Novel antibody-antibiotic conjugate using KRM-1657 as payload eliminates intracellular MRSA in vitro and in vivo.

Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S.aureus within host cells may cause long-term colonization and clinical failure. Current treatments have poor efficacy in clearing intracellular bacteria. Antibody-antibiotic conjugates (AACs) is a novel strategy for eliminating intracellular bacteria. Herein, we use KRM-1657 as payload of AAC for the first time, and we conjugate it with anti S. aureus antibody via a dipeptide linker (Valine-Alanine) to obtain a novel AAC (ASAK-22). The ASAK-22 exhibits good in vitro pharmacokinetic properties and inhibitory activity against intracellular MRSA, with 100 µg/mL of ASAK-22 capable of eliminating intracellular MRSA to the detection limit. Furthermore, the in vivo results demonstrate that a single administration of ASAK-22 significantly reduces the bacterial burden in the bacteremia model, which is superior to the vancomycin treatment.

SOD3 suppresses early cellular immune responses to parasite infection.

Host immune responses are tightly controlled by various immune factors during infection, and protozoan parasites also manipulate the immune system to evade surveillance, leading to an evolutionary arms race in host‒pathogen interactions; however, the underlying mechanisms are not fully understood. We observed that the level of superoxide dismutase 3 (SOD3) was significantly elevated in both Plasmodium falciparum malaria patients and mice infected with four parasite species. SOD3-deficient mice had a substantially longer survival time and lower parasitemia than control mice after infection, whereas SOD3-overexpressing mice were much more vulnerable to parasite infection. We revealed that SOD3, secreted from activated neutrophils, bound to T cells, suppressed the interleukin-2 expression and concomitant interferon-gamma responses crucial for parasite clearance. Overall, our findings expose active fronts in the arms race between the parasites and host immune system and provide insights into the roles of SOD3 in shaping host innate immune responses to parasite infection.

Toll-like receptor 9 signaling is associated with immune responses to Trypanosoma brucei infection.

Trypanosoma brucei, a causative agent of human and animal trypanosomiasis, regularly switches its major surface antigen to avoid elimination by the immune system. Toll-like receptor 9 (TLR9) is a key modulator for resistance to host-infective trypanosomes; however, the underlying molecular mechanism remains indistinct. Thus, we first approached the issue using Tlr9-mutant mice that render them non-responsive to TLR9 agonists. After infection, T cells in the spleens of Tlr9-mutant mice were analyzed by flow cytometry and a reduction in CD8+, CD4+ T, and NKT cells was observed in Tlr9-mutant mice compared to WT mice. We further found that the responses of inflammatory cytokines in the sera were reduced in Tlr9-mutant mice after T. brucei infection. The underlying molecular mechanism was that T. b. brucei DNA activated TLR9, which consequently upregulated the expression of p38 and ERK/MAPK, resulting in host resistance to trypanosome infection. In conclusion, these findings provide novel insights into the TLR9-mediated host responses to trypanosome infection.

Interactions between plants and bacterial communities for phytoremediation of petroleum-contaminated soil.

Plants can stimulate the microbes to degrade ubiquitous petroleum hydrocarbons (PHCs), which has prompted a novel view on rhizoremediation. In the present study, the degradation rate of PHCs was investigated and 16S rRNA gene analysis was performed to investigate the PHC-degrading bacteria in petroleum-contaminated soil with different plants. Mirabilis jalapa (M. jalapa) has a higher PHC degradation rate than Lolium perenne (L. perenne) under petroleum contamination. The bacterial diversity in rhizospheric soil was decreased but the relative abundance of Actinobacteriota, Proteobacteria, and Candidatus Saccharibacteria were significant increased on 45 days petroleum-contaminated rhizospheric soil. In addition, the relative expression of PHC degradation-related genes, the content of malic acid and citric acid of the root exudates in the two plants was significantly increased in response to petroleum stress. The content of citric acid increased 11.9 times in M. jalapa and 3.4 times in L. perenne, respectively, in response to petroleum stress. These results indicate that M. jalapa changes the hydrocarbon-degrading microbial community to enhance the degradation of PHCs by root exudates and phytostimulation.

