Helminth-derived molecules: pathogenic and pharmacopeial roles.

Parasitic helminths, taxonomically comprising trematodes, cestodes, and nematodes, are multicellular invertebrates widely disseminated in nature and have afflicted people continuously for a long time. Helminths play potent roles in the host through generating a variety of novel molecules, including some excretory/secretory products and others that are involved in intracellular material exchange and information transfer as well as the initiation or stimulation of immune and metabolic activation. The helminth-derived molecules have developed powerful and diverse immunosuppressive effects to achieve immune evasion for parasite survival and establish chronic infections. However, they also improve autoimmune and allergic inflammatory responses and promote metabolic homeostasis by promoting metabolic reprogramming of various immune functions, and then inducing alternatively activated macrophages, T helper 2 cells, and regulatory T cells-mediated immune responses. Therefore, a deeper exploration of the immunopathogenic mechanism and immune regulatory mechanisms of helminth-derived molecules exerted in the host is crucial for understanding host-helminth interactions as well as the development of therapeutic drugs for infectious or non-infectious diseases. In this review, we focus on the properties of helminth-derived molecules to give an overview of the most recent scientific knowledge about their pathogenic and pharmacopeial roles in immune-metabolic homeostasis.

The rebalancing of the immune system at the maternal-fetal interface ameliorates autism-like behavior in adult offspring.

Maternal immune activation (MIA) is critical for imparting neuropathology and altered behaviors in offspring; however, maternal-fetal immune cell populations have not been thoroughly investigated in MIA-induced autism spectrum disorders (ASDs). Here, we report the single-cell transcriptional landscape of placental cells in both PBS- and poly(I:C)-induced MIA dams. We observed a decrease in regulatory T (Treg) cells but an increase in the M1 macrophage population at the maternal-fetal interface in MIA dams. Based on the Treg-targeting approach, we investigate an immunoregulatory protein, the helminth-derived heat shock protein 90α (Sjp90α), that induces maternal Treg cells and subsequently rescues the autism-like behaviors in adult offspring. Furthermore, in vivo depletion of maternal macrophages attenuates placental inflammatory reaction and reverses behavioral abnormalities in adult offspring. Notably, Sjp90α induces CD4+ T cell differentiation via scavenger receptor A (SR-A) on the macrophage in vitro. Our findings suggest a maternal Treg-targeted approach to alleviate MIA-induced autism-like behavior in adult offspring.

A comparative study of the relationship between time in range assessed by self-monitoring of blood glucose and continuous glucose monitoring with microalbuminuria outcome, HOMA-IR and HOMA-ß test.

AIMS: To compare the time in range (TIR) obtained from self-monitoring of blood glucose (SMBG) with that obtained from continuous glucose monitoring (CGM), and explore the relationship of TIR with microalbuminuria outcome, HOMA-IR and HOMA-ß test. METHODS: We recruited 400 patients with type 2 diabetes to carry out blood glucose monitoring by both SMBG and CGM for 3 consecutive days. TIR, TAR, TBR and other blood glucose variation indices were calculated respectively through the glucose data achieved from SMBG and CGM. The HOMA-IR and HOMA-ß test was evaluated by an oral glucose tolerance test. Urinary microalbumin-to-creatinine ratio completed in the laboratory. RESULTS: The median (25 %, 75 % quartile) of TIRCGM and TIRSMBG were 74.94(44.90, 88.04) and 70.83(46.88, 87.50) respectively, and there was no significant difference, p = 0.489; For every 1 % increase in TIRCGM, the risk of microalbuminuria decreased by 1.6 % (95%CI:0.973, 0.995, p = 0.006) and for every 1 % increase in TIRSMBG, the risk of microalbuminuria decreased by 1.3 % (95%CI:0.975, 0.999, p = 0.033). Stepwise multiple linear regression analysis showed an independent positive correlation between TIR (including TIRCGM and TIRSBMG) and LnDI30 and LnDI120 levels (p = 0.000). CONCLUSIONS: The TIR calculated by SMBG was highly consistent with that reported by CGM and was significantly associated with the risk of microalbuminuria and the HOMA-ß. Higher TIR quartiles were associated with lower incidence of microalbuminuria as well as higher lever of HOMA-ß. For patients with limited CGM application, SMBG-derived TIR may be an alternative to CGM-derived TIR, to assess blood glucose control.

Novel anti-inflammatory peptide alleviates liver ischemia-reperfusion injury.

