IL-27 signalling promotes adipocyte thermogenesis and energy expenditure.

Thermogenesis in brown and beige adipose tissue has important roles in maintaining body temperature and countering the development of metabolic disorders such as obesity and type 2 diabetes1,2. Although much is known about commitment and activation of brown and beige adipose tissue, its multiple and abundant immunological factors have not been well characterized3-6. Here we define a critical role of IL-27-IL-27Rα signalling in improving thermogenesis, protecting against diet-induced obesity and ameliorating insulin resistance. Mechanistic studies demonstrate that IL-27 directly targets adipocytes, activating p38 MAPK-PGC-1α signalling and stimulating the production of UCP1. Notably, therapeutic administration of IL-27 ameliorated metabolic morbidities in well-established mouse models of obesity. Consistently, individuals with obesity show significantly decreased levels of serum IL-27, which can be restored after bariatric surgery. Collectively, these findings show that IL-27 has an important role in orchestrating metabolic programs, and is a highly promising target for anti-obesity immunotherapy.

Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells.

BACKGROUND: Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC. METHODS: The clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA+ B cells. RESULTS: HCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8+ T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA+ B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha, resulting in the induction of IgA+ B cells. CONCLUSIONS: IL-21R plays a cancer-promoting role by inducing IgA+ B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.

Arthroscopy-assisted reduction and simultaneous robotic-assisted screw placement in the treatment of fractures of the posterior talar process.

PURPOSE: A fracture of the posterior talar process is easily missed because of its hidden position. Inappropriate treatment is likely to result in complications, such as nonunion of the fracture and traumatic arthritis. This study evaluated the outcomes of arthroscopy-assisted reduction combined with robotic-assisted screw placement in the treatment of fractures of the posterior talar process. METHODS: The clinical data for nine patients who underwent surgical treatment of a fracture of the posterior talar process at our institution between September 2017 and January 2021 were retrospectively reviewed. Arthroscopy-assisted reduction of the fracture was performed, and a cannulated screw was placed using three-dimensional orthopedic robotic-assisted navigation. RESULTS: The patients (seven men, two women) had a mean age of 36.33 ± 9.77 years and were followed up for 21 ± 5.43 months. The operation time was 106.67 ± 24.5 min with blood loss of 47.78 ± 9.05 ml. Primary healing was obtained in all cases, and no patient sustained a nerve or tendon injury, had fracture nonunion, or developed talar osteonecrosis. One patient developed subtalar arthritis, for which subtalar joint fusion was performed; pain was markedly less severe after cleaning. CONCLUSION: Arthroscopy-assisted reduction and robotic-assisted screw placement have the advantages of visualization of fracture reduction, minimal injury, and precise screw placement in the treatment of fractures of the posterior talar process.

Dihydro-ß-agarofuran-type sesquiterpenoids from the seeds of Tripterygium wilfordii (Thunder God Vine) and evaluation of their anti-osteoclastogenesis and immunosuppressive activities.

Extensive phytochemical investigation of the seeds of Tripterygium wilfordii led to the identification of 54 polyesterified dihydro-ß-agarofuran-type sesquiterpenoids, including 27 previously undescribed ones, named Tripwilin I-XXVII (1-27). Comprehensive spectroscopic and single-crystal X-ray diffraction analyses, along with electronic circular dichroism (ECD) calculations were used for the structural elucidation of the new compounds. Biological assay revealed that 37 compounds among the isolates exhibited significant inhibition against osteoclastogenesis induced by receptor activator of nuclear factor-κB ligand (RANKL) at 10 µM. Further investigation indicated that Triptogelin C-3 (54), with the most potent osteoclastogenesis inhibitory activity, regulated the osteoclast marker genes (MMP-9, c-Fos, CTSK, and TRAP) and proteins in a dose-dependent manner in vitro. Besides, celaforin D-1 (28), 1α,6ß,15-triacetoxy-8α,9α-dibenzoyloxy-2α-hydroxydihydro-ß-agarofuran (34), triptogelin A-2 (37), and chiapen D (49) showed moderate suppressive effects on the proliferation of T and B lymphocytes with IC50 values ranging between 8.1 ± 0.8 and 19.0 ± 0.9 µM.

m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways.

