Research strategies of small molecules as chemotherapeutics to overcome multiple myeloma resistance.

Multiple myeloma (MM), a cancer of plasma cells, is the second most common hematological malignancy which is characterized by aberrant plasma cells infiltration in the bone marrow and complex heterogeneous cytogenetic abnormalities. Over the past two decades, novel treatment strategies such as proteasome inhibitors, immunomodulators, and monoclonal antibodies have significantly improved the relative survival rate of MM patients. However, the development of drug resistance results in the majority of MM patients suffering from relapse, limited treatment options and uncontrolled disease progression after relapse. There are urgent needs to develop and explore novel MM treatment strategies to overcome drug resistance and improve efficacy. Here, we review the recent small molecule therapeutic strategies for MM, and introduce potential new targets and corresponding modulators in detail. In addition, this paper also summarizes the progress of multi-target inhibitor therapy and protein degradation technology in the treatment of MM.

VEGF-induced Nrdp1 deficiency in vascular endothelial cells promotes cancer metastasis by degrading vascular basement membrane.

Vascular endothelial cells (VECs) are key players in the formation of neovessels and tumor metastasis, the ultimate cause of the majority of cancer-related human death. However, the crosstalk between VECs and metastasis remain greatly elusive. Based on our finding that tumor-associated VECs present significant decrease of Nrdp1 protein which is closely correlated with higher metastatic probability, herein we show that the conditional medium from hypoxia-incubated cancer cells induces extensive Nrdp1 downregulation in human and mouse VECs by vascular endothelial growth factor (VEGF), which activates CHIP, followed by Nrdp1 degradation in ubiquitin-proteasome-dependent way. More importantly, lung metastases of cancer cells significantly increase in conditional VECs Nrdp1 knockout mice. Mechanically, Nrdp1 promotes degradation of Fam20C, a secretory kinase involved in phosphorylating numerous secreted proteins. Reciprocally, deficiency of Nrdp1 in VECs (ecNrdp1) results in increased secretion of Fam20C, which induces degradation of extracellular matrix and disrupts integrity of vascular basement membrane, thus driving tumor metastatic dissemination. In addition, specific overexpression of ecNrdp1 by Nrdp1-carrying adeno-associated virus or chemical Nrdp1 activator ABPN efficiently mitigates tumor metastasis in mice. Collectively, we explore a new mechanism for VEGF to enhance metastasis and role of Nrdp1 in maintaining the integrity of vascular endothelium, suggesting that ecNrdp1-mediated signaling pathways might become potential target for anti-metastatic therapies.

Unraveling the Promise of RET Inhibitors in Precision Cancer Therapy by Targeting RET Mutations.

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.

Association of composite dietary antioxidant index with prevalence of stroke: insights from NHANES 1999-2018.

Background: There is a growing acknowledgment of the potential influence of antioxidative effects resulting from dietary decisions on the occurrence of stroke. The objective of this study was to elucidate the correlation between the composite dietary antioxidant index (CDAI) and the incidence of stroke in the general population of the United States. Methods: We gathered cross-sectional data encompassing 40,320 participants from the National Health and Nutrition Examination Survey (NHANES) spanning the years 1999 to 2018. Employing weighted multivariate logistic regression, we assessed the correlation between CDAI and stroke, while also investigating potential nonlinear relationships through restricted cubic spline (RCS) regression. Further, the intake of CDAI components were then incorporated into a predictive nomogram model, subsequently evaluated for its discriminatory prowess in stroke risk assessment using the receiver operating characteristic (ROC) curve. Results: Post-adjustment for confounding variables, we found that higher CDAI score were associated with a decreased risk of stroke, the odds ratio (OR) [95% CI] of CDAI associating with prevalence was 0.96 [0.94-0.98] (P< 0.001). Moreover, the adjusted OR [95% CI] for stroke across ascending CDAI quartiles stood at 0.90 [0.74-1.09], 0.74 [0.60-0.91], and 0.61 [0.50-0.76] compared to the reference quartile, respectively. The RCS analysis indicated a nonlinear yet negative correlation between CDAI and stroke. The nomogram model, constructed based the intake of antioxidants, exhibited a significant predictive capacity for stroke risk, boasting an area under the curve (AUC) of 77.4% (76.3%-78.5%). Conclusion: Our investigation ascertained a nonlinear negative relationship between CDAI and stroke within the broader American population. However, given the inherent limitations of the cross-sectional design, further comprehensive research is imperative to establish the causative nature of this association.