Ischemia-reperfusion injury (IRI) remains inevitable in liver surgeries, macrophages play a critical role in the development of IRI, but little is known about the macrophages regulate pathogenesis of IRI. Based on target-guided screening, we identified a small 3 kDa peptide (SjDX5-271) from various schistosome egg-derived peptides that induced M2 macrophage polarization. SjDX5-271 treatment protected the mice against liver IRI through promoting M2 macrophage polarization, the protective effect was abrogated when the macrophages were depleted. Transcriptomic sequencing showed that the TLR signaling pathway was significantly inhibited in macrophages derived from the SjDX5-271 treatment group. We further identified that SjDX5-271 promotes M2 macrophage polarization by inhibiting the TLR4/MyD88/NF-κB signaling pathway and further alleviates hepatic inflammation in liver IRI. Collectively, SjDX5-271 exhibits promising therapeutic effects in IRI and represents a novel therapeutic approach for IRI, even in immune-related diseases. This study revealed the development of a new biologic from the parasite and enhanced our understanding of host-parasite interplay, providing a blueprint for future therapies for immune-related diseases.

Computer-aided designing of a novel multi­epitope DNA vaccine against severe fever with thrombocytopenia syndrome virus.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne viral disease caused by the SFTS virus (Dabie bandavirus), which has become a substantial risk to public health. No specific treatment is available now, that calls for an effective vaccine. Given this, we aimed to develop a multi-epitope DNA vaccine through the help of bioinformatics. The final DNA vaccine was inserted into a special plasmid vector pVAX1, consisting of CD8+ T cell epitopes, CD4+ T cell epitopes and B cell epitopes (six epitopes each) screened from four genome-encoded proteins--nuclear protein (NP), glycoprotein (GP), RNA-dependent RNA polymerase (RdRp), as well as nonstructural protein (NSs). To ascertain if the predicted structure would be stable and successful in preventing infection, an immunological simulation was run on it. In conclusion, we designed a multi-epitope DNA vaccine that is expected to be effective against Dabie bandavirus, but in vivo trials are needed to verify this claim.

Washed microbiota transplantation reduces glycemic variability in unstable diabetes.

BACKGROUND: Dysbiosis of gut microbiota is causally linked to impaired host glucose metabolism. We aimed to study effects of the new method of fecal microbiota transplantation, washed microbiota transplantation (WMT), on reducing glycemic variability (GV) in unstable diabetes. METHODS: Fourteen eligible patients received three allogenic WMTs and were followed up at 1 week, 1 month, and 3 months. Primary outcomes were daily insulin dose, glucose excursions during meal tests, and GV indices calculated from continuous monitoring or self-monitoring glucose values. Secondary outcomes were multiomics data, including 16S rRNA gene sequencing, metagenomics, and metabolomics to explore underlying mechanisms. RESULTS: Daily insulin dose and glucose excursions markedly dropped, whereas GV indices significantly improved up to 1 month. WMT increased gut microbial alpha diversity, beta diversity, and network complexity. Taxonomic changes featured lower abundance of genera Bacteroides and Escherichia-Shigella, and higher abundance of genus Prevotella. Metagenomics functional annotations revealed enrichment of distinct microbial metabolic pathways, including methane biosynthesis, citrate cycle, amino acid degradation, and butyrate production. Derived metabolites correlated significantly with improved GV indices. WMT did not change circulating inflammatory cytokines, enteroendocrine hormones, or C-peptide. CONCLUSIONS: WMT showed strong ameliorating effect on GV, raising the possibility of targeting gut microbiota as an effective regimen to reduce GV in diabetes.

Effects of virtual reality simulation on medical students' learning and motivation in human parasitology instruction: a quasi-experimental study.