Fe(III)/peroxymonosulfate oxidation system for the degradation of rhein, a toxic component abundance in rhubarb residue.

Rhubarb is widely used in health care, but causing a great amount of rhein-containing herbal residue. Rhein with several toxicities might pollute environment, damage ecology and even hazard human health if left untreated. In this study, the degradation effects of bisulfite- (BS) and peroxymonosulfate- (PMS) based oxidation systems on rhein in rhubarb residue were compared and investigated. The effects of BS and PMS with two valence states of ferric ion (Fe) on the degradation of rhein in rhubarb residue were optimized for the selection of optimal oxidation system. The influences of reaction temperature, reaction time and initial pH on the removal of rhein under the optimal oxidation system were evaluated. The chemical profiles of rhubarb residue with and without oxidation process were compared by UPLC-QTOF-MS/MS, and the degradation effects were investigated by PLS-DA and S plot/OPLS-DA analysis. The results manifested that PMS showed relative higher efficiency than BS on the degradation of rhein. Moreover, Fe(III) promoted the degradation effect of PMS, demonstrated that Fe(III)/PMS is the optimal oxidation system to degrade rhein in rhubarb residue. Further studies indicated that the degradation of rhein by the Fe(III)/PMS oxidation system was accelerated with the prolong of reaction time and the elevation of reaction temperature, and also affected by the initial pH. More importantly, Fe(III)/PMS oxidation system could degrade rhein in rhubarb residue completely under the optimal conditions. In conclusion, Fe(III)/PMS oxidation system is a feasible method to treat rhein in rhubarb residue.

Plasmodium falciparum selectively degrades α-spectrin of infected erythrocytes after invasion.

Remodeling the erythrocyte membrane and skeleton by the malarial parasite Plasmodium falciparum is closely associated with intraerythrocytic development. However, the mechanisms underlying this association remain unclear. In this study, we present evidence that erythrocytic α-spectrin, but not ß-spectrin, was dynamically ubiquitinated and progressively degraded during the intraerythrocytic development of P. falciparum, from the ring to the schizont stage. We further observed an upregulated expression of P. falciparum phosphatidylinositol 3-kinase (PfPI3K) in the infected red blood cells during the intraerythrocytic development of the parasite. The data indicated that PfPI3K phosphorylated and activated erythrocytic ubiquitin-protein ligase, leading to increased α-spectrin ubiquitination and degradation during P. falciparum development. We further revealed that inhibition of the activity of PfPI3K impaired P. falciparum development in vitro and Plasmodium berghei infectivity in mice. These findings collectively unveil an important mechanism of PfPI3K-ubiquitin-mediated degradation of α-spectrin during the intraerythrocytic development of Plasmodium species. Proteins in the PfPI3K regulatory pathway are novel targets for effective treatment of severe malaria. IMPORTANCE: Plasmodium falciparum is the causative agent of severe malaria that causes millions of deaths globally. The parasite invades human red blood cells and induces a cascade of alterations in erythrocytes for development and proliferation. Remodeling the host erythrocytic cytoskeleton is a necessary process during parasitization, but its regulatory mechanisms remain to be elucidated. In this study, we observed that erythrocytic α-spectrin is selectively degraded after P. falciparum invasion, while ß-spectrin remained intact. We found that the α-spectrin chain was profoundly ubiquitinated by E3 ubiquitin ligase and degraded by the 26S proteasome. E3 ubiquitin ligase activity was regulated by P. falciparum phosphatidylinositol 3-kinase (PfPI3K) signaling. Additionally, blocking the PfPI3K-ubiquitin-proteasome pathway in P. falciparum-infected red blood cells reduced parasite proliferation and infectivity. This study deepens our understanding of the regulatory mechanisms of host and malarial parasite interactions and paves the way for the exploration of novel antimalarial drugs.