N6-methyladenosine (m6A) is the most common and abundant messenger RNA modification, modulated by 'writers', 'erasers' and 'readers' of this mark. In vitro data have shown that m6A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates. However, its in vivo physiological function in mammals and adult mammalian cells is still unknown. Here we show that the deletion of m6A 'writer' protein METTL3 in mouse T cells disrupts T cell homeostasis and differentiation. In a lymphopaenic mouse adoptive transfer model, naive Mettl3-deficient T cells failed to undergo homeostatic expansion and remained in the naive state for up to 12 weeks, thereby preventing colitis. Consistent with these observations, the mRNAs of SOCS family genes encoding the STAT signalling inhibitory proteins SOCS1, SOCS3 and CISH were marked by m6A, exhibited slower mRNA decay and showed increased mRNAs and levels of protein expression in Mettl3-deficient naive T cells. This increased SOCS family activity consequently inhibited IL-7-mediated STAT5 activation and T cell homeostatic proliferation and differentiation. We also found that m6A has important roles for inducible degradation of Socs mRNAs in response to IL-7 signalling in order to reprogram naive T cells for proliferation and differentiation. Our study elucidates for the first time, to our knowledge, the in vivo biological role of m6A modification in T-cell-mediated pathogenesis and reveals a novel mechanism of T cell homeostasis and signal-dependent induction of mRNA degradation.

The spatial variation and driving factors of soil total carbon and nitrogen in the Heihe River source region.

Soil carbon and nitrogen levels are key indicators of soil fertility and are used to assess ecological value and safeguard the environment. Previous studies have focused on the contributions of vegetation, topography, physical and chemical qualities, and meteorology to soil carbon and nitrogen change, but there has been little consideration of landscape and ecological environment types as potential driving forces. The study investigated the horizontal and vertical distribution and influencing factors of total carbon and total nitrogen in soil at 0-20 and 20-50 cm depths in the source region of the Heihe River. A total of 16 influencing factors related to soil, vegetation, landscape, and ecological environment were selected, and their individual and synergistic effects on the distributions of total carbon and total nitrogen in soil were assessed. The results show gradually decreasing average values of soil total carbon and total nitrogen from the surface layer to the bottom layer, with larger values in the southeast part of the sampling region and smaller values in the northwest. Larger values of soil total carbon and total nitrogen at sampling points are distributed in areas with higher clay and silt and lower soil bulk density, pH, and sand. For environmental factors, larger values of soil total carbon and total nitrogen are distributed in areas with higher annual rainfall, net primary productivity, vegetation index, and urban building index, and lower surface moisture, maximum patch index, boundary density, and bare soil index. Among soil factors, soil bulk density and silt are most closely associated with soil total carbon and total nitrogen. Among surface factors, vegetation index, soil erosion, and urban building index have the greatest influence on vertical distribution, and maximum patch index, surface moisture, and net primary productivity have the greatest influence on horizontal distribution. In conclusion, vegetation, landscape, and soil physical properties all have a significant impact on the distribution of soil carbon and nitrogen, suggesting better strategies to improve soil fertility.

NK007 helps in mitigating paclitaxel resistance through p38MAPK activation and HK2 degradation in ovarian cancer.

Ovarian cancer resistance to available medicines is a huge challenge in dire need of a solution, which makes its recurrence and mortality rate further exacerbated. A promising approach to overcome chemoresistance is drug screening from natural products. Here, we report that NK007, a (±)-tylophorine malate isolated from the Asclepiadaceae family, selectively inhibited the proliferation of A2780 and A2780 (Taxol) cells and migration of paclitaxel-sensitive and -resistant ovarian cancer cells. Interestingly, the decline of cell viability, including cell multiplication, clonality, and migration capacity was independent on cell apoptosis. At the molecular level, NK007 considerably induced G1/S arrest and upregulated the expression of phospho-p38 mitogen-activated protein kinase (p-p38MAPK). In addition, hexokinase 2 (HK2) protein degradation was considerably elevated in the presence of NK007, which resulted in the reduction of oxygen consumption rate and extracellular acidification rate. Altogether, our results indicate that NK007, an analog of tylophorine, can overcome paclitaxel (PTX) resistance through p38MAPK activation and HK2 degradation. As an effective, alternative antiresistance agent, NK007 exhibits a promising potential to treat PTX-resistant ovarian cancer.

