Background and Objectives: Retinopathy of prematurity (ROP) is the leading cause of blindness in preterm infants. We studied the relationship between different perinatal characteristics, i.e., sex; gestational age (GA); birth weight (BW); C-reactive protein (CRP) and lactate dehydrogenase (LDH) concentrations; ventilation, continuous positive airway pressure (CPAP), and surfactant administration; and the incidence of Stage 1–3 ROP. Materials and Methods: This study included 247 preterm infants with gestational age (GA) < 32 weeks that were successfully screened for ROP. Univariate and multivariate binary analyses were performed to find the most significant risk factors for ROP (Stage 1–3), while multivariate multinomial analysis was used to find the most significant risk factors for specific ROP stages, i.e., Stage 1, 2, and 3. Results: The incidence of ROP (Stage 1–3) was 66.40% (164 infants), while that of Stage 1, 2, and 3 ROP was 15.38% (38 infants), 27.53% (68 infants), and 23.48% (58 infants), respectively. Following univariate analysis, multiple perinatal characteristics, i.e., GA; BW; and ventilation, CPAP, and surfactant administration, were found to be statistically significant risk factors for ROP (p < 0.001). However, in a multivariate model using the same characteristics, only BW and ventilation were significant ROP predictors . Multivariate multinomial analysis revealed that BW was only significantly correlated with Stage 2 and 3 ROP , while ventilation was only significantly correlated with Stage 2 ROP (p < 0.05). Conclusions: The results indicate that GA; BW; and the use of ventilation, CPAP, and surfactant were all significant risk factors for ROP (Stage 1–3), but only BW and ventilation were significantly correlated with ROP and specific stages of the disease, namely Stage 2 and 3 ROP and Stage 2 ROP, respectively, in multivariate models. Retinopathy of prematurity (ROP) is one of the main causes of visual impairment during childhood and the leading cause of blindness in preterm infants . ROP is ROP incidence is approximately 60% in preterm infants with a birth weight (BW) < 1500 g, consistent with most studies over time, while the rate of progression to severe ROP (Stages 3–5) has been reported to be approximately 15% ,9. The vUnderstanding the mechanisms through which risk factors determine the onset and progress of ROP can improve the screening and treatment of this disease. One possible strategy is closely examining the connection between risk factors and different ROP stages. Although associations between ROP and various risk factors have been extensively researched over the past decades ,20,21,22The study cohort included 247 very and extremely preterm infants that were admitted to the Neonatology Department of the Timişoara County Emergency Clinical Hospital between January 2017 and December 2019. The GA was calculated based on the last menstrual period and BW was measured during the first postnatal minutes. Levels of C-reactive protein (CRP), an inflammation marker, and lactate dehydrogenase (LDH), a hemolysis marker, were measured during the first six postnatal hours, usually prior to commencing artificial ventilation treatment and, in exceptional cases, during the first hour of ventilation treatment. CRP and LDH levels below 5 mg/L and 600 U/L, respectively, were considered normal, while levels above these thresholds were considered pathological. Surfactant was administered as a curative treatment for patients who were diagnosed with moderate or severe RDS from the first hours after birth. These patients required longer ventilation and CPAP treatment compared to those who were diagnosed with mild RDS, and this could have influenced the incidence and stage of ROP. ROP diagnostic examinations were performed by an experienced ophthalmologist using indirect ophthalmoscopy. Therapeutic interventions were immediately performed for all infants that developed Stage 3 ROP, and subsequently, none of the 247 patients included in this study developed Stage 4 and 5 ROP. Approval was obtained from the local Ethical Committee.t-test and χ2 test to examine continuous and dichotomous variables, respectively. Univariate binomial logistic regression analysis was performed, and factors with a statistically significant correlation to ROP (Stage 1–3) were then analyzed by multivariate binomial logistic regression analysis, and the odds ratios (ORs) were calculated. These factors were then used in a multivariate multinominal logistic regression analysis to analyze the relationship between multiple independent factors and specific ROP stages, namely Stages 1, 2, and 3. All statistical tests have been 2-tailed and a p-value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS Version 26 .Continuous variables are expressed as mean ± standard deviation (SD), while categorical variables are expressed as numbers and/or percentages. Univariate analysis was performed using the Student’s In this study, 247 infants with GA < 32 weeks and BW of ≤2560 g were screened for ROP. The male to female ratio was 1.09 , with no statistically significant difference being found between sexes in regard to GA, BW, ventilation and CPAP duration, CRP and LDH concentrations, administration of surfactant, and ROP (Stage 1–3) incidence.The incidence of ROP (Stage 1–3) in our study was 66.40% (164 infants) and 15.38% (38 infants), 27.53% (68 infants), and 23.48% (58 infants) for Stages 1, 2, and 3, respectively, as shown in the schematic diagram below .The perinatal characteristics of infants that developed and did not develop ROP (Stage 1–3) have been listed in p < 0.001). As shown in p = 0.150, p = 0.166, and p = 0.283, respectively). Therefore, following the independent analysis of these factors, ventilation treatment was the risk factor with the strongest correlation to ROP (Stage 1–3), followed by surfactant treatment, CPAP treatment, GA, and BW.A logistic regression analysis of each risk factor revealed that there were statistically significant differences between infants of different GAs, BWs, and treatment in regard to ROP (Stage 1–3) development , while ventilation was positively correlated with the disease. Out of the two factors, the BW had less impact on ROP (Stage 1–3) incidence and is, therefore, a less significant risk factor compared to ventilation treatment .The perinatal characteristics mentioned in the previous section that were demonstrated to be significant ROP (Stage 1–3) risk factors, i.e., GA; BW; and ventilation, CPAP, and surfactant treatments were analyzed by multivariate binary logistic regression analysis, and the ORs were calculated. As seen in p = 0.056). However, both BW and ventilation treatment were significant predictors for Stage 2 ROP , as infants with a high BW were less likely to have ROP and those who underwent ventilation treatment were more likely to have Stage 2 ROP. The only significant predictor of Stage 3 ROP was BW .The same perinatal characteristics mentioned in the previous section were analyzed by multivariate multinomial logistic regression analysis to study their relationship to specific stages of ROP, and the ORs were calculated. As presented in As expected, in this study, BW has been found to be a nearly significant predictor of Stage 1 ROP and a significant predictor of Stage 2 and 3 ROP. In Artificial ventilation treatment, another well-known ROP risk factor, has been found to be a significant predictor of Stage 2 ROP, but it did not have statistical significance as a predictor of Stage 1 and 3 ROP. In The primary purpose of this report was to analyze whether differences in perinatal characteristics alter the incidence of ROP (Stage 1–3) and specific ROP stages, namely Stages 1, 2, and 3 ROP. The latter has not been as extensively analyzed and discussed in the literature as the former, with most studies focusing on the incidence of ROP  rather than specific ROP stages. There has been extensive research on ROP incidence in the past years; however, there is yet no consensus regarding which risk factors are the more significant predictors of ROP or its various stages, nor on the underlying mechanisms through which these risk factors influence the onset and severity of ROP . In addiCPAP treatment has been shown to be significantly correlated with ROP (any stage) in a multivariate model ; howeverIn this study, surfactant treatment, which has also been reported as a statistically significant ROP risk factor , was admThe larger the number of perinatal factors taken into account, the more ROP risk factors can be associated with ROP, and their respective levels of correlation with ROP, as well as the statistical significance of these correlations, can be better assessed. This is due to the interlinked mechanisms between risk factors, and any new risk factor that is identified improves the statistical model and can ultimately assist ophthalmologists in ROP diagnosis, prediction, and treatment . TherefoTo our knowledge, LDH and CRP levels have been scarcely studied as possible risk factors for ROP. Although our results did not show any strong relationship between these two markers and ROP, these may be revealed to be significant in future studies that include larger cohorts and Stage 4 and 5 ROP.The main limitation of our study is the low number of perinatal characteristics recorded. As seen in our results, the statistical significance of a risk factor changes when an additional variable is taken into account, and, given the complex inter-relationships between these characteristics and ROP, the more potential risk factors are considered in the analysis, the more accurately this depicts the correlation of independent risk factors to ROP incidence. The absence of Stage 4 and 5 ROP in this study is another possible limitation, as the addition of other stages of the disease would influence the statistical model and, therefore, the p-values would be different for all the correlations mentioned above. A third limitation may be that all the patients included in this study had a GA < 32 weeks and, therefore, ROP can be more clearly associated with lower GA in models where infants with a higher GA were included.This study confirms several known ROP risk factors, i.e., GA; BW; and ventilation, CPAP, and surfactant administration, which were all significant risk factors for ROP (Stage 1–3) in a univariate statistical model, but in multivariate models, only BW and ventilation are significant predictors of ROP (Stage 1–3) and specific stages of the disease, namely Stage 2 and 3 ROP and Stage 2 ROP, respectively.