Effects of Dietary Eucommia ulmoides Leaf Extract Supplementation on Growth Performance, Meat Quality, Antioxidant Capacity, and Lipid Metabolism of Finishing Pigs.

This study aimed to investigate the effects of dietary Eucommia ulmoides leaf extract (ELE) on meat quality, antioxidant capacity, and lipid metabolism in finishing pigs. A total of 240 "Duroc × Landrace × Yorkshire" crossbred pigs with an initial weight of 74.70 ± 0.77 kg were randomly assigned to two groups: control group and 0.2% ELE group, with each group containing 10 replicates of 12 pigs per pen (half barrows and half gilts). The data showed dietary 0.2% ELE supplementation did not affect growth performance but tended to reduce the backfat thickness of the finishing pigs (p = 0.07). ELE diets increased pH value (p < 0.05) and meat color score (p = 0.01) and decreased 45 min L* value (p < 0.05), 24 h L* value (p = 0.01), pressurization loss (p = 0.01), and 24 h drip loss (p < 0.05) in longissimus dorsi (LD) muscle, accompanied by an increased (p < 0.05) proportion of monounsaturated fatty acids (MUFA) and decreased polyunsaturated fatty acids (PUFA) (p = 0.06) and n-6/n-3 PUFA ratio (p = 0.05) compared to controls. In addition, ELE supplementation increased inosine monophosphate (IMP) (p = 0.01), sweet amino acids (AAs) (p < 0.05), and total free AA content (p = 0.05) in LD. Meanwhile, increased activity of glutathione peroxidase (p < 0.05) and superoxide dismutase (p < 0.01) in both serum and LD muscle and decreased malondialdehyde content (p < 0.01) in LD muscle were detected with ELE treatment. Moreover, pigs fed ELE had a higher total protein (p < 0.01), albumin (p < 0.05), and high-density lipoprotein cholesterol (p < 0.05) and a lower total cholesterol (p < 0.01) and triacylglycerols (p = 0.06) in serum. Consistently, significant effects of dietary ELE were observed on the relative mRNA expression of lipid metabolism in the backfat and the LD muscle, respectively. ELE attenuated lipogenic processes in backfat, decreasing the relative expression of acetyl-CoA carboxylase and upregulating the relative expression of adipose triacyl glyceride lipase, carnitine palmitoyl transferase 1B, and fatty acid-binding protein 4 (p < 0.05). ELE also decreased the relative expression of CCAAT/enhancer-binding protein α (p < 0.05), fatty acid translocase (p < 0.05), carnitine palmitoyl transferase 1B (p < 0.01), and adipose triacyl glyceride lipase (p < 0.05) in LD muscle (p < 0.05). More specifically, lipogenesis appeared to be inhibited in both LD muscle and backfat, with the difference being that lipolysis was enhanced in backfat and inhibited in LD muscle. In conclusion, dietary ELE supplementation can potentially enhance carcass traits, sensory quality, and nutritional value of pork without negatively affecting intramuscular fat content. The underlying mechanism for these positive effects may be linked to the alterations in lipid metabolism and increased antioxidant capacity induced by ELE.

A helicase-independent role of DHX15 promotes MYC stability and acute leukemia cell survival.

DHX15 has been implicated in RNA splicing and ribosome biogenesis, primarily functioning as an RNA helicase. To systematically assess the cellular role of DHX15, we conducted proteomic analysis to investigate the landscape of DHX15 interactome, and identified MYC as a binding partner. DHX15 co-localizes with MYC in cells and directly interacts with MYC in vitro. Importantly, DHX15 contributes to MYC protein stability at the post-translational level and independent of its RNA binding capacity. Mechanistic investigation reveals that DHX15 interferes the interaction between MYC and FBXW7, thereby preventing MYC polyubiquitylation and proteasomal degradation. Consequently, the abrogation of DHX15 drastically inhibits MYC-mediated transcriptional output. While DHX15 depletion blocks T cell development and leukemia cell survival as we recently reported, overexpression of MYC significantly rescues the phenotypic defects. These findings shed light on the essential role of DHX15 in mammalian cells and suggest that maintaining sufficient MYC expression is a significant contributor to DHX15-mediated cellular functions.