γδ T cells are indispensable for interleukin-23-mediated protection against Concanavalin A-induced hepatitis in hepatitis B virus transgenic mice.

Hepatitis B virus surface antigen (HBsAg) carriers are highly susceptible to liver injury triggered by environmental biochemical stimulation. Previously, we have reported an inverse correlation between γδ T cells and liver damage in patients with hepatitis B virus (HBV). However, whether γδ T cells play a role in regulating the hypersensitivity of HBsAg carriers to biochemical stimulation-induced hepatitis is unknown. In this study, using HBV transgenic (HBs-Tg) and HBs-Tg T-cell receptor-δ-deficient (TCR-δ-/- ) mice, we found that mice genetically deficient in γδ T cells exhibited more severe liver damage upon Concanavalin A (Con A) treatment, as indicated by substantially higher serum alanine aminotransferase levels, further elevated interferon-γ (IFN-γ) levels and more extensive necrosis. γδ T-cell deficiency resulted in elevated IFN-γ in CD4+ T cells but not in natural killer or natural killer T cells. The depletion of CD4+ T cells and neutralization of IFN-γ reduced liver damage in HBs-Tg and HBs-Tg-TCR-δ-/- mice to a similar extent. Further investigation revealed that HBs-Tg mice showed an enhanced interleukin-17 (IL-17) signature. The administration of exogenous IL-23 enhanced IL-17A production from Vγ4 γδ T cells and ameliorated liver damage in HBs-Tg mice, but not in HBs-Tg-TCR-δ-/- mice. In summary, our results demonstrated that γδ T cells played a protective role in restraining Con A-induced hepatitis by inhibiting IFN-γ production from CD4+ T cells and are indispensable for IL-23-mediated protection against Con A-induced hepatitis in HBs-Tg mice. These results provided a potential therapeutic approach for treating the hypersensitivity of HBV carriers to biochemical stimulation-induced liver damage.

Prognostic Value of VEGF in Hepatocellular Carcinoma Patients Treated with Sorafenib: A Meta-Analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by rich vascularization in the tumor, and vascular endothelial growth factor (VEGF) plays important roles in vascularization. The results of the roles of VEGF in predicting efficacy of sorafenib in HCC are conflicting. In this meta-analysis, we aimed to investigate the prognostic and predictive value of VEGF in HCC patients receiving sorafenib. MATERIAL AND METHODS: PubMed, Embase, and Cochrane library electronic databases were systematically searched for eligible studies. The baseline characteristics were recorded and overall qualities of the eligible studies were assessed by 2 reviewers independently. VEGF levels and data relevant to efficacy of sorafenib were extracted and used for meta-analysis. RESULTS: The comprehensive search yielded 9 studies that evaluated the relationship between VEGF level and clinical outcome in advanced HCC patients treated with sorafenib. Pooled estimates suggested that high level of VEGF was associated with poor overall survival (HR=1.85; 95% CI: 1.24-2.77; P=0.003) and poor progression-free survival (HR=2.09; 95% CI: 1.43-3.05; P<0.01) in HCC. Mutation of VEGF had a favorable effect on hand-foot skin reaction in HCC patients treated with sorafenib (P<0.05). CONCLUSIONS: High level of VEGF is associated with poor outcomes in HCC patients treated with sorafenib, indicating that VEGF could be used as an indicator of clinical efficacy in patients with HCC. However, more well-designed studies are needed to strengthen our findings.

High susceptibility to liver injury in IL-27 p28 conditional knockout mice involves intrinsic interferon-γ dysregulation of CD4+ T cells.