Extracorporeal membrane oxygenation (ECMO) is a common treatment for cardiopulmonary failure. Although it can effectively reduce the mortality of patients with cardiopulmonary failure, it still has a high mortality rate, such as acute limb ischemia (ALI), stroke, liver and kidney failure, and other related complications and related causes of death. This study aims to explore the impact of ALI on the mortality of VA-ECMO patients in hospital and 6 months after discharge and analyze the occurrence of ALI and related factors that affect the mortality of VA-ECMO in hospital and 6 months after discharge. The results showed that the smoking history was an independent risk factor for ALI, and age, diabetes, cardiac arrest, first time of ECMO, and hyperbilirubinemia were associated risk factors for in-hospital mortality. Cardiac arrest and ALI were associated risk factors for mortality at 6 months after discharge. Although ALI is not significantly associated with VA-ECMO in-hospital mortality, it is a risk factor for mortality at 6 months after discharge, and medical personnel should therefore strive to reduce and avoid ALI. Extracorporeal membrane oxygenation (ECMO) is a continuous extracorporeal vital sign treatment method, which uses extracorporeal equipment to replace or partially replace the human heart and lung functions, and supports life to fight for the chance of heart and lung disease healing and functional recovery , 2. The A retrospective analysis of the clinical data of 124 VA-ECMO patients admitted to the ICU in our hospital from August 2017 to August 2020. Inclusion criteria: all received VA-ECMO treatment; survived more than two hours after VA-ECMO was initiated (regardless of whether there is cardiogenic shock or respiratory failure); clinical data are complete. Exclusion criteria: there are contraindications for ECMO supportive treatment; those with congenital heart disease; those with unrepaired aortic dissection; those with severe valve insufficiency; those who fall off during follow-up. This study was approved by the ethics committee of our hospital, and informed consent was signed by the patients and their families.The specific intubation method of ECMO is the same as previous research reports . The appIschemic vascular complications were defined as ALI  with chaAll patients were divided into the limb ischemia group and nonlimb ischemia group according to the presence or absence of ALI. The in-hospital mortality and the mortality 6 months after discharge were recorded and compared between the two groups. Age, sex, chronic medical history, ECMO intubation , and other clinical data of all patients were recorded. The hospitalized death/survival status of the patients was recorded. The hospitalized surviving patients were followed up from the first day after discharge, and all were followed up for 6 months. The death/survival status was recorded through outpatient follow-up, telephone, or on-site follow-up.t-test was used for their comparison between groups. Nonnormally distributed measurement data are represented by the median  ), and the Mann–Whitney U test is used for analysis. Count data were expressed by (rate), and the chi-square test was used for their comparison between groups. Multivariate analysis adopts the multiple logistic regression model. P < 0.05 indicates that the difference is statistically significant.The results of this experiment were statistically analyzed by SPSS 20.0 . Normally distributed measurement data are represented by (mean ± standard deviation), and the P < 0.05), as given in A total of 124 patients were included in this study, including 16 patients with acute limb ischemia  and 108 patients without limb ischemia. Univariate analysis showed that the smoking history was associated with ALI (P > 0.05). Smoking history was an independent factor of ALI (P < 0.05), as given in Tables Multivariate logistic analysis showed that age, proportion of female, BMI, hypertension, diabetes, cardiac arrest, drainage tube model, perfusion tube model, drainage-perfusion tube ipsilateral, distal perfusion tube DPC, first auxiliary time of ECMO, and hyperbilirubinemia had no significant correlation with the occurrence of ALI (P < 0.05), as shown in In the limb ischemia group, 6 patients died in hospital, 9 patients died within 6 months after discharge, the in-hospital mortality rate was 37.50% (6/16), and the mortality at 6 months after discharge was 56.25% (9/16). In the nonlimb ischemia group, 50 patients died in hospital, 25 patients died within 6 months after discharge, the in-hospital mortality rate was 46.30% (50/108), and the mortality at 6 months after discharge was 23.15% (25/108). The mortality at 6 months after discharge of the limb ischemia group was higher than that of the nonlimb ischemia group (P < 0.05), as given in Among the 124 ECMO patients, 56 died in hospital and 68 survived in hospital. According to the death/survival of the patients, they were divided into the hospitalized death group and hospitalized survival group for analysis. Univariate analysis showed that age, diabetes, cardiac arrest, ECMO first auxiliary time, and hyperbilirubinemia were related to hospital death of ECMO patients (P < 0.05), as given in Tables Multivariate logistic analysis showed that age, diabetes, cardiac arrest, ECMO first assist time, and hyperbilirubinemia were independent influencing factors of hospital death in ECMO patients P < 0.0, as giveP), as given in Among 68 ECMO patients, 35 died and 33 survived 6 months after discharge. According to the death/survival of patients, they were divided into 6-month discharged death group and 6-month discharged survival group for analysis. Univariate analysis showed that cardiac arrest and ALI were related to death of ECMO patients at 6 months after discharge (P < 0.05), as given in Tables Multivariate logistic analysis showed that cardiac arrest and ALI were independent factors influencing the death of ECMO patients at 6 months after discharge  [There is literature that age, history of diabetes, history of stroke, and history of peripheral arterial disease are predisposing factors related to limb ischemia in ECMO patients . HoweverP=0.02) . HoweverIn this study, why is ALI a predictor of mortality at 6 months after discharge, but not of in-hospital death? In 16 patients with ALI, 8 of them were treated with open thrombectomy and fasciotomy and decompression, all of them survived and were discharged, 7 died 6 months after discharge, and 1 survived. 8 patients were treated conservatively, 6 died during hospitalization, and 2 died 6 months after discharge. Presumably, ALI was actually associated with in-hospital mortality, but the intervention of the vascular surgeon improved ALI and saved the patient's life, so the effect on in-hospital mortality was statistically reduced. It can be concluded that ALI has an impact on in-hospital mortality, but further data and evidence are needed to support this. Although specific perspectives and conclusions vary from literature to literature, there is a common view that ischemic vascular complications have a significant impact on mortality and prognosis in ECMO patients, so we believe that prevention is critical. Early diagnosis of ECMO patients at risk of acute limb ischemia through clinical examination, Doppler ultrasound, ECG monitoring, and angiography, thus enabling patients to achieve better outcomes and has received increasing attention . Once liThis study also has multiple limitations. (1) This is a single institution study and a retrospective study with a small sample size. (2) Considering the urgency of ECMO patients, peripheral artery-related diseases are often less considered in rescue, and the analysis of causes of vascular complications may be biased. (3) The placement of the ECMO tube and distal perfusion tube (DPC) is not standardized, but determined by the rescue physician.Smoking history was an independent risk factor for ALI, while age, diabetes, cardiac arrest, first time of ECMO, and hyperbilirubinemia were associated risk factors for in-hospital mortality. Cardiac arrest and ALI were associated risk factors for mortality at 6 months after discharge. Although ALI is not significantly associated with VA-ECMO in-hospital mortality, it is a risk factor for mortality at 6 months after discharge, and medical personnel should therefore strive to reduce and avoid ALI.


Pleural effusion (PE) is an important predictor for severity and prognosis of severe acute pancreatitis (SAP). However, there are few studies focused on the effects and timing of indwelling pleural catheter (IPC) on SAP. Considering this, we designed a retrospective study to verify the relationship between PE and severity of SAP and observe the effects and timing of IPC in SAP.  A total of 309 SAP patients were enrolled. Based on the presence or absence of PE and IPC and IPC time, the enrolled patients were divided into 6 groups. Then, baseline parameters, disease severity, critical complications, ventilator supporting time (VST), length of stay (LOS), and 60-day mortality were compared between each two groups. p < 0.001), along with longer VST (p < 0.001) and LOS (p < 0.001). And the critical complication rates were lower in group 1 (IPC within 1 week of onset) than group 2 (IPC after 1 week of onset). Further, patients in group 1 also had shorter LOS (p = 0.042) and VST (p = 0.001) than those in group 2. In addition, the survival analysis showed the risk of death in the PE group was higher than the non-PE group . And the risk of death in group 1 was lower than group 2 .  PE was a risk factor for death of SAP, but not an independent risk factor. SAP patients with PE rather without PE had higher critical complication rates ( PE is a risk factor for death of SAP, but not an independent risk factor. IPC, especially IPC within 1 week of onset, has clinical practical value in SAP. Acute pancreatitis (AP) is an acute inflammatory process involving the pancreas and extrapancreatic tissue, and its global incidence is increasing . About 2Pleural effusion (PE) is a common intrathoracic complication in SAP . Recent The Ethics Committee of the First Affiliated Hospital of Nanchang University had approved the protocol of this study. Because of the retrospective nature of the study, we gave written informed consent. Between January 1, 2017, and January 1, 2021, AP patients were evaluated within 72 hours after admission according to the inclusion and exclusion criteria .Patients with two or more of the following three manifestations were diagnosed with AP: (1) imaging (ultrasound or computed tomography) indicates AP; (2) acute epigastric pain; (3) serum enzyme level was more than 3 times higher than normal . And PE Based on the revised Atlanta classification, AP was classified as mild AP, moderate AP, and SAP . The modThe Extra Pancreatic Inflammation on CT (EPIC) score is based on the presence of signs of extrapancreatic inflammation, which is range from 0 to 7. For predicting the severity and prognosis of SAP, EPIC score ≥ 4 has a 100% sensitivity and is better than the Balthazar score and CT Severity Index . TherefoThe laboratory indicators  were obtained from blood samples taken from enrolled patients within 48 hours of symptom onset.The following two conditions need to be met during IPC: (1) imaging showed the fluid thickness on thoracic ultrasound > 1 cm; (2) there was a safe puncture path. IPC process was described in more detail in earlier study . The sigThe 309 SAP patients selected were divided into the PE and non-PE groups. Then, patients in the PE group were divided into the IPC and non-IPC groups, and IPC group patients were divided into the IPC within 1 week of onset and IPC after 1 week of onset groups.The follow-up data for this study were the patients' 60-day mortality. The 60-day mortality data could be collected from the