RIPK1 inhibitor ameliorates pulmonary injury by modulating the function of neutrophils and vascular endothelial cells.

Acute lung injury (ALI) is an acute and progressive hypoxic respiratory failure that could progress to acute respiratory distress syndrome (ARDS) with a high mortality rate, thus immediate medical attention and supportive care are necessary. The pathophysiology of ALI is characterized by the disruption of the alveolar-capillary barrier and activation of neutrophils, leading to lung tissue damage. The receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising target for the treatment of multiple inflammatory diseases, but the role of RIPK1 in the ALI remains poorly understood. In this study, we aimed to figure out the pathological role of RIPK1 in ALI, especially in the pulmonary immune microenvironment involving neutrophils and endothelial cells. In vivo experiments showed that RIPK1 inhibitor protected against lipopolysaccharide (LPS)-induced lung injury in mouse models, with reduced neutrophils and monocytes infiltration in the lungs. Further studies demonstrated that, besides the inhibitory action on necroptosis, RIPK1 inhibitor directly suppressed reactive oxygen species (ROS) generation and inflammatory cytokines secretion from neutrophils. Furthermore, RIPK1 inhibition maintains the barrier function in TNF-α-primed vascular endothelial cells and prevents their activation induced by the supernatant from LPS-stimulated neutrophils. Mechanistically, the aforementioned effects of RIPK1 inhibitor are associated with the NF-κB signaling pathway, which is partially independent of necroptosis inhibition. These results provide new evidence that RIPK1 inhibitor directly regulates the function of neutrophils and endothelial cells, as well as interferes with the interactions between these two cell types, therefore contributing to a better understanding of RIPK1 in ALI and providing a potential avenue for future therapeutic interventions.

Discovery of RORγ Allosteric Fluorescent Probes and Their Application: Fluorescence Polarization, Screening, and Bioimaging.

Retinoic acid receptor-related orphan receptor γ (RORγ) acts as a crucial transcription factor in Th17 cells and is involved in diverse autoimmune disorders. RORγ allosteric inhibitors have gained significant research focus as a novel strategy to inhibit RORγ transcriptional activity. Leveraging the high affinity and selectivity of RORγ allosteric inhibitor MRL-871 (1), this study presents the design, synthesis, and characterization of 11 allosteric fluorescent probes. Utilizing the preferred probe 12h, we established an efficient and cost-effective fluorescence polarization-based affinity assay for screening RORγ allosteric binders. By employing virtual screening in conjunction with this assay, 10 novel RORγ allosteric inhibitors were identified. The initial SAR studies focusing on the hit compound G381-0087 are also presented. The encouraging outcomes indicate that probe 12h possesses the potential to function as a powerful tool in facilitating the exploration of RORγ allosteric inhibitors and furthering understanding of RORγ function.

Vitamin D binding protein (VDBP) hijacks twist1 to inhibit vasculogenic mimicry in hepatocellular carcinoma.

Rationale: Vitamin D (VD) has been suggested to have antitumor effects, however, research on the role of its transporter vitamin D-binding protein (VDBP, gene name as GC) in tumors is limited. In this study, we demonstrated the mechanism underlying the inhibition of vasculogenic mimicry (VM) by VDBP in hepatocellular carcinoma (HCC) and proposed an anti-tumor strategy of combining anti-PD-1 therapy with VD. Methods: Three-dimensional cell culture models and mice with hepatocyte-specific GC deletion were utilized to study the correlation between VDBP expression and VM. A patient-derived tumor xenograft (PDX) model was further applied to validate the therapeutic efficacy of VD in combination with an anti-PD-1 drug. Results: The study revealed that VDBP expression is negatively correlated with VM in HCC patients and elevated VDBP expression is associated with a favorable prognosis. The mechanism studies suggested VDBP hindered the binding of Twist1 on the promoter of VE-cadherin by interacting with its helix-loop-helix DNA binding domain, ultimately leading to the inhibition of VM. Furthermore, VD facilitated the translocation of the vitamin D receptor (VDR) into the nucleus where VDR interacts with Yin Yang 1 (YY1), leading to the transcriptional activation of VDBP. We further demonstrated that the combination of VD and anti-PD-1 led to an improvement in the anti-tumor efficacy of an anti-PD-1 drug. Conclusion: Collectively, we identified VDBP as an important prognostic biomarker in HCC patients and uncovered it as a therapeutic target for enhancing the efficacy of immune therapy.