BACKGROUND: Despite the proven effectiveness of simulation-based learning activities, its adoption in medical education remains limited, and the influence of simulation on student motivation, particularly subjective task values, is seldom explored. This study aimed to investigate the impact of a simulation-based learning activity on student learning and subjective task values in a medical morphology-related course of Human Parasitology. METHODS: A quasi-experimental study was conducted with 113 Chinese undergraduate medical students who participated in a Human Parasitology course during April to May 2022. Students were divided into two groups: Simulation Group (n = 55), where students used the simulation, and Lecture Group (n = 58), where students attended an online lecture. Students' learning was measured prior to the intervention, immediately after the intervention, and three weeks later to assess knowledge retention. The subjective task values questionnaire was administered before and after the interventions. Data were analyzed using one-way ANCOVA and MANOVA. RESULTS: Students in the Simulation Group exhibited significantly higher knowledge gain compared to the Lecture Group [F (1,110) = 23.69, p < 0.01]. Additionally, the Simulation Group retained knowledge significantly better than the Lecture Group [F (1,101) = 10.05, p < 0.005]. Furthermore, students in the Simulation Group experienced a significant increase in subjective task values after the intervention [F (3, 52) = 3.57, p < 0.05, ηp2 = 0.17], while students in the Lecture Group reported a significant decrease in subjective task values [F (3, 55) = 2.96, p < 0.05, ηp2 = 0.14]. CONCLUSIONS: Simulation-based learning not only leads to superior learning but also enhances students' subjective task values. These findings offer valuable insights into designing effective simulation-based learning experiences in medical education and have significant practical implications for educators and medical professionals.

A target-based discovery from a parasitic helminth as a novel therapeutic approach for autoimmune diseases.

BACKGROUND: Regulatory T cells (Tregs) can alleviate the development of autoimmune and inflammatory diseases, thereby proposing their role as a new therapeutic strategy. Parasitic helminths have co-evolved with hosts to generate immunological privilege and immune tolerance through inducing Tregs. Thus, constructing a "Tregs-induction"-based discovery pipeline from parasitic helminth is a promising strategy to control autoimmune and inflammatory diseases. METHODS: The gel filtration chromatography and reverse-phase high-performance liquid chromatography (RP-HPLC) were used to isolate immunomodulatory components from the egg extracts of Schistosoma japonicum. The extracted peptides were evaluated for their effects on Tregs suppressive functions using flow cytometry, ELISA and T cell suppression assay. Finally, we carried out colitis and psoriasis models to evaluate the function of Tregs induced by helminth-derived peptide in vivo. FINDINGS: Here, based on target-driven discovery strategy, we successfully identified a small 3 kDa peptide (SjDX5-53) from egg extracts of schistosome, which promoted both human and murine Tregs production. SjDX5-53 presented immunosuppressive function by arresting dendritic cells (DCs) at an immature state and augmenting the proportion and suppressive capacity of Tregs. In mouse models, SjDX5-53 protected mice against autoimmune-related colitis and psoriasis through inducing Tregs and inhibiting inflammatory T-helper (Th) 1 and Th17 responses. INTERPRETATION: SjDX5-53 exhibited the promising therapeutic effects in alleviating the phenotype of immune-related colitis and psoriasis. This study displayed a screening and validation pipeline of the inducer of Tregs from helminth eggs, highlighting the discovery of new biologics inspired by co-evolution of hosts and their parasites. FUNDING: This study was supported by the Natural Science Foundation of China (82272368) and Natural Science Foundation of Jiangsu Province (BK20211586).

Advances in research on schistosomiasis and toxoplasmosis in China: A bibliometric analysis of Chinese academic journals published from 1980 to 2021.

BACKGROUND: The scale-up of zoonoses prevention control and eradication in China, coupled with numerous academic articles in Chinese journals has led to the development of new tools and strategies aimed at further consolidating parasite control goals. As a result, there is a growing need for an up-to-date understanding of the research progress and prevention and control experience of parasitic diseases in China. METHODS: To understand the research status of schistosomiasis and toxoplasmosis in China, academic articles published in Chinese journals from 1980 to 2021 were retrieved from China National Knowledge Infrastructure (CNKI) and Wanfang databases. The Bibliographic Items Co-occurrence Matrix Builder (BICOMB) software was used to extract and analyze the keyword frequencies. The 'K/A ratio' as the frequency of a keyword that occurred in all the articles within a certain time stage was calculated to compare the popularity of the same keyword in different time stages. Keyword co-occurrence network maps were constructed by VOSviewer software. RESULTS: A total of 18,508 articles in the research field of Schistosoma and 13,289 articles in the field of Toxoplasma gondii were included. Results in both fields showed some similarities: the annual number of articles presented an increasing trend before entering the 21st century and decreased rapidly in recent years. Two opposite changing trends of keyword frequency could be observed in the K/A ratio analysis: the K/A ratios of 'Surveillance' and 'Infection' continuously increased over time, while those of 'Schistosoma mansoni' and 'Mesenteric lymph nodes' decreased. The diversification of keyword co-occurrence networks could be observed in the co-occurrence network maps. CONCLUSIONS: This bibliometric analysis reveals trends in research themes in the fields of Schistosoma and Toxoplasma gondii from 1980 to 2021, presenting China's experience such as a high degree of government involvement and multidisciplinary participation in schistosomiasis and toxoplasmosis control and elimination.

