Search Results (7,418)

Ciliopathies are disorders that affect primary or secondary cellular cilia or structures associated with ciliary function. Primary cilia (PC) are essential for metabolic regulation and embryonic development, and pathogenic variants in cilia-related genes are linked to several pediatric conditions, including renal-hepatic diseases and congenital defects. Biliary atresia (BA) is a progressive infantile cholangiopathy and the leading cause of pediatric liver transplantation. Although the exact etiology of BA remains unclear, evidence suggests a multifactorial pathogenesis influenced by both genetic and environmental factors. Patients with BA and laterality defects exhibit genetic variants associated with ciliopathies. Interestingly, even isolated BA without extrahepatic anomalies presents morphological and functional ciliary abnormalities, suggesting that environmental triggers may disrupt the ciliary function. Among these factors, hypoxia has emerged as a potential modulator of this dysfunction. Hypoxia-inducible factor 1-alpha (HIF-1α) plays a central role in hepatic responses to oxygen deprivation, influencing bile duct remodeling and fibrosis, which are key processes in BA progression. This review explores the crosstalk between hypoxia and hepatic ciliopathies, with a focus on BA. It discusses the molecular mechanisms through which hypoxia may drive disease progression and examines the therapeutic potential of targeting hypoxia-related pathways. Understanding how oxygen deprivation influences ciliary function may open new avenues for treating biliary ciliopathies and improving patient outcomes. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health problem and the discovery of drugs is challenging. In this study, we aimed to investigate the effects of intestinal activation of the liver X receptor (LXR)α on MASH. Methods: An intestinal-specific LXRα activation model in mice was established and subjected to MASH development by combining a Western diet and carbon tetrachloride. Lipid metabolism, reverse cholesterol transport (RCT), steatosis, inflammation, and fibrosis were evaluated. In vitro models of steatosis and fibrosis were used to explore the role of scavenger receptor class B type 1 (SRB1). Results: We found that the intestinal activation of LXRα improved several MASLD features, including levels of triglycerides, RCT, steatosis, systemic and hepatic inflammatory profiles, and liver fibrosis. These effects were associated with increased high-density lipoprotein (HDL) levels and hepatic SRB1 expression. In vitro depletion of SRB1 hampered the beneficial effects of HDL on steatosis and fibrogenesis in liver cells by altering the activation of both peroxisome proliferator-activated receptors γ and small mothers against decapentaplegic homolog protein (SMAD)2/3 proteins. Conclusions: Our findings showed that the intestinal activation of LXRα and a parallel induction of hepatic SRB1 are protective against inflammation, steatosis, and advanced liver fibrosis in MASLD. Full article

This study aimed to assess the prevalence of HDV (hepatitis delta virus), HCV (hepatitis C virus), and HIV (human immunodeficiency virus) coinfections among HBsAg-positive patients and to determine the severity of liver fibrosis and biochemical markers. Furthermore, the study sought to evaluate the noninvasive fibrosis scores (APRI and FIB4) in predicting the severity of liver disease in patients with hepatitis B. A retrospective analysis of 1434 patients with chronic HBV admitted between January 2020 and December 2024 was conducted at Sincan Tertiary Hospital. The positivity rates of the following antibodies were the focus of the study: anti-HDV, anti-HCV, and anti-HIV. In addition to these, the levels of HIV-RNA, HCV-RNA and HBV-DNA, as well as several biochemical markers (ALT, AST, INR, albumin, bilirubin and platelet count) were also evaluated. The APRI and FIB-4 scores were calculated. Of the 1434 patients, 49 (3.4%) tested positive for anti-HDV, 784 were screened for anti-HCV, and 749 were screened for anti-HIV. The positivity rates were 3.4% (27/784) and 3.4% (26/749), respectively. According to ROC analysis, the FIB-4 score had a statistically significant effect on predicting anti-HDV negativity (AUC = 0.59, p = 0.031). However, the APRI score was not a significant predictor for anti-HDV positivity (AUC = 0.53, p > 0.05). APRI and FIB-4 scores did not have a statistically significant discriminatory power in predicting anti-HCV and anti-HIV positivity (p > 0.05). The cut-off value for the FIB-4 score in predicting anti-HDV positivity was 1.72, with a sensitivity of 61.4% and a specificity of 42.9% (p = 0.031). Among the HCV/RNA-positive patients (n = 5), all were male, and two also had positive anti-HBe results with undetectable HBV/DNA levels. One HIV/RNA-positive patient, a foreign national, was confirmed to have HIV/HBV/HDV infection. All HBsAg-positive patients should undergo routine anti-HDV testing. Vaccination programmes are vital in preventing the spread of HDV. Dual screening strategies are essential for identifying infected individuals and developing prevention and treatment programmes. Anti-HDV positivity indicates advanced liver fibrosis, emphasising the importance of screening and monitoring. However, the limited accuracy of the APRI and FIB-4 scores for detecting coinfections highlights the need to integrate noninvasive methods with molecular diagnostics for precise management. Full article