hospitalized cases, telephone, or outpatient  abdominal compartment syndrome (ACS), (2) acute necrosis pancreatitis (ANP), (3) organ failure, (4) fungus infection, (5) bleeding and thrombus, (6) VST, and (7) percutaneous catheter drainage (PCD) and minimally invasive debridement (MID).p < 0.05 stood for statistically significant. All statistical analyses were performed by SPSS 26.0 , and the survival curve graphs were drawn by GraphPad Prism 8 .Quantitative variables were analysed by ANOVA, and Fisher exact test was used to compare the categorical variables. The factors related to death of SAP were determined by Cox proportional hazards models. Due to our study had an exploratory nature, relevant clinical or biochemical variables  were evaPE was a risk factor for death of SAP, but it was not an independent risk factor. In addition, APACHE II score, EPIC score, modified Marshall score, CRP, WBC, Ca, Lac, amylase, fungal infection, bleeding, ACS, and organ failure were also the risk factors of death for SAP. However, only modified Marshall score, ACS, bleeding, and organ failure were the independent risk factors .p = 0.02) and serum creatinine values  were lower in the IPC group than the non-IPC group. All the baseline variables were balanced between group 1 and group 2 . And the risk of death of group 1 was lower than group 2 . However, there was no significant difference in risk of death between the IPC and non-IPC groups . Further, group 1 versus group 2 had a shorter LOS . However, there was no difference in LOS between the IPC and non-IPC groups , fungus infection , and necrosis  were higher in the PE group than the non-PE group. Furthermore, patients with PE rather without PE had longer VST . And incidence of multiple organ failure  and PCD  was significantly lower in the IPC group than the non-IPC group. Compared with group 2, group 1 had lower rates of PCD , MID , multiple organ failure , and necrosis , along with a shorter VST .The rates of multiple organ failure (51.6% vs. 19.8%), bleeding  PE is a risk factor for death of SAP, but not an independent risk factor; (2) SAP patients with PE rather without PE were more serious and had a worse outcome; (3) compared with IPC after 1 week, IPC within 1 week could reduce LOS, VST, complication rates, and risk of death in SAP.This study showed that SAP patients with PE rather without PE were more serious and had worse outcome, which was consistent with the previous studies , 9, 23. In the study, IPC could reduce the rates of multiple organ failure and PCD, suggesting IPC may have certain clinical value in SAP. The mechanism could be the following: (1) the PE of pancreatitis is usually exudative. When there is a tappable fluid, IPC may be considered to rule out an infected PE ; otherwiThere are two mortality peaks in AP, and the first peak is due to multiorgan dysfunction during the first week. Since 60% of AP deaths occurred in the first week , 28, we Limitations of the study are as follows: (1) this is a retrospective study, and randomized controlled trials are ideal, but retrospective studies are acceptable when a sufficient number of randomized controlled trials have not been conducted. (2) The study just involves a single digestive centre of Chinese population. (3) The number of patients who received IPC was more than that of non-IPC patients, and the number of patients who received IPC was more than that of IPC after 1 week of onset, and we can explain the difference through the attitudes of doctors and patients in our centre for PE of SAP. When conditions permit, prospective studies could be conducted to strictly control the timing of IPC to increase the reliability of experimental results. (4) Due to the limited time in this study, the sample size collected is small, so more cases can be included in the future study for a deeper and wider research.Despite these limitations, it still gives clinicians some implications: IPC, especially IPC within 1 week of onset, seems to have clinical practical value in SAP.In conclusions, (1) PE is a risk factor for SAP mortality, but not an independent risk factor. (2) IPC, especially IPC within 1 week of onset, seems to have clinical practical value in SAP.


Inhalation, ingestion, and dermal absorption are key portals of entry. Selected literature provides context for the US Environmental Protection Agency (US EPA) ambient air quality standards, the conclusions of an Independent Particulate Matter Review Panel, the importance of internal combustion emissions, and evidence suggesting UFPs/NPs cross biological barriers and reach the brain. NPs produce oxidative stress and neuroinflammation, neurovascular unit, mitochondrial, endoplasmic reticulum and DNA damage, protein aggregation and misfolding, and other effects. Exposure to ambient PM2.5 concentrations at or below current US standards can increase the risk for TIAs, ischemic and hemorrhagic stroke, cognitive deficits, dementia, and Alzheimer’s and Parkinson’s diseases. Residing in a highly polluted megacity is associated with Alzheimer neuropathology hallmarks in 99.5% of residents between 11 months and ≤40 y. PD risk and aggravation are linked to air pollution and exposure to diesel exhaust increases ALS risk. Overall, the literature supports that particle pollution contributes to targeted neurological and psychiatric outcomes and highlights the complexity of the pathophysiologic mechanisms and the marked differences in pollution profiles inducing neural damage. Factors such as emission source intensity, genetics, nutrition, comorbidities, and others also play a role. PM2.5 is a threat for neurological and psychiatric diseases. Thus, future research should address specifically the potential role of UFPs/NPs in inducing neural damage.We appraise newly accumulated evidence of the impact of particle pollution on the brain, the portals of entry, the neural damage mechanisms, and ultimately the neurological and psychiatric outcomes statistically associated with exposures. PM pollution comes from natural and anthropogenic sources such as fossil fuel combustion, engineered nanoparticles (NP ≤ 100 nm), wildfires, and wood burning. We are all constantly exposed during normal daily activities to some level of particle pollution of various sizes—PM We live surrounded by environmental hazards including toxic compounds in air, water, soil, and food. Pollution is ubiquitous and mostly unavoidable. Neurotoxic organic and inorganic compounds come from fossil fuel combustion, engineered nanoparticles, nanoplastics, and compounds resulting from disasters such as forest wildfires. We are constantly exposed to these environmental hazards, regardless of age, sex, or socioeconomic status. Some people are more vulnerable than others and the brain in development is a target. The complexities of our modern-day, fossil fuel-based society are a factor when we talk about central nervous system (CNS) effects and the role of specific pollutants.3), particulate matter (PM), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and lead (Pb)) are operationally defined. Comparisons of pollution burdens across regions and countries must begin by ensuring the application of identical measurement methods and analytical techniques, otherwise we risk comparing apples to oranges. In addition, PM and O3 are not singular entities; rather, they are lumped parameters representing a family of source-dependent constituents and precursors that can vary greatly in space and time and in physicochemical and toxicological characteristics. For these reasons, it is extremely difficult to make comparisons of PM2.5 pollution and health effects in, for example, Delhi versus New York City or Provo, Utah versus Metropolitan Mexico City. Moreover, the determinants of adverse health outcomes are numerous: the strength and nature of emission sources, exposure times, and cumulative exposures over a lifetime, age, morbidities, and occupational history are some of the most obvious. The cumulative effect of these and other factors will determine specific health outcomes and responses vary significantly by population in terms of genetics, nutrition, exercise patterns, and cultural factors. These arguments should be an alarm for the reader. The sophistication of instruments, methodologies, and models to characterize air pollutants, exposures, or the results and interpretation of a specific PM2.5 study, for example, may not equate to ability to understand and compare results, not even within the same country, let alone across the globe. Thus, local capacity to understand emission sources, implement PM control measures, and establish clinical, laboratory, and pathology links becomes paramount. Minding only criteria pollutants  does not2.5 air pollution exposure and cardiovascular morbidity and mortality [2.5 Air Quality Guideline Level is 5 µg/m3, with four interim targets proposed as incremental steps in a progressive reduction of air pollution and intended for use in highly polluted areas [There is strong evidence of causality between PMThis Review provides information about PM CNS effects with a focus on stroke, neurodegenerative diseases, and psychiatric symptoms preceding or concomitant with neurodegeneration. Our discussion covers the current policy landscape in the US regarding particle pollution, internal combustion engine PM emissions, the differences in ambient air quality standards between the US and WHO 2021 guidelines, the recent expert suggestions of an Independent Particulate Matter Review Panel, and the importance of UFPs and NPs for the mechanistic neural damaging pathways linked to exposure to them. Additionally, the reader will find arguments of specific neural damage from PM exposures and related NP experimental work, epidemiological studies establishing robust links between PM and neurological and psychiatric adverse outcomes, our opinion of the role of health workers in protecting patients from PM pollution, and lessons to be learned.1 for fine particulate matter PM2.5 (particles ≤ 2.5 µm). The primary standards are the focus of our concern in terms of potential adverse effects on the brain. The primary annual average and 24 h standards are 12.0 µg/m3 and 35.0 µg/m3, respectively [an annual standard between 10 μg per cubic meter and 8 μg per cubic meter would protect the general public and at-risk groups” and “the 24-h standard be set between 30 μg per cubic meter and 25 μg per cubic meter”. At the time of this writing, the EPA is revisiting its decision and undertaking another assessment. Keeping these observations, the 2021 WHO Global Air Quality Guidelines [2.5 are indeed related to exposures below the current US EPA standards [Last year, the US EPA decided to retain, without revision, the existing primary and secondary National Ambient Air Quality Standards (NAAQS)2.5 pollution across the world include industrial fuel combustion, wood burning, farming operations, construction and demolition, dust, managed burning, wildfires, and internal combustion engines powering vehicles, ships, locomotives, and equipment. Motor vehicle brake and tire wear are a growing PM2.5 source. Combustion of any fossil fuel or biofuel generates PM2.5 emissions and diesel engines are a particularly notorious source. The US has adopted aggressive emission standards for heavy-duty engines. Since 2007, the limit is no more than 10 milligrams of PM mass emissions per brake-horsepower-hour of energy output (10 mg/bhp-hr). However, this standard does not explicitly limit the emissions in the UFP size range [The anthropogenic sources of PMze range . Europe 0.2, PM2.5, and PM2.5–10 mass, respectively [0.2), will be increasingly important sources of PM0.2 and metals in the future [2.5 pollution and significant exposures for thousands of firefighters and millions of people in the smoke path. More than 50 million homes are located in the