Diagnostic Value of Echocardiography Combined with Residual Cholesterol for Asymptomatic Myocardial Ischaemia in Coronary Artery Disease.

This study aimed to investigate the diagnostic value of combined echocardiography and residual cholesterol in asymptomatic myocardial ischaemia. One hundred and fifty-seven patients were seen at Hefei BOE Hospital from 2019 to 2022. The patients were divided into two groups, the observation group (n=90, confirmed asymptomatic myocardial ischaemia) and the control group (n=67, negative diagnosis), based on coronary angiography. The observation group had significantly higher residual cholesterol levels (p=0.001). A combined approach of echocardiography and serum residual cholesterol values showed statistically higher accuracy (p<0.05), with ROC curve analysis supporting the superiority of this method [AUC 0.788 (0.711-0.865), Yoden index 0.576]. It also demonstrated higher sensitivity (88.9%) and specificity (68.7%). The study concluded that combined echocardiography and serum residual cholesterol testing offer superior diagnostic efficacy and practicality for asymptomatic myocardial ischaemia, recommending it for the clinical use. Key Words: Echocardiography, Residual cholesterol, Asymptomatic myocardial ischaemia, Diagnosis.

A modified nucleoside O6-methyl-2'-deoxyguanosine-5'-triphosphate exhibits anti-glioblastoma activity in a caspase-independent manner.

Resistance to temozolomide (TMZ), the frontline chemotherapeutic agent for glioblastoma (GBM), has emerged as a formidable obstacle, underscoring the imperative to identify alternative therapeutic strategies to improve patient outcomes. In this study, we comprehensively evaluated a novel agent, O6-methyl-2'-deoxyguanosine-5'-triphosphate (O6-methyl-dGTP) for its anti-GBM activity both in vitro and in vivo. Notably, O6-methyl-dGTP exhibited pronounced cytotoxicity against GBM cells, including those resistant to TMZ and overexpressing O6-methylguanine-DNA methyltransferase (MGMT). Mechanistic investigations revealed that O6-methyl-dGTP could be incorporated into genomic DNA, disrupting nucleotide pools balance, and inducing replication stress, resulting in S-phase arrest and DNA damage. The compound exerted its anti-tumor properties through the activation of AIF-mediated apoptosis and the parthanatos pathway. In vivo studies using U251 and Ln229 cell xenografts supported the robust tumor-inhibitory capacity of O6-methyl-dGTP. In an orthotopic transplantation model with U87MG cells, O6-methyl-dGTP showcased marginally superior tumor-suppressive activity compared to TMZ. In summary, our research, for the first time, underscores the potential of O6-methyl-dGTP as an effective candidate against GBM, laying a robust scientific groundwork for its potential clinical adoption in GBM treatment regimens.

Prenatal Exposure to PFAS, Associations with Preterm Birth and Modification by Maternal Estrogen Levels: The Maoming Birth Study.