Background: Over the last two decades, a fair number of echocardiographic studies have investigated the influence of metabolic dysfunction-associated steatotic liver disease (MASLD) on myocardial strain and strain rate parameters assessed by speckle tracking echocardiography (STE) in individuals without overt heart disease, reporting not univocal results. We aimed at analyzing the main findings of these studies. Methods: All studies examining conventional echoDoppler parameters by transthoracic echocardiography (TTE) and left ventricular (LV) mechanics [LV-global longitudinal strain (GLS), LV-global strain rate in systole (GSRs), in early diastole (GSRe) and late diastole (GSRl)] by STE in MASLD patients without known heart disease vs. healthy individuals, were searched on PubMed, Embase and Scopus databases. The primary endpoint was to quantify the effect of MASLD on LV-GLS in individuals without overt cardiac disease. Continuous data [LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and left ventricular ejection fraction (LVEF)] were pooled as the standardized mean difference (SMD) comparing MASLD cohorts with healthy controls. Results: A total of 11 studies were included, totaling 1348 MASLD patients and 6098 healthy controls. Overall, MASLD showed a medium effect on LV-GLS (SMD −0.6894; 95%CI −0.895, −0.472, p < 0.001) and LV-GLSRs (SMD −0.753; 95%CI −1.501, −0.006, p = 0.048), a large effect on LV-GLSRe (SMD −0.837; 95%CI −1.662, −0.012, p = 0.047) and a small and not statistically significant effect on LV-GLSRl (SMD −0.375; 95%CI −1.113, 0.363, p = 0.319) and LVEF (SMD −0.134; 95%CI −0.285, 0.017, p = 0.083). The overall I² statistic was 86.4%, 89.4%, 90.9%, 89.6% and 72.5% for LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and LVEF studies, respectively, indicating high between-study heterogeneity. Egger’s test for LV-GLS studies gave a p value of 0.11, 0.26, 0.40, 0.32 and 0.42 for LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and LVEF studies, respectively, thus excluding publication bias. Meta-regression analysis excluded any correlation between potential confounders and LV-GLS in MASLD individuals (all p > 0.05). Sensitivity analysis confirmed the robustness of study results. Conclusions: MASLD has a medium effect on LV-GLS, independently of demographics, anthropometrics and the cardiovascular disease burden. STE analysis may allow early detection of subclinical LV systolic dysfunction in MASLD patients, potentially identifying those who may develop heart failure later in life. Full article