Identification and Characterization of Antigenic Properties of Schistosoma japonicum Heat Shock Protein 90α Derived Peptides.

It is known that schistosome-derived antigens induce innate and adaptive immune responses that are essential for the formation of hepatic immunopathology. Here, we screened and synthesized four peptides derived from Schistosoma japonicum (S. japonicum) heat shock protein 90α (Sjp90α-1, -2, -3, and -4), which is widely expressed in adults and eggs of the genus S. japonicum and induces remarkable immune reactions. To define the antigenicity of these peptides, we stimulated splenocytes with peptides, and the results showed that only the Sjp90α-1 peptide could predominately induce the activation of dendritic cells (DCs) and macrophages as well as alter the proportion of follicular helper T (Tfh) cells. Next, CD4+ T cells were purified and cocultured with mouse bone-marrow-derived DCs (BMDCs) with or without Sjp90α-1 peptide stimulation in vitro, and the results showed that Sjp90α-1-stimulated BMDCs can significantly induce CD4+ T-cell differentiation into Tfh cells, while the direct stimulation of CD4+ T cells with Sjp90α-1 did not induce Tfh cells, indicating that the Sjp90α-1 peptide promotes Tfh cell differentiation depending on the presence of DCs. Furthermore, we selected and prepared an Sjp90α-1-peptide-based antibody and illustrated that it has excellent reactivity with the immunizing peptide and detects a single band of 29 kDa corresponding to the Sjp90α protein. The immunolocalization results showed that the protein recognized by this Sjp90α-1-peptide-based antibody is present in the mature eggs and the tegument of adults, implying that the parasite-derived peptide has a potential interaction with the host immune system. Finally, we evaluated antipeptide IgG antibodies and revealed a significantly higher level of anti-Sjp90α-1 peptide IgG antibodies in mice 3 weeks after S. japonicum infection. In conclusion, we illustrate that these synthetic peptides warrant further investigation by evaluating their antigen-specific immune response and their ability to efficiently induce Tfh cells. Moreover, they may constitute a potentially helpful method for the laboratory diagnosis of schistosomiasis japonica.

Oral berberine ameliorates high-fat diet-induced obesity by activating TAS2Rs in tuft and endocrine cells in the gut.

BACKGROUND AND AIMS: Although oral berberine, a natural compound extracted from the Chinese herbal medicine curcumin, has low bioavailability, it is still effective in suppressing obesity; however, the underlying mechanism is unclear. Berberine can bind to bitter-taste receptors (TAS2Rs) in intestinal endocrine secretin tumor (STC-1) cells to promote glucagon-like peptide-1 (GLP-1) secretion. Notably, TAS2Rs also exist in the tuft cells of the gut. Therefore, this study aimed to explore whether the beneficial effect of oral berberine on obesity is dependent on bitter-taste signaling in the tuft cells of the gut. METHODS AND RESULTS: Standard chow diet (SCD) or high-fat diet (HFD) was administered to C57BL/6 mice, with or without berberine (100 mg/kg, 200 mg/kg, p. o.). The PLCß2 inhibitor U73122 was used to verify whether the anti-obesity effect of berberine was dependent on the bitter-taste signaling pathway. In this study, we observed that the oral administration of berberine alleviated HFD-induced obesity in mice that U73122 partially inhibited. Both in vivo and ex vivo, berberine upregulated the release of GLP-1, promoted the proliferation of tuft cells and secretion of IL-25 in obesity via the TAS2R signaling pathway. CONCLUSIONS: Oral berberine ameliorated HFD-induced obesity through the TAS2R-IL-25 signaling pathway in tuft cells in the gut. SIGNIFICANCE: We identified and functionally characterized the TAS2Rs and Gα-gustducin/Gß1γ13 signaling pathway utilized by tuft cells in response to oral berberine in obese mice and proposed a new mechanism underlying the anti-obesity effect of berberine.

Differences in Insulin Sensitivity, Secretion, and the Metabolic Clearance Rate of Glucose in Newly Diagnosed Type 2 Diabetes Mellitus Patients: The Influences of Body Mass Index and Fatty Liver.