BACKGROUND: Estrogens play a critical role in parturition, and poly- and perfluoroalkyl substances (PFAS), which have estrogenic effects, have been associated with preterm birth. However, the impact of estrogens on the association between PFAS and preterm birth is unknown. OBJECTIVE: The objective of this study is to investigate if estrogens modified the association between PFAS and preterm birth, using a nested case-control study design. METHODS: A total of 371 preterm births and 508 controls were selected from a birth cohort study in China between 2016 and 2018. Perfluorobutanoic acid (PFBA), perfluorohexanesulfonic acid (PFHxS) and its branched isomer, perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS) and its branched isomer, and perfluorononanoic acid (PFNA) were quantified in maternal serum (mean gestational age of 32 wk). Estradiol and estriol were quantified in cord serum. Preterm birth was defined as live delivery at <37 gestational weeks. Causal mediation analysis was used to estimate the mediation and interaction effects of estrogen on the association between PFAS and preterm birth. Latent profile analysis was used to identify important estrogen profiles. Multiple linear regression was used to estimate associations between PFAS and preterm birth and interactions between PFAS and estrogens on preterm birth. RESULTS: Overall, higher odds ratios (ORs) of preterm birth were associated with each 1 ln-unit PFAS increase: PFBA [1.20, 95% confidence interval (CI): 1.14, 1.26], PFNA (1.30, 95% CI: 1.21, 1.39), PFOA (1.98, 95% CI: 1.54, 2.55), and PFOS (1.91, 95% CI: 1.76, 2.07) and its branched isomer (1.91, 95% CI: 1.90, 1.92). We detected statistically significant interactions between cord estradiol and PFAS on preterm birth, while no mediation effects of cord estrogen were observed. The ORs of PFOS (4.29, 95% CI: 1.31, 8.25), its branched isomer (6.71, 95% CI: 1.06, 11.91), and preterm birth were greater for participants with high cord estrogen levels than for participants with low cord estrogen levels. DISCUSSION: Our findings suggest that estrogen modified the association between maternal PFAS exposure and preterm birth. Further studies on maternal PFAS exposure and preterm birth, taking interaction effects of cord estrogens into account, are warranted. https://doi.org/10.1289/EHP11377.

Preclinical characterization of danatinib as a novel FLT3 inhibitor with excellent efficacy against resistant acute myeloid leukemia.

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.

[Association of Serine/Threonine Phosphoprotein Phosphatase 4C Expression With Prognosis of Gastric Cancer].

Objective To investigate the expression level of serine/threonine phosphoprotein phosphatase 4C(PPP4C)in gastric cancer,and analyze its relationship with prognosis and the underlying regulatory mechanism.Methods The clinical data of 104 gastric cancer patients admitted to the First Affiliated Hospital of Bengbu Medical College between January 2012 and August 2016 were collected.Immunohistochemical staining was employed to determine the expression levels of PPP4C and Ki-67 in the gastric cancer tissue.The gastric cancer cell lines BGC823 and HGC27 were cultured and transfected with the vector for PPP4C knockdown,the vector for PPP4C overexpression,and the lentiviral vector(control),respectively.The effects of PPP4C on the cell cycle and proliferation were analyzed and the possible regulatory mechanisms were explored.Results PPP4C was highly expressed in gastric cancer(P<0.001),and its expression promoted malignant progression of the tumor(all P<0.01).Univariate and Cox multivariate analysis clarified that high expression of PPP4C was an independent risk factor affecting the 5-year survival rate of gastric cancer patients(P=0.003).Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis suggested that PPP4C may be involved in the cell cycle.The correlation analysis showed that the expression of PPP4C was positively correlated with that of Ki-67 in gastric cancer(P<0.001).The up-regulation of PPP4C expression increased the proportion of tumor cells in the S phase,alleviated the G2/M phase arrest,and promoted the proliferation of gastric cancer cells and the expression of cyclin D1 and cyclin-dependent kinase 6(CDK6)(all P<0.05).The down-regulation of PPP4C decreased the proportion of gastric cancer cells in the S phase,promoted G2/M phase arrest,and inhibited cell proliferation and the expression of cyclin D1,CDK6,and p53(all P<0.05).p53 inhibitors promoted the proliferation of BGC823 and HGC27 cells in the PPP4C knockdown group(P<0.001,P<0.001),while p53 activators inhibited the proliferation of BGC823 and HGC27 cells in the PPP4C overexpression group(P<0.001,P=0.002).Conclusions PPP4C is highly expressed in gastric cancer and affects the prognosis of the patients.It may increase the proportion of gastric cancer cells in the S phase and alleviate the G2/M phase arrest by inhibiting p53 signaling,thereby promoting cell proliferation.

Early life exposure to F-53B induces neurobehavioral changes in developing children and disturbs dopamine-dependent synaptic signaling in weaning mice.