Insulin-like growth factors (IGFs) play crucial roles in the regulation of animal growth and reproduction. However, the functional and regulatory mechanisms underlying ovarian growth and oocyte maturation in teleosts remain unclear. In this study, the expression profiles of lncRNAs and mRNAs were analyzed in the ovaries of golden pompano (Trachinotus ovatus) treated with IGF1 and IGF2 proteins to gain insights into the role of these two IGF ligands in the regulation of ovarian development and maturation. A total of 1494 lncRNAs and 8728 mRNAs were differentially expressed following IGF1 treatment compared with the control group. A total of 101 lncRNAs and 377 mRNAs were differentially expressed after IGF2 treatment compared to those in the control group. The results revealed that KEGG pathways enriched by target genes of the DE lncRNAs overlapped significantly with those enriched by the DE mRNAs in both the IGF1 and IGF2 groups. The key overlapping enriched pathways included ECM receptor interaction, gap junction, Hedgehog signaling pathway, Ras signaling pathway, Rap1 signaling pathway, TGF beta signaling pathway, Wnt signaling pathway, GnRH signaling pathway, progesterone-mediated oocyte maturation, oocyte meiosis, cell cycle, and MAPK signaling pathway. The differentially expressed genes (DEGs) involved in ovarian development and oocyte maturation were cyp17a1, cyp19a1, star, hsd17b3, hsd17b7, adam23, slc26a6, htr2b, h2ax, nanos3, krt18, pgr, and inhbb, following IGF1 and IGF2 treatment. Furthermore, four lncRNAs (MSTRG.66521.1, MSTRG.49969.1, MSTRG.59923.1, and MSTRG.13767.1) for IGF1 and two (MSTRG.20896.2 and MSTRG.58123.2) for IGF2 within the lncRNA–mRNA network were found to target DEGs related to ovarian development and maturation. This suggests that IGFs may affect reproductive processes by regulating the expression of lncRNAs and mRNAs. RT-qPCR analysis revealed that these six lncRNAs showed high expression levels in the brain, pituitary, liver, and gonad tissues, indicating their potential involvement in regulating ovarian growth and development. This study elucidates the lncRNA–mRNA regulatory mechanism in response to IGF1 and IGF2 treatment during stage III of ovarian development in golden pompano, thereby deepening our understanding of its functional role. Full article

Background/Objectives: Given the rising incidence of early-onset endometrial cancer diagnosed before the age of 50 years, this study examined whether non-alcoholic fatty liver disease (NAFLD) served as an independent risk factor for early-onset endometrial cancer, irrespective of obesity status. Methods: This nationwide cohort study included 2,311,949 Korean women aged 20–39 years who underwent health screenings from 2009 to 2012. NAFLD severity was classified based on the fatty liver index: none (<30), moderate (30–59), and severe (≥60). Multivariable-adjusted Cox proportional hazards models were applied to estimate adjusted hazard ratios (aHRs) for early-onset endometrial cancer. Results: During a median follow-up of 7.6 years, 1289 women developed early-onset endometrial cancer. The cumulative incidence of early-onset endometrial cancer was significantly higher in women with NAFLD than in those without (log-rank p < 0.001). A dose-dependent association was observed, with increased risk corresponding to greater NAFLD severity (aHR [95% confidence interval (CI)]: moderate NAFLD, 2.38 [1.99–2.85]; severe NAFLD, 5.39 [4.44–6.53]; p for trend < 0.01). Compared with non-obese women without NAFLD, the aHRs for early-onset endometrial cancer were 2.53 [2.11–3.05] in non-obese women with NAFLD, 1.66 [1.10–2.52] in obese women without NAFLD, and 4.30 [3.60–5.13] in obese women with NAFLD (synergy index = 1.50, p < 0.01). Conclusions: NAFLD was independently associated with increased risk of early-onset endometrial cancer in both non-obese and obese women. Furthermore, young women with both NAFLD and obesity exhibited a synergistically elevated risk. Early identification and management of NAFLD may help mitigate the rapidly growing burden of early-onset endometrial cancer. Full article

Selenium-binding protein 1 (SELENBP1) has been implicated in cancer development, neurological disorders, tissue injury, metabolic regulation, and cell differentiation. Sepsis is characterized prominently by immunological dysregulation and severe organ damage. However, whether SELENBP1 improves sepsis by regulating immune cell activity remains unknown. Here, we detected an elevation of SELENBP1 levels in the blood of sepsis patients and in the livers of septic mice. Significantly, SELENBP1 knockout (KO) prolonged survival in septic mice. This phenomenon was accompanied by decreased liver damage, reduced inflammation levels, and an increased regulatory T cell/T helper 17 cell (Treg/Th17) ratio in the spleen. Additionally, SELENBP1 deficiency induced a redox imbalance and inhibited dendritic cell (DC) maturation, resulting in a tolerogenic DC (tolDC) phenotype and an increase in the Treg/Th17 ratio. Furthermore, SELENBP1-KO mature DCs (mDCs) alleviated liver injury by increasing the Treg/Th17 ratio in the spleen, thus improving the survival of septic mice. These findings indicate that SELENBP1 is involved in sepsis by regulating DC immune activity, which might provide a potential way for sepsis treatment. Full article