UNLABELLED: Interleukin (IL)-27, a newly discovered IL-12 family cytokine, is composed of p28 and EBI3. In this study, CD11c-p28(f/f) conditional knockout mice were generated to delete p28 specifically in dendritic cells (DCs). We demonstrated that in the absence of DC-derived p28, these mice were highly susceptible to both low and higher concentrations of concanavalin A (ConA) (5 mg/kg or 10 mg/kg), with extremely early and steady high levels of interferon-γ (IFN-γ) in sera. Neutralizing IFN-γ prevented ConA-induced liver damage in these mice, indicating a critical role of IFN-γ in this pathological process. Interestingly, the main source of the increased IFN-γ in CD11c-p28(f/f) mice was CD4+ T cells, but not natural killer T (NKT) cells. Depletion of CD4+ , but not NK1.1+ , cells completely abolished liver damage, whereas transferring CD4+ T cells from CD11c-p28(f/f) mice, but not from wild-type mice or CD11c-p28(f/f) -IFN-γ(-/-) double knockout mice to CD4(-/-) mice, restored the increased liver damage. Further studies defined higher levels of IFN-γ and T-bet messenger RNA in naïve CD4+ T cells from CD11c-p28(f/f) mice, and these CD4+ T cells were highly responsive to both low and higher concentrations of anti-CD3, indicating a programmed functional alternation of CD4+ T cells. CONCLUSION: We provide a unique model for studying the pathology of CD4+ T cell-mediated liver injury and reveal a novel function of DC-derived p28 on ConA-induced fulminant hepatitis through regulation of the intrinsic ability for IFN-γ production by CD4+ T cells.

Seasonal CO2 fluxes from alpine river influenced by freeze-thaw in the Qinghai Lake basin, northeastern of the Qinghai-Tibet Plateau.

River CO2 emissions, which contribute 53 % of the basin's overall carbon emissions, are essential parts of the global and regional carbon cycles. Previous CO2 flux calculates are mostly based on single samples collected during ice-free periods; however, little is known about the effects of freeze-thaw cycles on the river CO2 flux (FCO2) of inland rivers in alpine regions. Based on one year-round monthly continuous field sampling, we quantified the FCO2 and determined their driving factors in typical rivers during different freeze-thaw periods in the Qinghai Lake Basin (QLB) using the thin boundary layer model (TBL) and the path analysis method. The findings indicated that (1) the average FCO2 in the typical rivers was 184.98 ± 329.12 mmol/m2/d, acting as a carbon source during different freeze-thaw periods, and showed a decreasing trend with completely thawed periods (CTP, 303.15 ± 376.56 mmol/m2/d) > unstable freezing periods (UFP, 189.44 ± 344.08 mmol/m2/d) > unstable thawing periods (UTP, 62.35 ± 266.71 mmol/m2/d); (2) pH, surface water temperature (Tw) and total alkalinity (TA) were the dominant controlling factors during different freeze-thaw periods. Interestingly, they significantly affected FCO2 more before completely frozen than after frozen, with Tw and TA changing from having promoting effects to having limiting effects; (3) in addition, dissolved carbon components indirectly affected FCO2, primarily through the indirect effects of pH and Tw in the UTP; wind speed (U) directly promoted FCO2 in the CTP; and Ca2+ and dissolved inorganic carbon (DIC) were susceptible to indirect effects, which promoted/limited the release of FCO2 in the UFP, respectively. Our results reveal the changes of FCO2 and the factors influencing it in inland rivers within alpine regions during different freeze-thaw periods, thereby offering valuable support for carbon emission-related studies in alpine regions.

Lkb1 orchestrates γδ T-cell metabolic and functional fitness to control IL-17-mediated autoimmune hepatitis.