BACKGROUND: Previous studies have shown that F-53B exposure may be neurotoxic to animals, but there is a lack of epidemiological evidence, and its mechanism needs further investigation. METHODS: Serum F-53B concentrations and Wisconsin Card Sorting Test (WCST) were evaluated in 314 growing children from Guangzhou, China, and the association between them were analyzed. To study the developmental neurotoxicity of F-53B, experiments on sucking mice exposed via placental transfer and breast milk was performed. Maternal mice were orally exposed to 4, 40, and 400 µg/L of F-53B from postnatal day 0 (GD0) to postnatal day 21 (PND 21). Several genes and proteins related to neurodevelopment, dopamine anabolism, and synaptic plasticity were examined by qPCR and western blot, respectively, while dopamine contents were detected by ELISA kit in weaning mice. RESULTS: The result showed that F-53B was positively associated with poor WCST performance. For example, with an interquartile range increase in F-53B, the change with 95 % confidence interval (CI) of correct response (CR), and non-perseverative errors (NPE) was -2.47 (95 % CI: -3.89, -1.05, P = 0.001), 2.78 (95 % CI: 0.79, 4.76, P = 0.007), respectively. Compared with the control group, the highest exposure group of weaning mice had a longer escape latency (35.24 s vs. 51.18 s, P = 0.034) and a lesser distance movement (34.81 % vs. 21.02 %, P < 0.001) in the target quadrant, as observed from morris water maze (MWM) test. The protein expression of brain-derived neurotrophic factor (BDNF) and growth associated protein-43 (GAP-43) levels were decreased, as compared to control (0.367-fold, P < 0.001; 0.366-fold, P < 0.001; respectively). We also observed the upregulation of dopamine transporter (DAT) (2.940-fold, P < 0.001) consistent with the trend of dopamine content (1.313-fold, P < 0.001) in the hippocampus. CONCLUSION: Early life exposure to F-53B is associated with adverse neurobehavioral changes in developing children and weaning mice which may be modulated by dopamine-dependent synaptic plasticity.

Effect of depressive symptoms on quality of work life in female nurses: a cross-sectional study using propensity score matching.

Background: Female nurses have been considered as a vulnerable population in the context of mental health, due to the nature of their work, which can be stressful and emotionally taxing. Understanding the relationship between depressive symptoms and quality of work life (QWL) can contribute to improving mental health and job performance. However, limited studies have focused on the effect of depressive symptoms on QWL in female nurses. Objectives: The present study aimed to assess the effect of depressive symptoms on female nurses' QWL using propensity score matching (PSM). Methods: A cross-sectional, online study using convenience sampling was conducted among 1,401 female nurses in China. PSM was used to minimize the impact of potential confounders between no depressive symptoms and depressive symptoms. Stepwise multiple linear regression analyses were performed on the PSM samples to explore the effects of depressive symptoms on the QWL. Results: The results revealed there were 33.5% of the female nurses reported depressive symptoms before PSM. And female nurses in this study had a moderate level of QWL before PSM (122.11 ± 18.15), which remained steady after PSM (118.33 ± 18.04). After PSM, the final sample contained 864 female nurses. Stepwise multiple linear regression results indicated that depressive symptoms were the most strongly associated with QWL (ß = -0.454, p < 0.001). Conclusion: This study highlights the importance of developing mental health plans and psychological interventions for female nurses to maintain mental health and QWL, which is critical to the nursing workforce's sustainability.

Garbractin A, a Polycyclic Polyprenylated Acylphloroglucinol with a 4,11-dioxatricyclo[4.4.2.01,5]Dodecane Skeleton from Garcinia bracteata Fruits.

Garbractin A (1), a structurally complicated polycyclic polyprenylated acylphloroglucinol (PPAP) with an unprecedented 4,11-dioxatricyclo[4.4.2.01,5] dodecane skeleton, was isolated from the fruits of Garcinia bracteata, along with five new biosynthetic analogues named garcibracteatones A-E (2-6). Their structures containing absolute configurations were revealed using spectroscopic data, the residual dipolar coupling-enhanced NMR approach, and quantum chemical calculations. The antihyperglycemic effect of these PPAPs (1-6) was evaluated using insulin-resistant HepG2 cells (IR-HepG2 cells) induced through palmitic acid (PA). Compounds 1, 3, and 4 were found to significantly promote glucose consumption in the IR-HepG2 cells and, therefore, may hold potential as candidates for treating hyperglycemia.