Objectives: Obesity is a significant public health concern, as it is associated with the development of numerous chronic diseases. The prevalence of obesity and attendant diseases has been increasing over recent years. This study attempted to ascertain the frequency of chronic diseases in obese patients in Türkiye for the first time on this scale. Methods: A retrospective study was conducted, with patients admitted to the internal medicine outpatient clinics or obesity centers between December 2023 and December 2024 included in this study. Participants were recruited from seven regions, 20 provinces, and 28 centers, and the inclusion criteria were met by those aged 18 years and over with a body mass index (BMI) of 30 kg per square meter (kg/m²) or above. Their status, with respect to chronic diseases, and their anthropometric parameters were documented. Results: The total number of patients was 10,121, with a mean age of 45.2 ± 13.92. Of these, 7222 (71.35%) were female. The prevalence of type 2 diabetes mellitus (T2DM), hypertension (HT), dyslipidemia (DL), coronary artery disease (CAD), obstructive pulmonary disease (OPD), obstructive sleep apnea syndrome (OSAS), and fatty liver disease (FLD) was found to be 35.01%, 78.19%, 12.37%, 10.32%, 5.88%, and 75.12%, respectively. A subsequent analysis of the prevalence of these diseases by region revealed a statistically significant variation between regions (p < 0.001 for all regions). Conclusions: This study represents a substantial contribution to the existing body of knowledge in this field, particularly with regard to the identification of the current chronic disease rate of obese patients in Türkiye. Full article

Background: The most common cause of chronic liver disease is now known to be non-alcoholic fatty liver disease (NAFLD), recently redefined as metabolic-associated fatty liver disease (MAFLD). This review aims to synthesize current evidence on the pathophysiology and clinical implications of nephrological, pulmonary, and dermatological manifestations among NAFLD/MAFLD patients. In order to find safe and efficient treatments, NAFLD/MAFLD has emerged as a primary concern for hepatologists worldwide. Methods: We conducted a comprehensive review of the literature from major databases, focusing on studies that evaluated the extrahepatic manifestations of NAFLD/MAFLD. Emphasis was placed on identifying pathophysiological mechanisms and assessing their clinical impact on renal, pulmonary, and dermatological systems. Results: Recent developments in the management of chronic viral hepatitis have lowered the mortality rate associated with chronic liver disease. However, the prevalence of NAFLD/MAFLD continues to rise, making chronic liver disease a significant health concern for the future. An increasing percentage of patients on liver transplant waiting lists now have cirrhosis and hepatocellular carcinoma due to non-alcoholic liver disease. Furthermore, the incidence and prevalence of chronic kidney disease have surged, linking NAFLD/MAFLD to higher morbidity, mortality, and healthcare costs. Conclusions: NAFLD/MAFLD is underdiagnosed and underappreciated, yet its incidence is rapidly increasing, raising concerns about a potential global epidemic. Given its multisystemic impact—extending to renal, pulmonary, and dermatological complications—it is crucial to develop interdisciplinary strategies for early detection and effective management of the disease. Full article