γδ T cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity. However, the metabolic requirements and regulation of γδ T-cell development and function remain poorly understood. In this study, we investigated the role of liver kinase B1 (Lkb1), a serine/threonine kinase that links cellular metabolism with cell growth and proliferation, in γδ T-cell biology. Our findings demonstrate that Lkb1 is not only involved in regulating γδ T lineage commitment but also plays a critical role in γδ T-cell effector function. Specifically, T-cell-specific deletion of Lkb1 resulted in impaired thymocyte development and distinct alterations in γδ T-cell subsets in both the thymus and peripheral lymphoid tissues. Notably, loss of Lkb1 inhibited the commitment of Vγ1 and Vγ4 γδ T cells, promoted the maturation of IL-17-producing Vγ6 γδ T cells, and led to the occurrence of fatal autoimmune hepatitis (AIH). Notably, clearance of γδ T cells or blockade of IL-17 significantly attenuated AIH. Mechanistically, Lkb1 deficiency disrupted metabolic homeostasis and AMPK activity, accompanied by increased mTORC1 activation, thereby causing overactivation of γδ T cells and enhanced apoptosis. Interestingly, activation of AMPK or suppression of mTORC1 signaling effectively inhibited IL-17 levels and attenuated AIH in Lkb1-deficient mice. Our findings highlight the pivotal role of Lkb1 in maintaining the homeostasis of γδ T cells and preventing IL-17-mediated autoimmune diseases, providing new insights into the metabolic programs governing the subset determination and functional differentiation of thymic γδ T cells.

Therapeutic effects of a novel tylophorine analog, NK-007, on collagen-induced arthritis through suppressing tumor necrosis factor α production and Th17 cell differentiation.

OBJECTIVE: To analyze the effects of a novel compound, NK-007, on the prevention and treatment of collagen-induced arthritis (CIA) and the underlying mechanisms. METHODS: We determined the effect of NK-007 on lipopolysaccharide (LPS)-triggered tumor necrosis factor α (TNFα) production by murine splenocytes and a macrophage cell line (RAW 264.7) by enzyme-linked immunosorbent assay, intracellular cytokine staining, and Western blotting. The LPS-boosted CIA model was adopted, and NK-007 or vehicle was administered at different time points after immunization. Mice were monitored for clinical severity of arthritis, and joint tissues were used for histologic examination, cytokine detection, and immunohistochemical staining. Finally, stability of TNFα production and Th17 cell differentiation were studied using quantitative polymerase chain reaction and flow cytometry. RESULTS: NK-007 significantly suppressed LPS-induced TNFα production in vitro. Administration of NK-007 completely blocked CIA development and delayed its progression. Furthermore, treatment with NK-007 at the onset of arthritis significantly inhibited the progress of joint inflammation. Administration of NK-007 also suppressed production of TNFα, interleukin-6 (IL-6), and IL-17A in the joint and reduced percentages of IL-17+ cells among CD4+ and γ/δ T cells in draining lymph nodes. We further demonstrated that NK-007 acted on the stability of TNFα messenger RNA and reduced Th17 cell differentiation. In addition, it significantly inhibited levels of IL-6 and IL-17A in human coculture assay. CONCLUSION: For its effects on the development and progression of CIA and for its therapeutic effect on CIA, NK-007 has great potential to be a therapeutic agent for human rheumatoid arthritis.

Vγ4 γδ T cell-derived IL-17A negatively regulates NKT cell function in Con A-induced fulminant hepatitis.

Con A-induced fulminant hepatitis is a well-known animal model for acute liver failure. However, the role of γδ T cells in this model is undefined. In this report, using TCR δ(-/-) mice, we demonstrated a protective role of γδ T cells in Con A-induced hepatitis model. TCR δ(-/-) mice showed significantly decreased levels of IL-17A and IL-17F in the Con A-treated liver tissue, and reconstitution of TCR δ(-/-) mice with wild-type (Wt), but not IL-17A(-/-), γδ T cells significantly reduced hepatitis, strongly suggesting a critical role of IL-17A in mediating the protective effect of γδ T cells. Interestingly, only Vγ4, but not Vγ1, γδ T cells exerted such a protective effect. Furthermore, depletion of NKT cells in TCR δ(-/-) mice completely abolished hepatitis, and NKT cells from Con A-challenged liver tissues of TCR δ(-/-) mice expressed significantly higher amounts of proinflammatory cytokine IFN-γ than those from Wt mice, indicating that γδ T cells protected hepatitis through targeting NKT cells. Finally, abnormal capacity of IFN-γ production by NKT cells of TCR δ(-/-) mice could only be downregulated by transferring Wt, but not IL-17(-/-), Vγ4 γδ T cells, confirming an essential role of Vγ4-derived IL-17A in regulating the function of NKT cells. In summary, our report thus demonstrated a novel function of Vγ4 γδ T cells in mediating a protective effect against Con A-induced fulminant hepatitis through negatively regulating function of NKT cells in an IL-17A-dependent manner, and transferring Vγ4 γδ T cells may provide a novel therapeutic approach for this devastating liver disease.