Comparison of effects of HucMSCs, exosomes, and conditioned medium on NASH.

To investigate the effects and potential mechanisms of human umbilical cord mesenchymal stem cells, exosomes, and their conditioned media on lipid storage in oleic acid (OA) and palmitic acid (PA) treated hepatocytes and high-fat methionine- choline deficient diet (HFMRCD) induced non-alcoholic steatohepatitis (NASH) mice. AML12 cells were stimulated with OA and PA to establish the lipid storage cell model. HucMSCs, exosomes, and culture medium were then co-cultured. At the same time, C57BL/6 mice were fed an HFMRCD for 6 or 8 weeks to establish a NASH mouse model. The effect of HucMSCs, exosomes, and culture medium on lipid droplet repair of hepatocytes or NASH mice was then assessed. The weight of hepatocytes or liver tissue, Oil Red O, hematoxylin-eosin staining, Masson staining, Western blot, and qPCR were used to detect the related IL-6, TNF-α, TGF-ß1 andEI24/AMPK/mTOR pathway expression in hepatocytes and liver tissue. Compared with the model group, the effect of HucMSCs-Ex on inhibiting the accumulation of lipid droplets was more obvious at the cell level. In vivo study showed that HucMSCs-Ex reduces activity scores in NASH mice and improves liver tissue morphology by reducing vacuolar degeneration, fat deposition, and collagen deposition of liver tissue. Western blot and qPCR results showed that inflammatory factors and AMPK/mTOR or EI24-related autophagy pathways were altered before and after treatment. HucMSCs, HucMSC-Ex, and CM can promote autophagy in hepatocytes or NASH mice through the AMPK/mTOR or EI24-related autophagy pathway and alleviate injury associated with lipid deposition, collagen deposition or inflammation, reversing the progression of NASH.

High-Performance T1-T2 Dual-Modal MRI Contrast Agents through Interface Engineering.

Iron oxide nanoparticles (IONPs) have been developed as contrast agents for T1- or T2-weighted magnetic resonance imaging (MRI) on account of their excellent physicochemical and biological properties. However, general strategies to improve longitudinal relaxivity (r1) often decrease transverse relaxivity (r2), thus synchronously strengthening the T1 and T2 enhancement effect of IONPs remains a challenge. Here, we report interface regulation and size tailoring of a group of FePt@Fe3O4 core-shell nanoparticles (NPs), which possess high r1 and r2 relaxivities. The increase of r1 and r2 is due to the enhancement of the saturation magnetization (Ms), which is a result of the strengthened exchange coupling across the core-shell interface. In vivo subcutaneous tumor study and brain glioma imaging revealed that FePt@Fe3O4 NPs can serve as a favorable T1-T2 dual-modal contrast agent. We envision that the core-shell NPs, through interface engineering, have great potential in preclinical and clinical MRI applications.

RNA helicase DHX15 exemplifies a unique dependency in acute leukemia.