Objective: Accurate risk stratification at an early stage may reduce the incidence of infection and improve the survival rate of recipients by adopting targeted interventions. This study aimed to develop a nomogram to predict the risk of multidrug-resistant organism (MDRO) infections in liver transplant (LT) recipients. Methods: We retrospectively collected clinical data from 301 LT recipients and randomly divided them into a training set (210 cases) and validation set (91 cases) using a 7:3 split ratio. Factors related to the risk of MDRO infection after LT were determined using univariate and multivariate bidirectional stepwise logistic regression. The model’s predictive performance and discrimination ability were evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Results: 56 (18.60%) patients developed a MDRO infection, including 37 (17.62%) in the training cohort and 19 (20.88%) in the validation cohort. Ultimately, five factors related to MDRO infection after LT surgery were established: ascites (OR = 3.48, 95% CI [1.33–9.14], p = 0.011), total bilirubin (OR = 1.01, 95% CI [1.01–1.01], p < 0.001), albumin (OR = 0.85, 95% CI [0.75–0.96], p = 0.010), history of preoperative ICU stay (OR = 1.09, 95% CI [1.01–1.17], p = 0.009), and length of ICU stay (OR = 3.70, 95% CI [1.39–9.84], p = 0.019). The model demonstrated strong discrimination, and the area under the curve (AUC), sensitivity, and specificity of the training set were 0.88 (95% CI [0.81–0.94]), 0.82 (95% CI [0.76–0.87]), and 0.86 (95% CI [0.75–0.98]), respectively, while for the validation set, they were 0.77 (95% CI [0.65–0.90]), 0.76 (95% CI [0.67–0.86]), and 0.68 (95% CI [0.48–0.89]). The mean absolute error (MAE) in the validation cohort was 0.029, indicating a high accuracy. DCA showed a clinical benefit within a threshold probability range of 0.1 to 0.7. Conclusions: This study developed a clinically accessible nomogram to predict the risk of MDRO infection in LT recipients, enabling early risk stratification and the real-time assessment of infection risk based on the length of postoperative ICU stay. The model incorporates five easily obtainable clinical parameters (ascites, total bilirubin, albumin, preoperative ICU stay history, and length of ICU stay) and demonstrates strong predictive performance, facilitating the early identification of high-risk patients. Future research should focus on refining the model by incorporating additional clinical factors (e.g., immunosuppressive therapy adherence) and validating its generalizability in multicenter, large-sample cohorts to enhance its clinical utility. Full article

Background/Objectives: Hepatitis B virus (HBV) infection is a worldwide health problem responsible for chronic liver disease and hepatocellular carcinoma. Both innate immunity and the adaptive immune response play central roles in the development of chronic hepatitis and liver cancer. We previously performed a comprehensive analysis of gene expression in the livers of HBV-infected chimeric mice and found that several genes associated with cell growth or carcinogenesis via hypoxia and KRAS signaling were upregulated by HBV infection. However, due to the absence of adaptive immunity in uPA/SCID chimeric mice, we were unable to analyze the effect of the host immune response. Methods: In this study, we compared gene expression profiles in the livers obtained from HBV-infected chimeric mice with those of HBV carriers. Results: After HBV infection, the expression of genes associated with inflammation and immune response, especially involving the Th1 and Th2 activation pathways, was altered as HBV-specific intracellular immune responses both in vivo and in clinical samples. Interestingly, the proinflammatory gene IL12A was induced by HBV infection in the chimeric mouse livers but not in the human livers, and associated genes, such as SRDA5A2, AR, and CCR3, showed differential alteration by HBV infection between the chimeric mouse and human livers. Conclusions: These results suggest that hepatocarcinogenesis may be suppressed by host immunity in HBV carriers. This study highlights potential new implications for inhibiting the progression of HBV-related liver diseases, including hepatocarcinogenesis. Full article

Background/Objectives: As a result of metabolic changes and the disruption of tissue architecture and microcirculation, the regenerative potential of the liver decreases with violations at both micro and macro levels. The development of intraoperative approaches for assessing its regenerative potential is important for reducing the risk of the occurrence of post-resection liver failure. In this study, we used multimodal optical coherence tomography (MM OCT), a combination of three optical coherence tomography modalities—OCT–angiography (OCTA), attenuation coefficient mapping, and OCT–elastography (OCE) to provide real-time three-dimensional and label-free assessment of changes in microcirculation, and in the structure and stiffness of the liver during regeneration. Methods: In our study, the regeneration of a healthy liver was induced by 70% partial hepatectomy. Monitoring of changes was carried out on the 0 (normal liver), 3rd and 7th day of regeneration using modalities of MM OCT. OCT offers the benefits of higher resolution and specificity compared with other clinical imaging modalities, and can be used, even intraoperatively. Results: By the 3rd day of liver regeneration, a decreased density of all observable vessels, together with increased values of the liver tissue’s attenuation coefficient and stiffness, was revealed compared to their initial state. However, by the 7th day, the studied parameters tended to return to their normal values, except that the density of large-caliber vessels continued to increase further. Histological and biochemical blood analysis methods were used to verify the MM OCT data. Conclusions: Such data are a first step towards further investigation of liver regeneration in pathology, and, taken in perspective, this should serve as a basis for predictive intraoperative assessment of the regenerative potential of the liver in a clinical setting. Full article