land/urban interface (WUI) in the US and projections exist of an increment of 1 million houses in the WUI every 3 y [2.5 in recent years across the US, and up to 50% in certain Western regions. Of utmost importance for this Review, wildfire PM2.5 concentrations are on average 150.0 μg/m3 with recorded concentrations above 500 μg/m3 and with spatial patterns that do not follow traditional socioeconomic pollution exposure gradients [The contributions from tailpipe and non-tailpipe traffic sources to the traffic-related air pollution (TRAP) in the near-roadway environment constitute a key source of small size PM: 66%, 32%, and 18% of PMvery 3 y . Burke avery 3 y  used a sradients ,10. Thes2.5 mass emissions may or may not limit UFP emissions. The correlation between PM and UFPs or NPs depends on several factors and, in some cases, PM and UFP emissions are inversely related. The mass of PM emissions is a conserved quantity. The number of particles in those emissions is not. In addition, the US has no NAAQS for UFPs, although the definitions of PM2.5 and PM10 encompass these particles. PM2.5 ambient concentrations tend to be spatially homogeneous and regionally distributed. In contrast, UFP number concentrations in the air exhibit sharp gradients as a function of distance from a source. The atmospheric processes that lead to formation of particles from precursors are not well understood. The lack of UFP NAAQS has also discouraged the creation of a permanent network of ambient monitoring stations for UFP concentrations. Such a network would facilitate long-term epidemiological studies. Instead, exposure assessment of UFPs has to rely on other methods such as use of regression models or personal monitoring. For these reasons, much remains to be discovered about the explicit role that human exposure to UFP pollution plays in the well-documented morbidity and mortality effects of exposure to PM2.5.All internal combustion engines produce UFP emissions irrespective of the fuel or lubricant used. These can be volatile, semi-volatile, or solid particles. While UFPs are not regulated explicitly in the US, extensive research over the last two decades has led to a growing understanding of the sources and precursors, the mechanisms of formation in engine exhaust and in the atmosphere, metrology, and emission control approaches. However, clearly, some knowledge gaps remain. One important lesson learned is that limits on PM2 or SiO2 in pigments and foods are significant sources of NPs released to the environment [2 particles released into wastewater came from the environmental release of 22,400 tons of TiO2 particles in pigments. Solid inorganic NPs (TiO2 and ZnO) are used as UV filters in sunscreen formulations, causing serious concerns over the efficiency and safety of existing chemical and physical UV filters used in consumer products [Engineered nanoparticles are also in our environment, thus we inhale, swallow, and apply them to our skin regularly. Household and commercial products with TiOironment . Accordiironment  back in products . Iron oxproducts . 2.5, NPs were abundant in erythrocytes, unmyelinated submucosal, perivascular, and intramuscular nerve fibers, ganglionic neurons, and vagal nerves and associated with organelle pathology, in highly exposed urbanites [The respiratory tract is a key portal of entry through inhalation as the air passes through the nasal cavity, directly to the olfactory nerve and olfactory bulb, the trigeminal, facial, and glossopharyngeal nerves, and to the lower respiratory tract and the alveoli . UFPs acrbanites . Immunohrbanites . The skirbanites . Once NPs reach the systemic circulation, they can travel freely or hitchhike on red or white blood cells and start their journey through the body ,18. The Dysfunctional mitochondria are an early feature of neurodegenerative diseases  and earlA major pathway involved in NPs’ detrimental brain effects is ROS production . The oxiAll NPs in biological fluids are surrounded by a corona and protein corona–NP binding affinity depends on shape, size, and surface characteristics of NPs and hydrodynamic, electrodynamic, and magnetic forces ,23,24. HThe molecular chaperone function and the cellular efficiency of the degradation systems are key for the correct folding of the cellular protein and for preventing aggregation. Certain surfaces are very effective in promoting amyloid formation . Hartl’s work  emphasizWe also need an intact endoplasmic reticulum (ER) for eliminating abnormal proteins, thus any ER alterations will result in a protein degradation failure. Highly exposed urban megacity residents have severe alterations in the ER, widespread degenerated mitochondria–ER contacts (MERCs), and quadruple protein misfolding in close association with NPs .2.5 pollution and NPs, the current literature supports the following: (1) environmental NPs can directly alter brain proteins [In the scenario of PMproteins ,22,23,24proteins ,15,17; , with relatively low PM2.5 levels ; a piece of information very relevant for vulnerable populations [2.5 ambient concentrations are above the US EPA standard [We have had strong evidence in the last two decades of the causal role of PMg stroke ,27. The g stroke  and air globally ,29. Factglobally . Transiemissions . Remarkamissions . Black culations . Thus, sstandard ,29, but standard  shows, lCore message: Modifiable risk factors are 90% responsible of the stroke burden across the world, including indoor and outdoor air pollution and lead exposure. Stroke is a leading cause of morbidity and mortality in the United States and young adults are at risk.2.5 exposures below existing US EPA standard [3 cumulative PM2.5  [3 calculated for a 39-year-old with AD neurofibrillary tangle advanced stages V–VI and suggests the neurodegenerative process is at work in early pediatric ages with short exposure times, including intrauterine life. Elderly populations with cerebrovascular disease show accelerated cognitive decline associated with PM pollution [2.5 US EPA standard carrying higher dementia risk should be kept in mind for large city dwellers, highly industrial polluted towns—regardless of size—and for occupational exposures  [Epidemiological studies across countries support strong associations between risk of cognitive deficits, dementia, and PM exposures, including long-term PMstandard ,35,36,37cy time) ,26. Thisdrivers) .2.5 impacts millions of people and is associated with Mn found in fuel combustion, soil contamination in mining settings, welder workers’ exposures, and industrial smelting and steelmaking [2.5–Mn concentrations as high as 203 ng/m3 that could cause clinical parkinsonism [Parkinson’s disease risk, aggravation of the disease, and increased risk of first hospital admission have been linked to air pollution in the USA and elsewhere ,40,41. Ielmaking ,43. ResiAmyotrophic lateral sclerosis (ALS) is no exception in the literature linking the risk to PM pollution, metal, and metalloid exposures, diesel exhaust, and specific occupations ,45,46,47Core message: Heavy traffic and indoor and outdoor PM2.5 exposures carry higher dementia risk, including Alzheimer’s and vascular dementia. PD risk and disease aggravation are linked to air pollution and ALS risk increases with Pb exposures and specific occupations . AD, PD, and TDP-43 pathology start in childhood in the scenario of a polluted megacity.2.5 and a wide range of psychiatric disorders have been reported, the most consistent link has been demonstrated for mood disorders (particularly depression) and suicide [3 of chronic exposures to PM2.5 were associated with a ~18% increase in depression risk in Liu et al.’s [2.5 exposures and age, a situation very much relevant to the massive exposure in the US of millions of subjects during the 2020–2021 severe wildfire seasons [There is an overlap of neuro and psychiatric symptoms over the course of neurodegenerative diseases, including AD, PD, the behavioral variant of FTD (bvFTD), and ALS ,53,54. T suicide ,58. Incret al.’s . In an a2.5 exposures needs to be done [Thus, in the developing ATX (N) classification for use across the AD continuum , we will be done ,47,49,602.5 regional attainment. Meanwhile, the federal government is largely expected to follow the recommendations of the Independent Particulate Matter Review Panel [We have described the evolving landscape of PM pollution exposure effects and policy in the US. In the process we can identify some important lessons learned and the needs for future research. There is ample recognition that air pollution created mainly by fossil fuel combustion and other human activity adversely affects human health and the planet. While inhalation is an important and commonly recognized pathway for human exposure, particle ingestion and dermal absorption can be equally important. Similarly, indoor and outdoor air pollution contributes to the cumulative burden. Some viable behavioral and technological solutions to the PM emission problem have been identified and are beginning to be implemented. However, the transition to sustainability and a fossil fuel-free, cleaner environment will take time. Thus, we will need to continue to learn to deal with natural and human-made combustion emissions and other sources of particle pollution exposures. Specifically, exposures to traffic-related pollution, non-tailpipe vehicle emissions, engineered nanoparticles, and consumer product sources of particles will be around for some time. We cannot rest now. In fact, we should re-double all efforts at prevention and treatment of effects. This Review raises awareness specifically in the health community for these emerging concerns. Air quality practitioners around the country will continue working to bring all areas in the US into PMew Panel  and adop2.5, UFPs and NPs. We have shown a neuropathology overlap, i.e., Aβ, P-tau, alpha-synuclein, and TDP-43 in young air pollution-exposed urbanites [They should request and get involved in federal-supported multidisciplinary epidemiological studies examining targeted neurological and psychiatric outcomes along accurate measurements and definitions of the chemical composition of PMrbanites ,26. Ther2.5 pollution  is increasing and widely used engineered NPs  can result in high cumulative exposures. Clinicians can make patients aware of the adverse effects of exposure to PM pollution from wildfire smoke and other common sources. It may even be helpful to incorporate environmental exposure data to a medical history for potentially establishing a cumulative pollution dose profile. Exposures to complex mixtures of air pollutants and their health effects ought to be a greater public health priority, knowing that many of the higher risk neurological and psychiatric outcomes have fatal consequences and no current therapies have any impact on modification of their course.Additionally, we need to educate health professionals not just about air pollution effects, but also the potential role that specific constituents of UFPs and NPs may play in inducing short and long term neurologic and psychiatric effects. While many additional toxic compounds besides the six criteria pollutants are included in management practices throughout the country under the federal Clean Air Act, many of these compounds can be present in the UFP or NP phase either as nuclei or adsorbed material; right now, exposure risks to these compounds are technically ignored. This notion brings to bare consideration of just how protective air quality policies that largely focus only on total PM mass truly are. Health professionals should be the loudest voice here. Additionally, physicians can play a major role in the education process: the relative contribution of indoor PMWe are all at risk and protecting the critical brain developmental periods should be a priority. Preventive medicine ought to be at work.


