3T3 fibroblast cells induces a change in the 167 miRNAs expression. These epigenetic, genomic and non-genomic cellular changes which have been observed through ENM exposure are summarized in in vivo and in vitro studies have only summed up the fact that ENMs induce alterations in miRNA expression without going deeply into their associated underlying molecular mechanisms and their assisted repercussions. The role of lncRNA, siRNA, and piRNA in the epigenetic modifications during ENM exposure remain largely unknown.Early studies by Halappanavar et al. have established the fact that ENM exposure alters the expression of respective ncRNAs (Halappanavar et al., in vivo, in vitro, and epidemiological study considering modern molecular—omics strategies utilizing modern techniques and platforms would definitely help to identify detailed epigenetic mechanisms that link, or act as molecular markers of, environmental exposures and human health concerns. We anticipate that having a centralized database on ENMs toxicity in the context of physicochemical properties and a well-established in vivo system will be an added benefit in understanding the nature and extent of toxicity. Finally, there is an urgent need to develop guidelines on minimum concentrations, which could be possible only by establishing close collaboration between scientists from academia and industries, which should be closely monitored by the governmental and regulatory bodies, promoting the research within a regulatory context. These collaborative activities drive the development and implementation of epigenetically relevant integrated testing strategies and policies for the continued protection of public health.The ENMs are extensively being utilized in various commercial applications and are a constituent of numerous consumer products. Despite being a commercial commodity, many concerns have been raised regarding the potentially harmful effects of ENMs on the environment and human health. ENMs used in personalized medicines remain associated with several health issues and pose a great concern among researchers worldwide to overcome their toxicity. After entering into the human body, ENMs accumulate in the tissues/organs because of their insoluble, non-biodegradable, non-biocompatible nature, thus restricting the pace of excretion, resulting in long-term exposure and subsequent toxicity. ENMs have a tendency to aggregate and form large structures ranging from 5 to 500 nm in diameter and translocate the lung-blood barrier through an endocytic uptake mechanism and enter the blood circulation. These are transported through the body to various tissues and bodies such as the heart, body, spleen, gastrointestinal tract, cardiac system, and central nervous system where they have damaging impacts on health. Nanomaterials communicate with biomolecules i.e., DNA, proteins, and lipids within the body and altering the fundamental cellular and metabolic processes like cell division, cellular signaling, apoptosis and trigger inflammation epigenetic alteration and modifications in the chromosome. Among various toxicity mechanisms, epigenetic mechanisms are not very well-studied. Here we summarize the toxic effects of various ENMs leading to the epigenetic changes. It was well-established that epigenetic processes shape our development and enable us to adapt to a constantly changing environment. The epigenetic manipulation is associated with several reported disease conditions, such as allergic contact dermatitis, inflammatory bowel disease, childhood asthma, chronic obstructive pulmonary disease, and several type of cancers, neurodegenerative, and genetic disorders. Epigenetic mechanisms are also related with the progression of autoimmune diseases and several other inflammatory disorders like multiple sclerosis, rheumatoid systemic lupus erythematosus, arthritis, psoriasis, Crohn's disease (Smolkova et al., Epigenetic alterations have the potential to induce prolonged changes in the programming of gene expression and any failure in the detection of these changes could lead to unexpected and unpleasant effects in the biological system. ENMs have a little yet strong effect on epigenetics, so it becomes mandatory to scrutinize them before their extensive applications specifically in the biomedical field. Further studies on this subject matter seem necessary in order to outline/strategize an effective nano-focused risk evaluation strategy/approach that consists of more substantial information about ENMs and its interaction with the surroundings including human and environment.PB conceived the idea. PB and MG worked on study conception and design. MG, PB, KZ, and PM screened titles for relevance and abstracted the data from the eligible full-text articles. MG, PB, KZ, and PM analyzed and interpreted the data and drafted the manuscript. PB and MG critically revised the manuscript with input from the entire team. All authors have read and approved the final draft.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.