RNA-binding proteins (RBP) have emerged as essential regulators that control gene expression and modulate multiple cancer traits. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from transformation of T-cell progenitors that normally undergo discrete steps of differentiation in the thymus. The implications of essential RBP during T-cell neoplastic transformation remain largely unclear. Systematic evaluation of RBP identifies RNA helicase DHX15, which facilitates the disassembly of the spliceosome and release of lariat introns, as a T-ALL dependency factor. Functional analysis using multiple murine T-ALL models demonstrates the essential importance of DHX15 in tumor cell survival and leukemogenesis. Moreover, single-cell transcriptomics reveals that DHX15 depletion in T-cell progenitors hinders burst proliferation during the transition from doublenegative to double-positive cells (CD4-CD8- to CD4+CD8+). Mechanistically, abrogation of DHX15 perturbs RNA splicing and leads to diminished levels of SLC7A6 and SLC38A5 transcripts due to intron retention, thereby suppressing glutamine import and mTORC1 activity. We further propose a DHX15 signature modulator drug ciclopirox and demonstrate that it has prominent anti-T-ALL efficacy. Collectively, our data highlight the functional contribution of DHX15 to leukemogenesis through regulation of established oncogenic pathways. These findings also suggest a promising therapeutic approach, i.e., splicing perturbation by targeting spliceosome disassembly, may achieve considerable anti-tumor efficacy.

Independent and joint associations of general and abdominal obesity with the risk of conventional adenomas and serrated polyps: A large population-based study in East Asia.

Evidence regarding associations of general and abdominal obesity with the risk of conventional adenomas (ADs) and serrated polyps (SPs) from Asian population is scarce. Our study aimed to investigate the independent and joint associations of general obesity assessed by body mass index (BMI) and abdominal obesity assessed by waist circumference (WC) or waist-to-hip ratio (WHR) with the risk of ADs and SPs among 25 222 participants recruited by a population-based screening program. Compared to participants with normal BMI, those with a BMI ≥28 kg/m2 had increased risk of ADs (odds ratio [OR] 1.52, 95% confidence interval [CI]: 1.36-1.70) and SPs (OR 1.69, 95% CI: 1.38-2.07). For participants with a WC ≥102 cm (≥88 cm for females), the risk of ADs (OR 1.37, 95% CI: 1.25-1.51) and SPs (OR 1.81, 95% CI: 1.52-2.16) was higher than that of the reference group. For participants with a WHR ≥0.95 (≥0.90 for females), the risk of ADs (OR 1.26, 95% CI: 1.16-1.36) and SPs (OR 1.46, 95% CI: 1.26-1.69) was higher than that of the reference group. Moreover, participants with both BMI ≥28 kg/m2 and WC ≥102 cm (≥88 cm for females) had 61% and 119% higher risk of ADs (OR 1.61, 95% CI: 1.39-1.85) and SPs (OR 2.19, 95% CI: 1.70-2.82) compared to those with both normal BMI and WC. These findings indicate that both general and abdominal obesity are associated with SPs and ADs, presenting stronger association with SPs than ADs. Moreover, the association is more evident when both obesities exist.

Dihydroartemisinin imposes positive and negative regulation on Treg and plasma cells via direct interaction and activation of c-Fos.

Dihydroartemisinin (DHA), a potent antimalarial drug, also exhibits distinct property in modulation on Treg and B cells, which has been recognized for decades, but the underlying mechanisms remain understood. Herein we revealed that DHA could promote Treg proliferation, meanwhile, suppress B cell expansion in germinal centers, and consequently decrease the number of circulating plasma cells and the content of serum immunoglobulins. Further, DHA-activated Treg significantly mitigated lipopolysaccharide-induced and malaria-associated inflammation. All these scenarios were attributed to the upregulation of c-Fos expression by DHA and enhancement of its interaction with target genes in both Treg and circulating plasma cells with bilateral cell fates. In Treg, the c-Fos-DHA complex upregulated cell proliferation-associated genes and promoted cell expansion; whereas in plasma cells, it upregulated the apoptosis-related genes resulting in decreased circulating plasma cells. Thus, the bilateral immunoregulatory mechanism of DHA was elucidated and its application in the treatment of autoimmune diseases is further justified.

Nanoprobe Based on Biominerals in Protein Corona for Dual-Modality MR Imaging and Therapy of Tumors.