Multicentric reticulohistiocytosis (MRH) is a rare systemic disease of non-Langerhans cell histiocytosis. A number of studies in the literature have documented that it can coexist with malignancy or autoimmune disease, making it difficult to determine the most appropriate therapy. Here, we present a case study of MRH associated with posterior mediastinal adenosquamous carcinoma along with antinuclear antibody positivity and lupus anticoagulant positivity. The patient experienced 6 months of clinical benefit after surgical resection and chemoradiotherapy of the mediastinal malignancy. This case adds to the available literature on multicentric reticulohistiocytosis associated with different types of malignancy and provides supplementary clinical data on the coexistence of this syndrome with malignancy and immune system abnormalities. To the best of our knowledge, this is the first case study describing MRH accompanied by posterior mediastinal adenosquamous carcinoma and lupus anticoagulant positivity. The unknown aetiology and polymorphic clinical presentation of MRH warrants further investigation. Multicentric reticulohistiocytosis (MRH), also known as lipoid dermatoarthritis, is a rare systemic disease of non-Langerhans cell histiocytosis (N-LCH). The disease was first systematically reported in 1937 by Weber & Freudenthal, and there have been no more than 400 cases reported globally, mostly presenting in middle-aged white women . The maiSome researchers hold the view that MRH is a neoplastic or paraneoplastic disease, and approximately 25% of MRH patients do indeed have an underlying malignancy . On the A previously healthy, 36-year-old Chinese man presented with papulonodules on his face and hands that had emerged over an 8-month period, along with experiencing polyarthritis for half a year. He reported smoking half a pack per day for 17 years. His family history was significant for malignancy in that his mother had breast cancer.On admission, a physical examination revealed multiple flesh-coloured to pinkish papules and nodules on his face  level of 23.4 mg/L , erythrocyte sedimentation rate (ESR) of 49 mm/h , interleukin-6 (IL-6) level of 9.69 pg/ml  and tumour necrosis factor (TNF) level of 9.26 pg/ml . Routine blood, biochemistry, urinalysis, C3 and C4 levels were normal. The levels of tumour markers  did not exceed the reference range. Further analysis revealed that the patient showed ANA (titer 1:320), LA , PPD test and tuberculosis interferon-γ release assay positivity. The level of fibrinogen was 5.47g/L . Tests for anti-dsDNA, anti-Smith, anticentromere, anti-ribonucleoprotein, anti-Jo1, anti-neutrophil cytoplasmic antibodies, rheumatoid factor (RF), anti-cyclic citrullinated peptide antibodies (ACPA), anticardiolipin antibodies , anti-β2-glycoprotein I antibodies  and HbsAg were all negative. Radiographs of the joints revealed osteoporosis in both hands and wrists and a slightly narrowed space between the first and second metacarpophalangeal joints of both hands (The patient received methotrexate (15 mg once a week) accompanied by oral prednisone (10 mg twice a day) and was discharged after 20 days of treatment. He continued the above regimen after discharge according to his doctor’s instructions. Approximately one month later, he was admitted again for assessment, which indicated that the papulonodular lesions had shrunk and that the inflammatory cytokines and molecules described above had returned to normal levels. Nonetheless, the patient’s joint pain was not significantly relieved.The results of EBUS puncture biopsy of the mediastinal lymphoglandula were available at the second hospital admission and showed a small number of abnormal cells Figure 2To further clarify the diagnosis and treatment approach, the patient received video-assisted thoracoscopic surgery (VATS) to excise the mediastinal mass (6×3.5×2.8 cm) for genetic analysis. Malignant cells were identified in the background of abundant lymphoid tissue in the mediastinal mass  and radiotherapy for the mediastinal lymph nodes. After 6 months of follow-up from the diagnosis of malignancy (5 cycles of chemotherapy and 30 cycles of radiotherapy), the patient’s joint pain was significantly reduced, and the papulonodular lesions had almost cleared, without any specific treatment. The latest re-examination on June 29, 2021, revealed that the patient was ANA negative and the LA level had decreased to 1.32, with no signs of tumour recurrence. The patient is still being followed-up. The changes to the lesions on the hands are presented in N-LCH consists of a group of rare diseases with different clinical presentations, pathogeneses and morphologies, including MRH, Erdheim-Chester disease, and Rosai-Dorfman disease, among others . MRH canThe neoplastic and autoimmune nature of the disease has been a focus of previous MRH case reports since the first was published in 1937. MRH-related malignancies can involve various systems and organs, including the breast, bloodstream, gastrointestinal organs, gynaecological organs, lung, and skin. A previous study described an MRH patient presenting with two primary cancers, and metastatic occult cancer in the left axilla has also been reported , 17. AddSMARCA4. In the analysed literature, SMARCA4 encodes one of the enzymatic (ATPase) subunits of the mammalian SWI/SNF family, a chromatin remodelling complex that directs nucleosomes and modulates gene expression. The gene is located on chromosome 19p13.2 and encodes the BRG1 protein, inactivating mutations of which result in its loss of expression and characterize a group of malignancies (SMARCA4-deficient thoracic tumour (SMARCA4-DTT), a distinct entity of undifferentiated thoracic malignancy that was first described in 2015  for the publication of any potentially identifiable images or data included in this article.llected clinical data, summarized the case, reviewed the literature, and drafted the manuscript. ZW and YZ provided the case. YL reviewed and summarized the case. All authors contributed to the article and approved the submitted version.ZT, XW, and ZX coThis work was supported by 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University .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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Polydatin (resveratrol-3-O-β-mono-D-glucoside) is a polyphenol that can be easily accessed from peanuts, grapes, and red wine, and is known to have antiglycation, antioxidant, and anti-inflammatory effects. Diabetes mellitus is a very common disease, and diabetic complications are very common complications. The dry mouth symptom is one of the most common oral complaints in patients with diabetes mellitus. Diabetes mellitus is thought to promote hyposalivation. In this study, we aimed to investigate the improvement effect of polydatin on diabetes-induced hyposalivation in db/db mouse model of type 2 diabetes. We examined salivary flow rate, TUNEL assay, PAS staining, and immunohistochemical staining for AGEs, RAGE, HMGB1, 8-OHdG, and AQP5 to evaluate the efficacy of polydatin in the submandibular salivary gland. Diabetic db/db mice had a decreased salivary flow rate and salivary gland weight. The salivary gland of the vehicle-treated db/db mice showed an increased apoptotic cell injury. The AGEs were highly accumulated, and its receptor, RAGE expression was also enhanced. Expressions of HMGB1, an oxidative cell damage marker, and 8-OHdG, an oxidative DNA damage marker, increased greatly. However, polydatin ameliorated this hypofunction of the salivary gland and inhibited diabetes-related salivary cell injury. Furthermore, polydatin improved mucin accumulation, which is used as a damage marker for salivary gland acinar cells, and decreased expression of water channel AQP5 was improved by polydatin. In conclusion, polydatin has a potent protective effect on diabetes-related salivary gland hypofunction through its antioxidant and anti-glycation activities, and its AQP5 upregulation. This result suggests the possibility of the use of polydatin as a therapeutic drug to improve hyposalivation caused by diabetes. Most Saliva is a mixture of fluids secreted by the three major glands  and several minor glands, containing 99% water; electrolytes such as potassium, magnesium, calcium, sodium, and immunoglobulins; enzymes; etc., and protects the oral cavity . It is aXerostomia is a disease that decreases salivation, can occur even if an objective decrease in salivation is not observed, can be triggered by a change in the ingredients of the saliva, and can be caused by radiotherapy, Sjögren’s syndrome, pathologies of the salivary glands, or medications ,4. XerosDiabetes mellitus (DM) is divided into type 1 and prevalent type 2, with its symptoms appearing slowly after the age of 40, which triggers a chain reaction of increased protein glycation due to high blood glucose, causes functional damage generated in many organ systems by promoting the creation of advanced glycation end products (AGEs), and results in ultimate complications such as cardiovascular disease, nephropathy, and retinopathy ,8,9. OraSalivary stimulants such as chewing gum, vitamin C, malic acid, and pilocarpine or salivary substitutes are solutions for xerostomia, which only provide temporary symptom relief . AdditioPolygonum cuspidatum are widely used as traditional herbal medicines for analgesic, diuretic, antipyretic, and expectorant purposes, its main active ingredient being polydatin (resveratrol-3-O-β-mono-D-glucoside) [The rhizome and root of ucoside) . Polydatucoside) . Polydatucoside) . In addiucoside) ,20, and ucoside) . HoweverTherefore, this study aims to investigate the improvement effect of diabetes-induced salivary gland hyposalivation by polydatin in type 2 diabetic db/db mice.Polydatin, with purity greater than 95%, was obtained from Sigma-Aldrich .n = 5), polydatin 25 mg/kg , polydatin 50 mg/kg , polydatin 100 mg/kg . Polydatin was dissolved in 0.5% (w/v) sodium carboxymethylcellulose . Polydatin was administered orally to mice on a daily basis for 3 weeks.To determine the oral dose of polydatin for in vivo experiment, 5-week-old male C57BL/6 mice were purchased from Damul Science . The mice were adapted to the environment for 1 week and then randomly divided into four groups: normal control (n = 7), diabetic group , polydatin 100 mg/kg treated group . Polydatin was dissolved in 0.5% (w/v) sodium carboxymethylcellulose and orally administered for 5 weeks. The animals were housed in a barrier system controlled by temperature (20–25 °C) and humidity (40–70%), with a 12:12 h light and dark cycle. Animal experiments were carried out according to procedures approved by the Institutional Animal Care and Use Committee of the Jeonbuk National University Laboratory Animal Center .Fourteen male db/db leptin receptor-deficient type 2 diabetic mice aged 5 weeks and seven male wild type C57BL/6 mice aged 5 weeks were supplied by Central Lab Animal Inc. . The mice were adapted to the environment for 1 week and then randomly divided into 3 groups based on the weight and