Safety monitoring of oral iron supplements in pregnant women with anemia: a multi-center observational clinical study.

Aims: To investigate the safety of oral iron therapy in pregnant women with iron-deficiency anemia (IDA) in the real world. Methods: A retrospective analysis was performed on 1792 pregnant patients with IDA who received oral iron supplements from 12 hospitals in Shandong Province from 1 April to 31 June 2021; follow-up and adverse reactions were recorded. They were divided into six groups according to the treatment drugs. Results: The overall adverse reaction rate was 15.4%, and the main adverse reaction site was the digestive system. The incidence of all kinds of oral iron adverse reactions from high to low in order: compound ferrous sulfate and folic acid tablets (21.88%); iron proteinsuccinylate oral solution (20.90%); ferrous succinate tablets (19.76%); ferrous succinate sustained-release tablets (18.00%); iron polysaccharide complex capsule (12.06%); and iron dextran oral solution (6.94%). It was found that there was a significant difference in the incidence of adverse reactions among the six drugs (p < 0.05). Pairwise comparison showed that the incidence of adverse reactions was higher in the iron proteinsuccinylate oral solution than that in the iron polysaccharide complex capsule (p < 0.05). There was no significant difference in the incidence of adverse reactions in different ages (p > 0.05), but there was a significant difference in the incidence of adverse reactions in different gestational ages (p < 0.05). In Adverse Drug Reaction (ADR) patients, the adverse reaction result of most patients is recovery or improvement, and there was no serious adverse reaction outcome such as sequela and death. Conclusion: All the adverse reactions of oral iron were mainly gastrointestinal adverse reactions, and no heavy adverse reactions were found. Iron proteinsuccinylate oral solution has a higher incidence of adverse reactions than iron polysaccharide complex capsule. The results showed that oral iron was safer for anemia patients during pregnancy.

Safety of oral iron in the treatment of iron-deficiency anemia during pregnancy Introduction: The safety of different oral iron agents varies. At present, the safety evaluation of iron supplements in the treatment of anemia during pregnancy is mainly focused on intravenous iron supplements, and there is no comprehensive study on the safety of commonly used oral iron supplements. This study compared the safety of six commonly used oral iron supplements in the treatment of iron-deficiency anemia during pregnancy, aiming to provide a reference for clinical medication. Methods: We conducted a study involving 1792 patients in 12 hospitals in Shandong Province from 1 April to 31 June 2021. Results: Among the six groups, 276 ADR patients reported 302 adverse reactions. There were significant differences in the rates of adverse reactions among the six oral iron agents, and the incidence of adverse reactions in the iron proteinsuccinylate oral solution was significantly higher than that of iron polysaccharide complex capsules. The main incidence of adverse reactions was constipation (6.96%), and most of the outcomes were cured or improved. Conclusion: In this study, there were no heavy adverse reactions. The incidence of adverse reactions of iron proteinsuccinylate oral was higher than that of iron polysaccharide compound capsule. The results showed that oral iron had a good safety in patients with anemia during pregnancy.

SLC38A5 aggravates DC-mediated psoriasiform skin inflammation via potentiating lysosomal acidification.