Natural products as potential lead compounds to develop new antiviral drugs over the past decade.

Virus infection has been one of the main causes of human death since the ancient times. Even though more and more antiviral drugs have been approved in clinic, long-term use can easily lead to the emergence of drug resistance and side effects. Fortunately, there are many kinds of metabolites which were produced by plants, marine organisms and microorganisms in nature with rich structural skeletons, and they are natural treasure house for people to find antiviral active substances. Aiming at many types of viruses that had caused serious harm to human health in recent years, this review summarizes the natural products with antiviral activity that had been reported for the first time in the past ten years, we also sort out the source, chemical structure and safety indicators in order to provide potential lead compounds for the research and development of new antiviral drugs.

Advancement and Applications of Nanotherapy for Cancer Immune Microenvironment.

Cancer treatment has evolved rapidly due to major advances in tumor immunity research. However, due to the complexity, heterogeneity, and immunosuppressive microenvironment of tumors, the overall efficacy of immunotherapy is only 20%. In recent years, nanoparticles have attracted more attention in the field of cancer immunotherapy because of their remarkable advantages in biocompatibility, precise targeting, and controlled drug delivery. However, the clinical application of nanomedicine also faces many problems concerning biological safety, and the synergistic mechanism of nano-drugs with immunity remains to be elucidated. Our study summarizes the functional characteristics and regulatory mechanisms of nanoparticles in the cancer immune microenvironment and how nanoparticles activate and long-term stimulate innate immunity and adaptive immunity. Finally, the current problems and future development trends regarding the application of nanoparticles are fully discussed and prospected to promote the transformation and application of nanomedicine used in cancer treatment.

HSF4/COIL complex-dependent R-loop mediates ultraviolet-induced inflammatory skin injury.

Intense ultraviolet (UV) exposure can cause phototoxic reactions, such as skin inflammation, resulting in injury. UV is a direct cause of DNA damage, but the mechanisms underlying transcriptional regulation within cells after DNA damage are unclear. The bioinformatics analysis of transcriptome sequencing data from UV-irradiated and non-UV-irradiated skin showed that transcription-related proteins, such as HSF4 and COIL, mediate cellular response to UV irradiation. HSF4 and COIL can form a complex under UV irradiation, and the preference for binding target genes changed because of the presence of a large number of R-loops in cells under UV irradiation and the ability of COIL to recognize R-loops. The regulation of target genes was altered by the HSF4-COIL complex, and the expression of inflammation and ageing-related genes, such as Atg7, Tfpi, and Lims1, was enhanced. A drug screen was performed for the recognition sites of COIL and R-loop. N6-(2-hydroxyethyl)-adenosine can competitively bind COIL and inhibit the binding of COIL to the R-loop. Thus, the activation of downstream inflammation-related genes and inflammatory skin injury was inhibited.

Fetal Glucocorticoid Mediates the Association between Prenatal Per- and Polyfluoroalkyl Substance Exposure and Neonatal Growth Index: Evidence from a Birth Cohort Study.

Glucocorticoid plays a key role in the growth and organ maturation of fetus. However, the effect of glucocorticoid on the association between per- and polyfluoroalkyl substance (PFAS) exposure and fetal growth is still unknown. We detected cord cortisol (active glucocorticoid in human) and 34 PFAS concentrations in the maternal serum samples, which were collected from 202 mother-fetus pairs in the Maoming Birth Cohort from 2015 to 2018. The mediation effect of cord cortisol on the association between maternal PFAS and the neonatal growth index (NGI) was estimated. We found that higher PFAS concentrations were associated with lower NGI in terms of ponderal index, birth weight (BW), head circumference (HC), and its z-scores (BWZ and HCZ) (P < 0.05). Fetal cortisol could mediate 12.6-27.3% of the associations between PFAS and NGI. Specifically, cord cortisol mediated the association between branched perfluorooctane sulfonate (branched PFOS) and HCZ by 20.4% and between perfluorooctanoate (PFOA) and HCZ by 27.3%. Our findings provide the first epidemiological data evincing that fetal cortisol could mediate the association between prenatal PFAS exposure and fetal growth. Further investigations are recommended to elucidate the interactions among cord cortisol, PFAS, and fetal growth.