fasting blood glucose levels as follows: normal group  at a dose of 0.8 mg/kg. The volume of saliva was measured for 10 min after injection of pilocarpine using cotton balls. Cotton balls were kept in the oral cavity for 10 min to absorb saliva and were then immediately weighed on an electronic balance. Total saliva was calculated from the difference of pre and post-collection cotton ball weight in milligrams and converted to microliters. The salivary flow rate was calculated as microliters per minute.At necropsy, submandibular gland tissues were isolated. Formalin-fixed tissues were embedded in paraffin and sliced into 4 μm thick sections. The sections were deparaffinized and rehydrated using standard techniques and stained with hematoxylin solution gill no. 3 and eosin. The stained sections were dehydrated and cleared with xylene, before being observed under a light microscope.2O2 for 10 min at room temperature (RT). They were then washed with 1X TBST buffer for 10 min at RT. Primary antibodies were diluted in 2.5% normal horse serum . The primary antibodies were AGE , the receptor for AGE , high mobility group box 1 , 8-hydroxydeoxyguanosine , and aquaporin5 . Sections were visualized with the VECTASTAIN Elite ABC Universal Kit . The staining was observed using a BX51 light microscope . Ten unique fields of view were randomly selected in each slice at 100× magnification. Image-Pro software  was used for semi-quantitative analysis of the intensity of the immunohistochemical positive signal. The average optical density per unit area (mm2) was calculated for the relative amount of protein.The tissue sections were deparaffinized and rehydrated using standard techniques. The sections were incubated with 3% Hg for 10 min at 4 °C and the supernatant was collected for measurement of reactive oxygen species (ROS) levels. ROS levels were examined using a Mouse ROS ELISA Kit  according to the manufacturer’s instructions.Frozen salivary gland tissues were homogenized in lysis buffer  containing protease inhibitor. The homogenate was centrifuged at 10,000× The tissue sections were deparaffinized and rehydrated using standard techniques and oxidized in 1% periodic acid solution for 5 min and rinsed in distilled water. The sections were placed in Schiff reagent for 15 min and counterstained with hematoxylin.2) was counted in each field using image analysis software .Apoptotic cells in the tissue were detected by an in situ cell death detection kit , according to the manufacturer’s instructions. The numbers of TUNEL-positive cells were counted under a fluorescence microscope . Ten fields at 100× magnification were photographed randomly from each salivary gland with a fluorescence microscope. The total number of TUNEL-positive cells per unit area , followed by Tukey’s multiple comparison test. Differences with a Changes in salivation by polydatin A were chAt the endpoint, the body weight was higher in the DM group with no difference between the DM + PD groups. Additionally, blood glucose levels also increased in the DM group with no difference between the DM + PD groups . As a reH&E staining was conducted to evaluate the histological change of the submandibular gland. As shown in In hyperglycemia, an increase in the glycation process accelerates the accumulation of AGEs . TherefoTo confirm the change caused by oxidative stress-induced cell damage, the accumulation pattern of HMGB1 was checked . In the The change aspect of mucin accumulation in salivary gland acinar cells was confirmed through Periodic acid-Schiff (PAS) staining. In the DM group, it was possible to confirm the increase in mucin accumulation and that it decreased due to polydatin treatment A. In addHyperglycemia due to high blood glucose levels is a characteristic of diabetes, which causes many changes in the body through damage to various organs. Hyposalivation and submandibular gland dysfunction have been reported in in vivo models, especially in type 2 diabetic mice , non-obeThis study could not confirm the glycemic control effect of polydatin. Previous studies have confirmed a decrease in glucose in a STZ-induced diabetic mice model ,30. A deThe level of ROS maintained by the antioxidant system of cells in the body increases due to hyperglycemia, disrupting the balance; increased ROS causes apoptosis and inflammation through various signaling paths in cell compositions such as proteins and lipids and organ systems such as the brain, blood vessels, and kidneys, ultimately destroying the systems ,39,40.In addition, the Maillard reaction (non-enzymatic) initiated by the glycation of amino groups and carbonyl groups of proteins causes molecular glycation in circulating proteins, including albumin, lipoprotein, and insulin, and allows for the easy generation of ROS through increased oxidation sensitivity, resulting in the increase in the apoptosis pathway. Hyperglycemia promotes the generation of a substance called AGEs, the final form of products produced by glycation; AGEs produce irreversible cross-links between proteins, transform properties and structure, increase tissue fibrosis and stiffness, cause organic dysfunction, and combine with RAGE to increase oxidative stress and pro-inflammatory signaling pathways. Consequently, it induces vascular complications such as diabetic atherosclerosis, retinopathy, diabetic nephropathy, neuropathy, and impaired wound healing ,42,43. IIn this study, the accumulation of AGEs and the increased expression of RAGE in the DM group showed that the increase in glycation caused by hyperglycemia was related to salivary gland hyposalivation. There are reports about the accumulation inhibition of AGEs by resveratrol , the forHMGB1 is a chromatin-binding nuclear protein that acts as an extracellular signal in damaged cells, is related to oxidative stress, and is released in apoptosis ,49. In aResveratrol, commonly found in nature in things such as grapes, peanuts, wine, and chocolate products, is a type of polyphenol and is known to have various pharmacological effects, such as anti-inflammation, antioxidation, and anti-tumor effects . There iIn the present study, the effective dose of polydatin is 100 mg/kg. Considering an average body weight of an adult of 60 kg, this dose for a 60 kg human is equal to 0.4 g/day. The recommended dose of polydatin as a human food supplement is 160 mg/day . Even ifMucin, the main component of saliva, can change in the pathological condition of the salivary gland. In addition, the over-expression of mucin is promoted by pro-inflammatory cytokines, and cytokine production is associated with an increase in ROS ,59,60. H2+ in the acinar cells, which in turn creates osmotic pressure, and fluid is secreted by the AQP5 channel in the membrane by the osmotic gradient [Saliva is produced and secreted by the acinar cells and duct cells of the salivary gland with its flow initiated by an increase and release of Cagradient . AQP is gradient . Among tgradient , and micgradient . As a regradient , and it In the present study, polydatin also promoted saliva secretion in normoglycemic mice. we did not clearly show the mode-of-action of polydatin on salvation in normal mice. However, polydatin is a natural precursor of resveratrol. Polydatin showed better oral absorption and metabolic stability than resveratrol since its serum concentration was 3–4 times higher after oral administration at the same dosage . PolydatThe effects of polydatin on salivation in normoglycemic mice as well as db/db mice were studied in this work, but one of the limitations of this study was that the animal study using the normoglycemic mice was a pilot study to determine the oral dose of polydatin. Therefore, there is not enough analysis data at the molecular level. Another limitation of this study was that multiple oral doses of polydatin were required to determine the effective dose range in the animal study using the db/db mice. The detailed beneficial role of polydatin on salivation under normoglycemic and hyperglycemic conditions needs to be studied further.In conclusion, an increase in ROS, a glycation product in the submandibular gland; a decrease in AQP5, which plays an important role in salvation caused by hyperglycemia, an apoptotic signal increase; and a salivation decrease in type 2 diabetic mice were confirmed. Polydatin mitigated the generation of excessive ROS due to the reduction of the glycation process initiated by the anti-glycation effect of polydatin and upregulated AQP5 expression, which is presumed to lead to the improvement of diabetic salivary gland dysfunction . Overall


Prostate cancer (PCa) is one of the leading malignant tumors in US men. The lack of understanding of the molecular pathology on the risk of food supply chain exposures of environmental phenol (EP) and paraben (PB) chemicals limits the prevention, diagnosis, and treatment options. This research aims to utilize a risk assessment approach to demonstrate the association of EP and PB exposures detected in the urine samples along with PCa in US men (NHANES data 2005–2015). Further, we employ integrated bioinformatics to examine how EP and PB exposure influences the molecular pathways associated with the progression of PCa. The odds ratio, multiple regression model, and Pearson coefficients were used to evaluate goodness-of-fit analyses. The results demonstrated associations of EPs, PBs, and their metabolites, qualitative and quantitative variables, with PCa. The genes responsive to EP and PB exposures were identified using the Comparative Toxicogenomic Database (CTD). DAVID.6.8, GO, and KEGG enrichment analyses were used to delineate their roles in prostate carcinogenesis. The plug-in CytoHubba and MCODE completed identification of the hub genes in Cytoscape software for their roles in the PCa prognosis. It was then validated by using the UALCAN database by evaluating the expression levels and predictive values of the identified hub genes in prostate cancer prognosis using TCGA data. We demonstrate a significant association of higher levels of EPs and PBs in the urine samples, categorical and numerical confounders, with self-reported PCa cases. The higher expression levels of the hub genes  in the aggressive stages (Gleason score > 8) of PCa tissues indicate their potential role(s) in the carcinogenic pathways. Our results present an innovative approach to extrapolate and validate hub genes responsive to the EPs and PBs, which may contribute to the severity of the disease prognosis, especially in the older population of US men. The United States Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA) estimate more than 10,000 chemicals are added directly or indirectly to the human food supply chain . These oProstate cancer (PCa) is the most prevalent hormone-dependent cancer and the second leading cause of cancer deaths in US men. In 2021, there were an estimated 248,530 new cases and 34,130 deaths) in the US men , an appr0 deaths 3)2 C(C6H4OH)2)] is an organic and synthetic compound utilized in the production of polycarbonate plastics, epoxy, and phenolic resins [14H12O3] is