Background: Obesity and nonalcoholic fatty liver disease are strongly associated with type 2 diabetes mellitus (T2DM), affecting insulin sensitivity and ß-cell function. They interact, exacerbating the development of hyperinsulinemia to T2DM. Methods: Through oral glucose tolerance and insulin secretion tests, the relationships between insulin sensitivity and secretion, glucose clearance, body mass index (BMI), and fatty liver were studied in newly diagnosed T2DM patients. The homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of ß-cell function (HOMA-ß), insulin sensitivity index (ISI), and metabolic clearance rate (MCR) of glucose were calculated to analyze insulin sensitivity and ß-cell function. Results: There were no differences in HOMA-IR, HOMA-ß, first-phase insulin secretion (1st PH), second-phase insulin secretion (2nd PH), ISI, or MCR between lean fatty liver and lean nonfatty liver patients. Both overweight/obesity (ow/ob) and patients with fatty liver increased HOMA-IR, and decreased ISI and MCR. In the ow/ob subgroup, patients with fatty liver had severe insulin resistance but greater HOMA-ß, 1st PH, and 2nd PH than individuals with nonfatty liver. The difference in MCR between fatty liver and nonfatty liver groups was not significant. Conclusion: BMI and hepatic steatosis are independent determinants of increased insulin resistance and decreased MCR. However, it is steatosis, not BMI, related to the increase in insulin secretion.

Peritoneal GATA6+ macrophage drives hepatic immunopathogenesis and maintains the Treg cell niche in the liver.

The source of macrophages that contribute to human liver disease remains poorly understood. The purpose of this study is to investigate the functional mechanism of peritoneal macrophages in the development of hepatic immunopathology. By performing the natural infection with the blood fluke Schistosoma japonicum (S. japonicum) and the chemically carbon tetrachloride (CCl4 )-induced liver injured mouse model, we identified the peritoneal cavity as an essential source of hepatic macrophages. Here, we show that a large number of F4/80+ macrophages was accumulated in the peritoneal cavity during liver injury. An unknown source population of macrophages, which highly expressed GATA6 that is specific to peritoneal macrophages, was found to exist in the injured livers. Peritoneal macrophage deletion by injection with clodronate-containing liposomes led to an attenuated hepatic pathology and the inflammatory microenvironment, while adoptive transfer of macrophages into the abdominal cavity, by contrast, results in restoring liver pathology. Importantly, there are set genes of monocyte chemoattractant protein (MCP)-1, -2, and -3 that are highly related to recruit GATA6+ macrophages during S. japonicum infection, while administration of bindarit, a selective inhibitor of MCPs synthesis, dramatically decreased the hepatic expression of GATA6+ macrophages and thus attenuated hepatic pathology. Furthermore, in vivo study showed that peritoneal macrophages promote hepatic immunopathology is dependent on the accumulation of regulatory T cells (Tregs) in the liver. Altogether, these data provide the first clear evidence that GATA6+ peritoneal macrophages play critical roles in both the formation of hepatic immunopathology and the accumulation of Tregs cells.

Pipiserpin, a Culex factor Xa inhibitor, affects female reproductive capacity and serves as a potential target for mosquito control.

BACKGROUND: Mosquito control is still the main prevention and control measure for numerous mosquito-borne diseases causing millions of deaths each year. New strategies for mosquito control are in demand. Proteases play an important role in mosquito physiology, therefore this study explored the inhibition of a serpin (serine protease inhibitor) in mosquitoes and its effect on reproductive capacity. RESULTS: A factor Xa inhibitor homolog (named Pipiserpin) was amplified and identified in Culex pipiens pallens mosquitoes. We expressed a recombinant Pipiserpin protein in vitro against which a mouse antiserum was generated. We found that female mosquitoes expressed more Pipiserpin protein than male mosquitoes. After mating, female mosquitoes were fed with blood mixed with different amounts of antisera and results showed that consumption of Pipiserpin impeded ovary development and decreased eggs hatching rates compared to that of the pre-immune serum group. CONCLUSION: We identified a Culex mosquito factor Xa inhibitor, Pipiserpin, which affects female reproductive potential. Our results suggest that Pipiserpin may be a novel target for mosquito population control. The conclusions from our study on Cx. pipiens pallens might serve as a reference for the development of control measures for other mosquitoes as well. © 2022 Society of Chemical Industry.

Indolepropionic acid reduces obesity-induced metabolic dysfunction through colonic barrier restoration mediated via tuft cell-derived IL-25.