Various functional nanomaterials have been fabricated as diagnostic and therapeutic nanomedicines; however, the nanoparticles closely interact with proteins when immersed in biological fluids, forming a "protein corona" that critically alters the biological identity of nanomedicine. Here, we developed a robust strategy to construct theranostic nanoprobes based on protein-corona-coated Fe3O4 nanoparticles and biomineralization in the corona. Water-soluble carboxylic Fe3O4 nanoparticles were prepared by treating oleate-capped Fe3O4 nanoparticles with Lemieux-von Rudloff reagent. Bovine serum albumin (BSA) was used as a model protein to form a corona on the surface of Fe3O4 nanoparticles, endowing the Fe3O4 nanoparticles with biocompatibility and nonimmunogenicity. The protein corona also provides a template for biomimetic mineralization of Fe3+ with tannic acid (TA) to construct Fe3O4@BSA-TAFeIII nanoprobes. The TA-Fe(III) biominerals can not only act as photothermal therapy agents but also interact with unsaturated transferrin in plasma to form a "hybrid" corona, enabling the nanoprobes to target tumor cells through the mediation of transferrin receptors, which commonly overexpress on tumor cell membranes. Once taken in by tumor cells, the protonation of phenol hydroxyl groups in acidic lysosomes would lead to the release of Fe3+, inducing tumor cell death through a ferroptosis/apoptosis hybrid pathway. In addition, the released Fe3+ can boost the T1-weighted MR imaging performance, and the Fe3O4 nanoparticles serve as T2-weighted MR imaging contrast agents. It is thus believed that the current nanoprobes can realize the enhanced dual-modality MR imaging and combined therapy of tumors through controlling the protein corona and biomineralization.

Graphene quantum dots induce cascadic apoptosis via interaction with proteins associated with anti-oxidation after endocytosis by Trypanosoma brucei.

Trypanosoma brucei, the pathogen causing African sleeping sickness (trypanosomiasis) in humans, causes debilitating diseases in many regions of the world, but mainly in African countries with tropical and subtropical climates. Enormous efforts have been devoted to controlling trypanosomiasis, including expanding vector control programs, searching for novel anti-trypanosomial agents, and developing vaccines, but with limited success. In this study, we systematically investigated the effect of graphene quantum dots (GQDs) on trypanosomal parasites and their underlying mechanisms. Ultrasmall-sized GQDs can be efficiently endocytosed by T. brucei and with no toxicity to mammalian-derived cells, triggering a cascade of apoptotic reactions, including mitochondrial disorder, intracellular reactive oxygen species (ROS) elevation, Ca2+ accumulation, DNA fragmentation, adenosine triphosphate (ATP) synthesis impairment, and cell cycle arrest. All of these were caused by the direct interaction between GQDs and the proteins associated with cell apoptosis and anti-oxidation responses, such as trypanothione reductase (TryR), a key protein in anti-oxidation. GQDs specifically inhibited the enzymatic activity of TryR, leading to a reduction in the antioxidant capacity and, ultimately, parasite apoptotic death. These data, for the first time, provide a basis for the exploration of GQDs in the development of anti-trypanosomials.

Modulation of Magnetic Exchange Coupling via Constructing Bi- or Multimagnetic Heterointerfaces.

How to resolve contradictions between the nanoscale size and high saturation magnetization (Ms) remains one of the scientific challenges in nanoscale magnetism as the theoretical optimal Ms of nanocrystals is compromised by the surface spin disorder. Here, we proposed a novel nanotechnology solution, heterointerface constructions of exchange-coupling core-shell nanocrystals, to rearrange the surface spin for the enhancement of Ms of nanomagnetic materials. As a demonstration of this principle, single-interface coupling FePt@Fe3-δO4 core/shell nanocrystals and multi-interface coupling FePt@Fe3-δO4@MFe2O4 (M = Mn or Co) core/shell/shell nanocrystals were synthesized. The simulated and experimental results demonstrated that constructing coupling heterointerfaces orientates the overall magnetic moment, ultimately enhancing the Ms of nanomagnetic materials. Moreover, this work first demonstrated that the origin of coupling heterointerfaces arose from mismatched lattices rather than chemical composition mismatch at the core-shell interfaces, thus providing both a solution to unite different mechanisms and an explanation to explain the exchange coupling at heterointerfaces.