an organic solvent found in products such as food packaging, lotion, and sunscreen with a half-life between 5 and 10 h [12H7Cl3O2] is used as a germ-killing agent with a half-life of nearly 10 to 15 h [14H22O] is an alkylphenol utilized to produce anionic surfactants. The PBs are organic and estrogenic chemicals with suggested endocrine disrupting roles with a half-life of fewer than 24 h and are broadly used in food and beverage processing, pharmaceutical products, and personal care products , Propylparaben [C10H12O3], and Butylparaben [C11H14O3]. The chemical structures of all the EPs and PBs investigated in this study are presented in Several EPs were considered in this study because of their suggested endocrine disrupting roles in different cancers due to their estrogenic or androgenic action and a possible connection with PCa ,27. BPA c resins . Ingestic resins ,29, compc resins , thermalc resins , and denc resins . BPA mimc resins ,34, cervc resins , breast c resins , and proc resins  cancers.c resins ,39,40,41and 10 h ; Triclos to 15 h ; and 4-tproducts ,44. The Epidemiological and statistical association studies of EDCs or their metabolites with various human cancers lack information on the underlying causality of the exposures. The PSA is a prototypic androgen receptor that is utilized as one of the early diagnostic biomarkers for scanning PCa. However, there remain uncertainties in screening for PCa by PSA levels, which are influenced by various stimuli, ranging from inflammation to sexual activity, leading to overdiagnosis and overtreatment of PCa ,47. SomeIn this study, we: (1) applied a risk assessment approach to investigate the association of PCa cases with the levels of EPs and PBs in the urine samples of US men and 17-epidemiological covariates in the US men by comprehensibly utilizing the NHANES (2005–2015) data, and (2) investigated various influenced pathways of EPs and PBs in the etiology of PCa to discover hub genes for the development of robust diagnostics or therapeutic molecular targets for US men.2), overweight (25 to 30 kg/m2), and obese (≥30) for 39.2%, 30.6%, and 30.2%, respectively, of the selected population. The annual family income was reported to be ≤$24,999 (28.1%) and $25,000 to $54,999 (32.2%) in the study population, including cases and non-cases, and 54.9% of the population had ≤12th grade of education only. The record showed that 68.9% of the population reported yes to alcohol consumption, 74.7% were born in the US, 55.5% reported no physical activity, and 61.8% stated that they did not eat frozen food. Approximately 50% of the respondents were smokers. To consider the physiological conditions of the included subjects in this study, we recorded that 96.7% had no incidence of liver disease, and 96.6% had no incidence of kidney disease  did not report PCa incidence, while 152 (3.7%) reported PCa diagnosis  on their disease . When th disease . The mea2) to test a good-ness-of-fit for linear regression models and Pearson correlation coefficients (rs) to examine the strength and direction of the association between the eight EPs and PBs metabolites and numerical variables, as described in the PCa cases , Triclosan , Methylparaben, , Benzophenone-3 , and Propylparaben . Bodyweight (BW) recorded fitting for the linear regression model and a high positive correlation with BPA  and Ethylparaben . Total cholesterol was determined higher fitting for the linear regression model and a very high positive correlation with BPA  and Triclosan . Triglyceride was determined higher fitting for the linear regression model and had a very high positive correlation with BPA  and Triclosan , Benzophenone-3 , Propylparaben , and both Methylparaben and Ethylparaben . LDL noted fitting for the linear regression model and a very high positive correlation with BPA  and Triclosan , Benzophenone-3 , and both Methylparaben and Ethylparaben , and Propylparaben . HDL showed no fitting in the linear regression model and a negligible correlation with all the metabolites. Butylparaben and 4-tert-octyl phenol did not fit the linear regression model and had an insignificant correlation with all the numeric variables  and SBC  criterion for model selection. The BIC value increases as model complexity increases, and BIC decreases with the likelihood increase. Therefore, a lower BIC is better. Seventeen variables were examined by applying the stepwise regression procedure (forward and backward selection combination). The final selected model is the equivalent to the forward and backward methods until all the independent variables left in the model are significant or every significant independent variable is added.For PCa cases, BPA, Benzophenone-3, and Triclosan showed more fitting for a linear regression model and a higher positive correlation with age, total cholesterol, LDL, triglyceride, and weight. For PCa cases, Ethylparaben, Methylparaben, and Propylparaben conferred more fitting for a linear regression model and a higher positive correlation with LDL, triglyceride, total cholesterol, weight, and age. Further, 4-tert-octyl phenol and Butylparaben did not fit the linear regression model and negatively correlated with all the numerical variables.The three EPs  showed higher fit in linear regression models, higher linear relationship, and higher Pearson correlation coefficients of strength and direction of the association with all the numerical variables (except with weight and HDL) in the PCa cases than non-cases. The three PBs  showed higher fit in linear regression models, higher liner relationship, and higher Pearson correlation coefficients strength and direction of the association with all the numerical variables (except with weight and HDL) in the PCa cases than non-cases. The six above metabolites showed higher fit in linear regression models, a higher linear relationship, and higher Pearson correlation coefficients of strength and direction of the association with a weight in PCa cases than in non-cases.The estimated odds ratios (OR) and 95% confidence intervals  for the risk of having PCa, and the eight EPs and PBs metabolites are presented in Our CTD analysis showed that there were 993 differentially influenced (upregulated or downregulated) genes aligned with PCa outcome. The Venn diagram in p < 0.05) top ten terms of each enrichment analysis are assembled in The GO enrichment and KEGG pathway analysis were completed on the overlapping genes utilizing the DAVID database, including the Gene Association Diseases Database (GAD), BP, CC, MF, transcription factor binding sites (TFBS), and KEGG pathway. The statistically significant  in their association with PCa.The GAD enrichment analysis of 81 overlapping common gene functions showed that 35 genes  have the highest significance value  that were markedly enriched with pathways in cancer . In addinificant . Then, w12) hub genes in the network, as shown in The CytoHubba was utilized to explore important genes in the PPI network by implementing DNMC and MCC to identify the hub genes of PCa. The results discovered nine genes ranked as one  and two genes ranked as nine (ESR1 and CDH1) were considered as the most significant  aligned with the previously published studies.IKZF1, PPM1A, FBP1, SMCHD1, ALPL, CASP5, PYHIN1, DAPK1, and CASP8 .KLK3, CDH1, KLK2, FOXA1, and EPCAM RPS21, FOXO1, BIRC5, POLR2H, RPL22L1, and NPM1 EPCAM, TWIST1, CD38, and VEGFA .LMNB1, TK1, RACGAP1, and ZWINT .IGF2, GATA5, F10, CFI, AGTR1, FOXA1, BZRAP1-AS1, and KRT8 .PIK3R1, BIRC5, ITGB4, RRM2, TOP2A, ANXA1, LPAR1, and ITGB8 .CDH1, BMP2, NKX3-1, PPARG, and PRKAR2B .CDCA8, CDCA5, UBE2C, and TK1 .PPFIA2, PTPRT, PTPRR, PRR16, CHRM2, KRT23, CYP3A4, CYP3A7, and DPYS, and DUOXA1 .TSPAN1, BMPR1B, FOXA1, STEAP1, RCAN3, S100P, LYZ, SCGB3A1, IL8, and DPT .The results from the MCODE analysis of 81 genes show two modules. With a score of 21.36, Module-1 included 25 genes (nodes) and 175 edges, and Module-2, with a score of 5, included five genes (nodes) and 11 edges. A PPI network was then created by using five genes (nodes) and ten edges, which is displayed in p < 0.05). The statistical samples contained 497 PCa and 52 normal samples. As indicated in p < 0.001) for all the hub genes’ expression levels  in PCa compared to normal samples. Moreover, p < 0.001) for Gleason score = 9 with the highest aggressiveness and the poorest prognosis.The UALCAN database was utilized to validate the transcript expression levels of five hub genes in 549 samples derived from the TCGA project for PCa  on sex hormones . In animIn the follow-up analysis, we considered specific co-variates that may have increased the higher risks of EP and PB exposures in the PCa cases. Upon analysis of the NHANES 2005–2015) questionnaires filled out by the subjects in this study, high BPA levels with PCa were significantly associated with higher BMI and those who consumed canned and frozen food frequently. This observation aligns with studies that have also shown that consumption of fast food and canned food places the older population at a higher risk for weight gain and cancers ,63,65. D–2015 que2 (obesity) and positively associated with age. These results corroborate earlier studies [High Triclosan concentrations in adipose tissue have been reported in the older subjects, with higher BMI and overweight related to the consumption of unhealthy foods ,60. Stil studies ,19,24. U studies . These s studies .p < 0.0001) in PCa cases than non-cases in the subjects with higher BMI and older age. Earlier studies have shown that LDL, TC, and TG were positively associated with PCa, breast cancer, and colon cancer [Observation of the associated higher levels of EP and PB in the PCa cases with higher BMI and older age led us to investigate the total lipid profiles of the study population in the NHANES data (2005–2015). In a meta-analysis of cross-sectional data from NHANES (2003–2014), no associations were found between urinary BPA and the five different lipids (low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), triglycerides (TG), and apolipoprotein B (ApoB)) variables when investigated in both children (≤17 years old) and adults (≥18 years old) . This stn cancer . Furthern cancer . Moreoven cancer , and chon cancer . Therefon cancer . A studyn cancer . The stup = 0.012) [It is important to understand the influence of the combinations of the descriptive and quantitative covariates along with the EPs and PBs association with PCa outcome. As shown in The association of EP and PB with PCa then raises the question of how they (EP and PB) may be contributing to the etiology of PCa. Conventionally, in vitro studies or animal models can be employed to investigate the effects of different doses of EP and PB, alone or in their combinations, to map the genetic pathways on the development and prognosis of PCa. This method may allow extrapolating the EP and PB risk assessment results to apply in humans, still with a degree of uncertainty. On the contrary, we used in silico curated works of thousands of researchers who have investigated the effects of EP and PB at the