Previous studies have indicated that indolepropionic acid (IPA), derived from dietary tryptophan via gut microbiota conversion, is negatively correlated with type 2 diabetes mellitus and systemic low-grade inflammation. However, the effects of IPA administration on obesity, as well as the underlying mechanisms, remain unclear. In the present study, we observed that obesity leads to a dramatic reduction in IPA levels in both the serum and colonic mucosa, and IPA supplementation exerted beneficial effects on weight, as well as on glucose and lipid metabolism disorders. In adipose tissue, IPA treatment had no direct effect on adipocyte differentiation, but it significantly ameliorated adipose inflammation, thus preventing adipocyte enlargement. Moreover, IPA administration promoted gut integrity, increased the expression of tight junction proteins, and downregulated colonic inflammation; these effects were demonstrated to have a poor relationship with gut microbiota composition. Mechanistically, IPA significantly promoted the expansion of the tuft cell lineage in the gut and increased the secretion of interleukin-25 both in vivo and ex vivo, which contributes to the integrity of the gut barrier. This may partly depend on the free fatty acid receptor 3 pathway in tuft cells. Overall, our results demonstrate that IPA supplementation prevents the development of high-fat diet-induced obesity and metabolic disorders by restoring tuft cell-interleukin-25-mediated colonic barrier integrity; hence, IPA could be a potential agent for treatment of obesity.

Helminth-induced CD9+ B-cell subset alleviates obesity-associated inflammation via IL-10 production.

It has been shown that helminth infection can protect against obesity and improve insulin sensitivity to a certain extent, based on epidemiological investigations and animal experiments. Meanwhile, helminths induce a network of regulatory immune cells, including regulatory B cells (Bregs). However, the molecule characteristics and function of these Bregs in improving whole-body metabolic homeostasis remains largely unclear. We established a mouse model with chronic Schistosoma japonicum infection, and compared the differences in B10 cells (CD19+CD5+CD1dhi) and B10- cells (CD19+CD5-CD1d-) from splenic B cells of infected mice using RNA-seq. A unique Breg population was identified. Furthermore, these Bregs were evaluated for their ability to produce inhibitory cytokines in vitro and suppress obesity when adoptively transferred into mice on a high-fat diet. We found that schistosome infection could expand Breg cell populations in mice. CD9 was demonstrated to be a key surface marker for most murine IL-10+ B cells in spleen. CD19+CD9+ B cells produced more IL-10 than conventional B10 cells. Adoptive transfer of CD9+ B cells had the capacity to alleviate obesity-associated inflammation via promoting Tregs, Th2 cells and decreasing Th1, Th17 cells in high-fat diet mice. In conclusion, schistosome infection can induce regulatory CD9+ B cell production, which plays a critical role in the regulation of metabolic disorders through IL-10 production.

Up-regulation of MELK by E2F1 promotes the proliferation in cervical cancer cells.

Cervical cancer is a common gynecologic cancer and a frequent cause of death. In this study, we investigated the role of MELK (maternal embryonic leucine zipper kinase) in cervical cancer. We found that HPV 18 E6/E7 promoted MELK expression by activating E2F1. MELK knockdown blocked cancer cells growth. Furthermore, we used MELK-8A to inhibit the kinase activity of MELK and caused the G2/M phase arrest of cancer cells. Under the treatment of inhibitors, Hela cells formed multipolar spindles and eventually underwent apoptosis. We also found that MELK is involved in protein translation and folding during cell division through the MELK interactome and the temporal proteomic analysis under inhibition with MELK-8A. Altogether, these results suggest that MELK may play a vital role in cancer cell proliferation and indicate a potential therapeutic target for cervical cancer.

Predictive Modeling of MAFLD Based on Hsp90α and the Therapeutic Application of Teprenone in a Diet-Induced Mouse Model.