Amino acid (aa) metabolism is closely correlated with the pathogenesis of psoriasis; however, details on aa transportation during this process are barely known. Here, we find that SLC38A5, a sodium-dependent neutral aa transporter that counter-transports protons, is markedly upregulated in the psoriatic skin of both human patients and mouse models. SLC38A5 deficiency significantly ameliorates the pathogenesis of psoriasis, indicating a pathogenic role of SLC38A5. Surprisingly, SLC38A5 is almost exclusively expressed in dendritic cells (DCs) when analyzing the psoriatic lesion and mainly locates on the lysosome. Mechanistically, SLC38A5 potentiates lysosomal acidification, which dictates the cleavage and activation of TLR7 with ensuing production of pro-inflammatory cytokines such as interleukin-23 (IL-23) and IL-1ß from DCs and eventually aggravates psoriatic inflammation. In summary, this work uncovers an auxiliary mechanism in driving lysosomal acidification, provides inspiring insights for DC biology and psoriasis etiology, and reveals SLC38A5 as a promising therapeutic target for treating psoriasis.

METTL3-mediated m6A methylation orchestrates mRNA stability and dsRNA contents to equilibrate γδ T1 and γδ T17 cells.

γδ T cells make key contributions to tissue physiology and immunosurveillance through two main functionally distinct subsets, γδ T1 and γδ T17. m6A methylation plays critical roles in controlling numerous aspects of mRNA metabolism that govern mRNA turnover, gene expression, and cellular functional specialization; however, its role in γδ T cells remains less well understood. Here, we find that m6A methylation controls the functional specification of γδ T17 vs. γδ T1 cells. Mechanistically, m6A methylation prevents the formation of endogenous double-stranded RNAs and promotes the degradation of Stat1 transcripts, which converge to prevent over-activation of STAT1 signaling and ensuing inhibition of γδ T17. Deleting Mettl3, the key enzyme in the m6A methyltransferases complex, in γδ T cells reduces interleukin-17 (IL-17) production and ameliorates γδ T17-mediated psoriasis. In summary, our work shows that METTL3-mediated m6A methylation orchestrates mRNA stability and double-stranded RNA (dsRNA) contents to equilibrate γδ T1 and γδ T17 cells.

Potential Sources, Pollution, and Ecological Risk Assessment of Potentially Toxic Elements in Surface Soils on the North-Eastern Margin of the Tibetan Plateau.

Due to increased levels of human activity, various pollutants are frequently detected on the Tibetan Plateau, where the environment is extremely fragile and sensitive. Therefore, this study investigated the sources, pollution, and ecological risks of soil potentially toxic elements (PTEs) in different landscape areas within the Qaidam Basin in the northeastern part of the Qinghai−Tibet Plateau. The contents of seven PTEs (Cd, Cu, Pb, Zn, As, Cr, and Ni) in 32 topsoil samples (0−2 cm) were analyzed in different regions of the Qaidam Basin. The concentrations of As, Cd, Cr, Cu, Ni, Pb, and Zn were 10.4−29.9 mg/kg, 0.08−4.45 mg/kg, 19−66 mg/kg, 8.2−40 mg/kg, 11.7−30.8 mg/kg, 11.1−31.2 mg/kg, and 32−213 mg/kg, respectively. The correlation between Pb and Cd in unpopulated areas was 0.896 (p < 0.01). The correlations among Pb, Cd, and Zn in agricultural areas, among As, Cd, Cr, and Zn in saline lake areas, and among As, Cd, Cr, Cu, Ni, Pb, and Zn in residential areas were all greater than 0.65 (p < 0.05). The principal component analysis results showed that Pb and Cd in unpopulated areas, Pb, Cd, and Zn in agricultural areas, As, Cd, Cr, Zn, and Pb in saline lake areas, and As, Cd, Cr, Cu, Ni, Pb, and Zn in residential areas were affected by human activities (significant factor >0.70). Based on the geological accumulation index and single-factor pollution index results, the maximum Cd values were found to be 4.93 and 45.88, respectively; Cd was thus the most serious PTE pollutant. The comprehensive pollution index of Nemero showed that moderately and severely polluted areas accounted for 18.89% and 18.46% of the total area, respectively. The results of the potential risk index showed that very strong and strong ecological risk points together accounted for 18.8% of the total points. The spatial variations in PTE pollution and the potential ecological risk index had similar patterns; both increased from the unpopulated areas in the northeastern Qaidam Basin to Golmud city in the south-western Qaidam Basin. These results indicate that human activities negatively impacted the soil ecological environment in the Qaidam Basin during the rapid development of the economy and urbanization and that these negative impacts tended to spread to unpopulated areas. Therefore, it is necessary to emphasize the significant impacts of human activities on environmental quality and formulate preventive measures to reduce PTE pollution in the Qinghai−Tibet Plateau.