molecular level in mammalian cell cultures or mammalian models to compare and describe the potential role of EP and PB in the PCa etiology, especially when our results show more relevance to the older population. In addition, we have utilized numerous available public databases and web-based bioinformatics that have separately mapped the networks and pathways of carcinogenesis of different tissues, including PCa. It is important because, despite the progress achieved in understanding the molecular processes and the progression in PCa, it remains a high risk for morbidity and mortality in the male population of the US . With thIn the next step, our results illustrated that EP and PB gene ontology and pathway enrichment analysis influenced 81 overlapping genes aligned with their curated function in PCa for core genes that were increased in different categories of biological processes (BP). They included a response to estradiol and positive regulation of transcription from RNA polymerase II promoter, suggesting their role in the PCa progression via different BP. The androgen receptor is the typical target for PCa detection and therapy, and estrogens and their receptors have also been implicated in the development of PCa . The RNATATA-box-binding protein (TBA)—which is a general TF that operates at the core of the DNA-binding multiprotein factor and regulates the transcriptional activity of RNA polymerase II .CEBPB—an important TF that regulates the expression of genes involved in immune and inflammatory responses .E2F is a TF that binds with DNA for genes involved in the cell cycle and DNA replication, which can mediate cell proliferation and TP53 mediated apoptosis .SRY is a TF that regulates the genetic switch to male development and is affected by various gene regulations, including promoter activation or repression .NFKAPPAB (NF-kappa-B) is a TF that is found in almost all cell types and is affected in multiple biological processes, such as immunity, cell growth, inflammation, differentiation, apoptosis, and tumorigenesis .When this identified set of EPs and PBs that influenced 81 overlapping genes was subjected to transcription factor binding sites enrichment analyses, specifically for the PCa pathway, the most significant top five TFs were as follows:However, the question remains as to how 81 EP- and PB-influenced genes may be working together in a PCa network. We used Cytoscape, a web-based bioinformatics software, to visualize molecular interaction networks. The CytoHubba plugin screened for core genes following a PCa prognosis analysis that was comparable to previous studies ,48,74,83MCODE specified with Module-1 was associated with 26 genes, and Module-2 was associated with five genes and 11 edges. The analysis of the selected five genes from Module-2  was further validated by using PCa samples and normal tissue from TCGA. A significant increase in the gene expression levels of all five hub genes in PCa tumors compared to normal tissues suggests their role in the PCa. BUB1B is a critical mitotic checkpoint kinase. BUB1B is identified as the top-scoring kinase by RNA interaction. It is possible that a novel antimitotic target involves impaired spindle checkpoint function in any form of cancer, including PCa ,57. DNA The observation of different Gleason scores  and normal tissues in the TCGA samples by expression of the hub genes depending on the Gleason score method is illustrated in Our study has limitations as it is a cross-sectional study with self-reported PCa data on NHANES (2005–2015) without the information on the family history of hormonal cancers. Only the men who reported no cancer diagnosis (non-cases group) or PCa diagnosis (cases group) were covered in our research population. It is also highly challenging to establish the food chain exposure as the primary route of human exposures of the selected EPs and PBs. Nonetheless, using the available in silico information and integrated bioinformatic tools, we identified a set of EP- and PB-responsive hub genes of the PCa pathway that can be further investigated in the biological models for their use as diagnostic or therapeutic targets.The NHANES is continuous cross-sectional population-based datasets. It is nationally representative by collecting data and sampling from the noninstitutionalized U.S population, confidential, voluntary participants, and civilian populations. NHANES considers multistage datasets, complex, and probability of sampling and subgroups designs ,87. It iMedical conditions (self-reported cancers) were collected utilizing the medical questionnaires in NHANES. The participants’ ≥20 years old responded to “Have you ever been told by a doctor or other health professionals that you had cancer or malignancy of any kind? Men who responded “yes” were consequently asked, “What kind of cancer was it”? and “What was your age at diagnosis?” According to the questions, the person was required to report physician-diagnosed cancers. There was no additional validation of the cancer diagnosis in these data. Only men who reported no cancer diagnosis (non-cases group) or PCa diagnosis (cases group) were covered in our research population. Other kinds of cancers were eliminated from this analysis. The authors of Refs. ,88 have We integrated three independent sources, the CPCat , the EPA Toxicity Forecaster (ToxCast), and the FDA/Total Diet Study (TDS) through the Center for Food Safety and Applied Nutrition (CFSAN), as shown in A detection limit variable is presented for all EPs and PBs in the datasets. For chemicals measured in urine, LOD computations were conducted utilizing the chemical concentration shown per urine volume. LOD values may change by survey year because of improvements in analytical techniques, while most LODs were constant for all the analytes in the dataset. Two variables are given for each of these analytes. The variables were identified by (URDXXXLC), which shows whether the result was under the LOD, and (URXXXX), which presents the analytic result for that analyte, which was above LOD. Therefore, there are two values given (0) to indicate that the result was >LOD and (1) to suggest that the result was <LOD. For metabolites with analytic effects less than the LOD, a claimed fill value was assigned in the analyte results area and called a lower limit of detection (LLOD) and (LLOD/√ (2 & 2)).t-test statistics (depending on the variables) were conducted to compare the means and distribution of covariates by PCa status. Logistic regression models were applied to estimate the association and investigate the risk between PCa occurrence, urinary levels of EPs and PBs, and the selected covariables by calculating ORs and their 95% CIs. All statistical analyses were performed using SAS Studio for Windows (SAS version 9.4 software), and p-values < 0.05 were recognized statistically significant (we used a 5% significance level).Our analyses used male participants ≥20 years of age only with available data for EP and PB levels, demographics, and medical health data for all five NHANES survey cycles. All urinary compounds and metabolites for EP and PB were log-transformed and creatinine corrected to satisfy normality assumptions. According to the NCHS guidelines, all measures were weighted to provide accurate national estimates . Chi-squ2) and then rounded one decimal place (dp). Participants reported race/ethnicity, family income, education level, birth in the US, physical activity, eating frozen food in the past 30 days, alcohol use, smoking status, and liver diseases, including cancer and kidney disease. The categorical variables are described with questions provided to participants and divided into groups in The potential covariates were obtained from the questionnaire interviews (self-reported) or collected as laboratory measurements. The possible variables were inputted as numerical variables and as categorical variables. At the assessment time, age is the only variable entered as numerical (years) and categorical (three groups of age). The study also alleviated the selection biases in the observation of the significant association of EPs and PBs with PCa in higher age groups by bootstrapping the data (data not shown here) for different age groups. Body mass index (BMI) was calculated for participants as weight (kg)/height meters squared  is a functional enrichment tool that provides biological descriptions of gene datasets and proteomic research from high-throughput sequencing [The next step included identifying genes that are influenced (underexpression or overexpression) by EP and PB exposures using the Comparative Toxicogenomic Database (CTD). Biocurators at CTD manually curate gene–disease connections, chemical–disease relationships, and chemical–gene interactions from the literature . Our seaquencing .https://www.genome.jp/kegg/, accessed on 31 December 2021) [http://www.geneontology.org, accessed on 31 December 2021) [p-value of < 0.05. Together, the GO and KEGG pathway analysis was used to associate genes with their potential biological functions and their roles in PCa pathways.We also used Kyoto Encyclopedia of Genes and Genomes (KEGG), which is a database used for high-level functions of the biological system, molecular-level data generated by genome sequencing, and other high-throughput experimental technologies (er 2021) . The gener 2021)  of the ihttp://string-db.org/, accessed on 31 December 2021) that functions as an access point for the more reasonable interpretation of relationships between various proteins on a genome-wide scale. It is helpful to understand the protein functions [p-value < 1.0 × 10−16, the minimum required interaction score of 0.4, active interaction, human species, experiments, and gene fusion databases, and co-recurrence.We implemented the Search Tool for the Retrieval of Interacting Genes (STRING) to build direct and indirect protein–protein interaction networks analysis. STRING is an online database tool (unctions . We combThe Molecular Complex Detection (MCODE) plug-in in Cytoscape (version 3.9.0) software was utilized to examine the significant modules and determine potential functional modules in the protein–protein interaction (PPI) network with the following parameters  . The hubhttp://ualcan.path.uab.edu, accessed on 19 December 2021) [The relative expression of hub genes between PCa and normal samples and Gleason grade and recurrence situation was examined using the online UALCAN database. The analysis of relative expression of the hub genes in PCa was conducted utilizing UALCAN (er 2021) . UALCAN To the best of our knowledge, this is the first research that has comprehensively used NHANES human data collected between 2005 and 2015 (five cycles of data collection) to associate EPs and PBs, assumed to be mostly present in the food supply chain, as risk factors for PCa in the US men population. We selected these chemicals monitored by the EPA and FDA in the food products and NHANES (CDC) in the human urine samples for over a decade. They are also on the priority list of the US national toxicology program . We demo