Patients affected by the rare disease pseudoxanthoma elasticum (PXE) exhibit the calcification of elastic fibers in ocular, dermal, and vascular tissues. These symptoms are triggered by mutations in the ATP-binding cassette transporter subfamily C member 6 (ABCC6), whose substrate remains unknown. Interestingly, ABCC6 is predominantly expressed in the liver tissue, leading to the hypothesis that PXE is a metabolic disorder. We developed a genome-editing system targeting ABCC6 in human immortalized hepatocytes (HepIms) for further investigations. The HepIms were transfected with an ABCC6-specific clustered regulatory interspaced short palindromic repeat (CRISPR-Cas9) genome-editing plasmid, resulting in the identification of a heterozygous (ht^ABCC6HepIm) and a compound heterozygous (cht^ABCC6HepIm) clone. These clones were analyzed for key markers associated with the PXE pathobiochemistry. Hints of impaired lipid trafficking, defects in the extracellular matrix remodeling, the induction of calcification inhibitor expression, and the down regulation of senescence and inflammatory markers in ABCC6-deficienct HepIms were found. Our ABCC6 knock-out model of HepIms provides a valuable tool for studying the metabolic characteristics of PXE in vitro. The initial analysis of the clones mirrors various features of the PXE pathobiochemistry and provides an outlook on future research approaches. Full article

Liver metastases from soft tissue sarcoma (STS) (excluding gastrointestinal stromal tumors) are rare and more commonly arise from retroperitoneal and intra-abdominal primary sites. Chemotherapy remains the mainstay of treatment for disseminated disease, but its effectiveness is limited and patients typically have a dismal prognosis with short survival. However, when metastases are confined to the liver (without pulmonary involvement), some patients may benefit from local techniques, either surgical or nonsurgical, that can provide long periods of disease-free survival. Due to the rarity of STS, especially with liver metastases, and the heterogeneity of histologies and biological behavior, there is a lack of standardized treatment guidelines and universally accepted criteria for this specific setting. To fill this gap, a multidisciplinary working group of experts in sarcoma and liver surgery reviewed the literature and available evidence and developed a set of clinical recommendations to be voted and discussed in the I Ibero-American Consensus on the Management of Metastatic Sarcoma, held at the III Spanish-Portuguese Update Meeting on the Treatment of Sarcomas in May 2024. Herein, the voting results of this meeting and the resulting consensus recommendations are presented, and their applicability, strengths, and limitations are discussed. Full article

Flavonoids, like Hesperetin, have been shown to be an ACE2 receptor agonists with antioxidant and pro-apoptotic activity and can induce apoptosis in cancer cells. ACE2 receptors are abundant in lung cancer cells. Here, we explored the application of Hesperetin bound to PegPLGA-coated nanoparticles (Hesperetin nanoparticles, HNPs) and anti-CD40 antibody as an aerosol treatment for lung tumor-bearing mice. The Hesperetin nanoparticles (HNPs) were engineered using a nano-formulation microfluidic technique and polymeric nanoparticles. The in vitro studies were performed in human A549 (ATCC) and murine LL/2-Luc2 (ATCC) lung cancer cell lines. A syngeneic orthotopic murine model of lung cancer was generated in wild (+/+) C57/BL6 background mice with luciferase-positive cell line LL/2-Luc2 cells. Lung tumor-bearing mice were treated via aerosol inhalation with HNP, anti-CD40 antibody, or both. Survival was used to analyze the efficacy of the aerosol treatment. The cohorts were also analyzed for body condition score, weight, and liver and kidney function. Analysis of an orthotopic murine lung cancer model demonstrated a differential uptake of the HNPs and anti-CD40 by the cancer cells. A higher survival rate was observed when the combination of aerosol treatment with HNPs was added with the treatment with anti-CD40 (p < 0.001), as compared to anti-CD40 alone (p < 0.01). Moreover, two tumor-bearing mice survived long-term with the combination treatment, and their tumors were diminished. Subsequently, these two mice were shown to be refractory to the development of subcutaneous tumors, indicating systemic resilience to developing new tumors. Using an inhalation-based administration, we successfully established a treatment model of increased therapeutic efficacy with HNPs and anti-CD40 in an orthotopic murine lung cancer model. Our findings open the possibility of improved lung cancer treatment using nanoparticles like flavonoids and immunoadjuvants. Full article