Fabrication of magnetic nanoprobes for ultrahigh-field magnetic resonance imaging.

Ultrahigh-field magnetic resonance imaging (UHF-MRI) has been attracting tremendous attention in biomedical imaging owing to its high signal-to-noise ratio, superior spatial resolution, and fast imaging speed. However, at UHF-MRI, there is a lack of proper imaging probes that can impart superior imaging sensitivity of disease lesions because conventional contrast agents generally produce pronounced susceptibility artifacts and induce very strong T2 decay effects, thus hindering satisfactory imaging performance. This review focused on the recent development of high-performance nanoprobes that can improve the sensitivity and specificity of UHF-MRI. Firstly, the contrast enhancement mechanism of nanoprobes at UHF-MRI has been elucidated. In particular, the strategies for modulating nanoprobe performance, including size effects, metal alloying and magnetic-dopant effects, surface effects, and stimuli-response regulation, have been comprehensively discussed. Furthermore, we illustrate the remarkable advances in the design of UHF-MRI nanoprobes for medical diagnosis, such as early-stage primary tumor and metastasis imaging, angiography, and dynamic monitoring of biosignaling factors in vivo. Finally, we provide a summary and outlook on the development of cutting-edge UHF-MRI nanoprobes for advanced biomedical imaging.

Pilose antler polypeptides enhance chemotherapy effects in triple-negative breast cancer by activating the adaptive immune system.

Water-soluble polypeptides from pilose antler (PAWPs) are a traditional Chinese functional food and have been reported to inhibit triple-negative breast cancer (TNBC) in mice. Thus, in this study, we characterized PAWPs through peptidomics, and 405 total polypeptides were finally identified. Subsequently, our results indicate that PAWPs combined with neoadjuvant chemotherapy (NAC) result in a markedly lower spleen index compared with that in other groups. Next, 25 subpopulations of T cells were identified by multi-parametric flow cytometry in the lungs, spleen, and peripheral blood of different groups. These results indicated that PAWPs combined with NAC promote the proliferation of CD3+ T cells in the spleen and significantly affect the fate of the T-cell subpopulation. Moreover, PAWPs combined with NAC increased the infiltration of CD4+ interferon-γ+ T cells into tumor tissues. Our results showed that PAWPs have immunoregulatory functions and chemosensitizing effects, with good prospects for future clinical application.

Dihydroartemisinin regulates immune cell heterogeneity by triggering a cascade reaction of CDK and MAPK phosphorylation.

Artemisinin (ART) and dihydroartemisinin (DHA), apart from their profound anti-malaria effect, can also beneficially modulate the host immune system; however, the underlying molecular mechanisms remain unclear. Here, we report that DHA selectively induced T-cell activation, with an increased proportion of Ki67+CD4+ T cells, CD25+CD4+ T cells, interferon (IFN)-γ-producing CD8+ T cells, Brdu+ CD8+ T cells and neutrophils, which was found to enhance cellular immunity to experimental malaria and overcome immunosuppression in mice. We further revealed that DHA upregulated the expression of cell proliferation-associated proteins by promoting the phosphorylation of mitogen-activated protein kinase (MAPK), cyclin-dependent kinases (CDKs), and activator protein 1 in the spleen. This study is the first to provide robust evidence that DHA selectively induced the expansion of subsets of splenic T cells through phosphorylated CDKs and MAPK to enhance cellular immune responses under non-pathological or pathological conditions. The data significantly deepened our knowledge in the mechanism underlying DHA-mediated immunomodulation.