Background and Aims: The heat shock protein (Hsp) 90α is induced by stress and regulates inflammation through multiple pathways. Elevated serum Hsp90α had been found in nonalcoholic steatohepatitis (NASH). Geranylgeranylacetone (GGA, also called teprenone) is a terpenoid derivative. It was reported to induce Hsp and alleviate insulin resistance. We aimed to evaluate the Hsp90α as a biomarker in predicting metabolic-associated fatty liver disease (MAFLD) and define the therapeutic effects of geranylgeranylacetone for the disease. Methods: A clinical study was conducted to analyze the elements associated with Hsp90α, and a predictive model of MAFLD was developed based on Hsp90α. The histopathological correlation between Hsp90α and MAFLD was investigated through a diet-induced mouse model. Furthermore, GGA was applied to the mouse model. Results: Serum Hsp90α was increased in patients with MAFLD. A positive linear relationship was found between age, glycosylated hemoglobin (HbA1c), MAFLD, and serum Hsp90α. Meanwhile, a negative linear relationship with body mass index (BMI) was found. A model using Hsp90α, BMI, HbA1c, and ALT was established for predicting MAFLD. The area under the receiver operating characteristic (ROC) curves was 0.94 (95% CI 0.909-0.971, p = 0.000). The sensitivity was 84.1%, and the specificity was 93.1%. In vitro experiments, GGA induced Hsp90α in steatosis cells. In the mice model, Hsp90α decreased in the GGA treatment group. Hepatic steatosis, inflammation, insulin resistance, and glucose intolerance were improved in the GGA-treated group. Serum Hsp90α was positively correlated with steatohepatitis activity according to hepatic histopathology. Conclusions: Serum Hsp90α was elevated in MAFLD, and a positive correlation between serum Hsp90α and the grade of activity of steatohepatitis was observed. The model using BMI, HbA1c, and alanine aminotransferase (ALT) had a good value to predict MAFLD. The findings also revealed the effectiveness of GGA in the treatment of MAFLD.

Rescue of maternal immune activation-induced behavioral abnormalities in adult mouse offspring by pathogen-activated maternal Treg cells.

Maternal immune activation (MIA) induced by lipopolysaccharides or polyinosinic:polycytidylic acid injections can induce behavioral abnormalities in adult mouse offspring. Here, we used the soluble tachyzoite antigen from Toxoplasma gondii, a parasite that infects approximately two billion people, to induce MIA in mice. The adult male offspring showed autism-relevant behaviors and abnormal brain microstructure, along with a pro-inflammatory T-cell immune profile in the periphery and upregulation of interleukin-6 in brain astrocytes. We show that adoptive transfer of regulatory T (Treg) cells largely reversed these MIA-induced phenotypes. Notably, pathogen-activated maternal Treg cells showed greater rescue efficacy than those from control donors. Single-cell RNA sequencing identified and characterized a unique group of pathogen-activated Treg cells that constitute 32.6% of the pathogen-activated maternal Treg population. Our study establishes a new preclinical parasite-mimicking MIA model and suggests therapeutic potential of adoptive Treg cell transfer in neuropsychiatric disorders associated with immune alterations.

Therapeutic inhibition of miR-802 protects against obesity through AMPK-mediated regulation of hepatic lipid metabolism.

Background: The host-parasite relationship is based on subtle interplay between parasite survival strategies and host defense mechanisms. It is well known that helminth infection, which afflicts more than one billion people globally, correlates with a decreased prevalence of obesity. Dissecting the underlying mechanisms can provide new targets for treating obesity from the host-parasite interaction perspective. Methods: C57BL/6 mice received a normal or high-fat diet (HFD) with or without Sjp40 (one main component of schistosome-derived soluble egg antigens) treatment. Both the loss and gain-of-function experiments by the inhibitor suppression and lentivirus treatment of miR-802 were utilized to elucidate the role of miR-802/AMPK axis in host lipid metabolism. Hepatocyte lipogenesis assay and metabolic parameters were assessed both in vivo and in vitro. The potential interactions among Sjp40, CD36, miR-802, Prkab1, and AMPK were clarified by pull-down, miRNA expression microarray, quantitative RT-PCR, dual-luciferase reporter assay, and western blotting analysis. Results: We showed a link between decreased miR-802 and impaired lipid metabolism in Schistosoma japonicum infected mice. The decreased miR-802 promotes murine Prkab1 or human Prkaa1 expression, respectively, which increases levels of phosphorylated AMPK, resulting in a decrease in hepatic lipogenesis. Also, injection with schistosome-derived soluble egg antigens (SEA) attenuated metabolism. We demonstrated that Sjp40 as a main component of SEA interacted with CD36 on hepatocytes to inhibit miR-802, resulting in the activation of AMPK pathway and subsequent attenuation of lipogenesis. Collectively: Our study reveals the significant role of miR-802/AMPK axis in hepatic lipid metabolism and identifies the therapeutic potential of Sjp40 in treating obesity-related fatty liver.