Dihydro-ß-agarofuran-type sesquiterpenoids from the seeds of Celastrus virens with lifespan-extending effect on the nematode Caenorhabditis elegans.

Twelve dihydro-ß-agarofuran-type sesquiterpenoids, including five new ones (1-5), were purified from the seeds of Celastrus virens (Wang et Tang) C. Y. Chent et T. C. Kao. Their chemical structures were characterized via comprehensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and computational prediction of ECD, as well as comparison of observed and reported NMR spectral data. Among the isolates, nine abundant dihydro-ß-agarofuran-type sesquiterpenoids were evaluated for their lifespan-extending activity using the nematode Caenorhabditis elegans model. As a result, compounds 1, 2, 5, 6, 8, and 9 (50 µM) significantly extended the mean survival time of C. elegans, respectively, compared with the blank control group (p < 0.05). Further Quantitative RT-PCR showed that the prolonging of lifespan mediated by compounds 1, 6, 8, and 9 were dependent on the transcription factors skn-1 and hsf-1.

1α,25(OH)2D3 reverses exhaustion and enhances antitumor immunity of human cytotoxic T cells.

BACKGROUND: Epidemiological surveys have revealed that low serum vitamin D level was correlated with increased risk of tumors. Dysfunctional T cells in patients with tumor are characterized as exhausted with high levels of immune checkpoint receptors (ICRs). However, whether the reduced level of vitamin D in patients with cancer correlates with cytotoxic T-cell exhaustion is unknown. METHODS: Periphery blood samples from 172 patients with non-small cell lung cancer (NSCLC) were prospectively collected. Patients with NSCLC received one course of intravenous docetaxel (75 mg/m2) followed by treatment with or without rocaltrol at a dose of 0.5-2.0 µg/day for total of 3 weeks. We performed phenotypical and functional analysis of T-cell through flow cytometry. Vitamin D receptor (VDR) knockout and overexpression CD8+ and Vδ2+ T cells were constructed using Cas9-gRNA targeted and overexpressing approaches to identify 1α,25(OH)2D3/VDR-mediated transcription regulation for ICRs or antitumor activity in T cells. RESULTS: We show that serum level of vitamin D is negatively correlated with expression of programmed cell death-1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), but positively correlated with CD28 expression on CD8+ and Vγ9Vδ2+ T cells in patients with NSCLC. 1α,25(OH)2D3, the active form of vitamin D, promotes the nuclear translocation of VDR, which binds to the promoter region of Pdcd1, Tim3, and Tigit genes and inhibits their expression. Besides, 1α,25(OH)2D3 pretreatment also promotes the methylation of CpG island in the promoter region of the Pdcd1 gene and increases H3K27 acetylation at the promoter region of the Cd28 gene, which leads to surface PD-1 downregulation and CD28 upregulation, respectively. We further reveal that VDR-mediated Ca2+ influx enhanced expression of Th1 cytokines via T-cell receptor activation. Functionally, 1α,25(OH)2D3 pretreated CD8+ T cells or Vγ9Vδ2+ T cells showed increased Th1 cytokine production and enhanced antitumor immunity. Finally, oral 1α,25(OH)2D3 could also decrease expression of PD-1, Tim-3, TIGIT and increase expression of CD28, resulting in cytokine production (associated with antitumor immunity) by cytotoxic T cells of patients with NSCLC. CONCLUSIONS: Our findings uncover the pleiotropic effects of 1α,25(OH)2D3 in rescuing the exhausted phenotype of human cytotoxic T cells in patients with tumor and in promoting their antitumor immunity. TRIAL REGISTRATION NUMBER: ChiCTR2100051135.