Electrostimulation suppresses allograft rejection via promoting lymphatic regulatory T cell migration mediated by lymphotoxin - lymphotoxin receptor ß signaling.

Conventional immunosuppressants that suppress allograft rejection cause various side effects. Although regulatory T cells (Tregs) are essential for allograft survival, the limited efficacy of Treg therapy demands improvement. Thus, it is imperative to seek new approaches to enhancing Treg suppression. Low-intensity electrostimulation (ES) has been shown to exert antiinflammatory effects without causing major adverse reactions. However, it remains unknown whether and how ES regulates alloimmunity. Here, we found that regional ES delayed murine skin allograft rejection and promoted long-term allograft survival induced by an mTOR inhibitor, rapamycin. ES also extended islet allograft survival. Mechanistically, ES enhanced the expression of lymphotoxin α (LTα) on Tregs after transplantation. Blockade of lymphotoxin ß receptor-mediated nonclassical NFκB signaling suppressed lymphatic Treg migration and largely reversed the effects of ES on allograft survival. Moreover, ES failed to extend allograft survival when recipients lacked LTα/lymph nodes or if transferred Tregs lacked LTα. Therefore, ES promoted the lymphatic migration of CD4+Foxp3+ Tregs by upregulating their surface expression of LTα. Finally, ES augmented expression of LTα on murine or human Tregs, but not conventional T cells, while promoting their calcium influx in vitro. This ES-mediated upregulation of LTα relied on calcium influx. Thus, our findings have unveiled novel mechanisms underlying ES-mediated immunoregulation.

Effectiveness of nursing intervention in the operating room to prevent pressure ulcer and wound infection in patients undergoing intertrochanteric fracture: A meta-analysis.

In this study, a meta-analysis was conducted to comprehensively assess the effectiveness of nursing intervention in the operating room to prevent pressure ulcers and wound infections in patients with intertrochanteric fractures. A computerised search of PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), VIP Database of Chinese Technical Periodicals, and Wanfang databases was performed to identify randomised controlled studies (RCTs) on the effectiveness of nursing intervention in the operating room for patients undergoing intertrochanteric fractures from the time of construction of the respective databases to June 2023. Two researchers independently searched and screened the literature, extracted information and performed quality assessments of the included literature. The meta-analysis was performed using RevMan 5.4 software. Eighteen studies were finally included, including 1517 patients, with 757 in the intervention group and 760 in the control group. The results showed that nursing intervention in the operating room significantly reduced the incidence of postoperative pressure ulcers in patients with intertrochanteric femoral fractures compared to the control group (1.69% vs. 6.01%, odds ratio [OR]: 0.32, 95% confidence interval [CI]: 0.18-0.57, p < 0.001) and reduced the incidence of surgical site wound infection (1.00% vs. 6.15%, OR: 0.23, 95% CI: 0.11-0.50, p < 0.001). Current evidence suggests that nursing intervention in the operating room is superior to routine care in reducing the incidence of pressure ulcers and wound infections in patients with intertrochanteric fractures and that such interventions should be promoted for clinical use.

[Study on mechanism of curcumol against liver fibrosis based on autophagy and apoptosis of hepatic stellate cells].

The present study clarified the molecular mechanism of curcumol against liver fibrosis based on its effects on the autopha-gy and apoptosis of hepatic stellate cells. The hepatic stellate cells were divided into a blank control group, a transforming growth factor-ß1(TGF-ß1)(10 ng·mL~(-1)) group, and low-(12.5 mg·L~(-1)), medium-(25 mg·L~(-1)), and high-dose(50 mg·L~(-1)) curcumol groups. The effect of curcumol on the viability of hepatic stellate cells induced by TGF-ß1 was detected by the MTT assay kit. The apo-ptosis in each group was determined by flow cytometry. Real-time fluorescence-based quantitative PCR(RT-PCR) was employed for the detection of mRNA expression of α-smooth muscle actin(α-SMA), type Ⅰ collagen(collagen Ⅰ), and type Ⅲ collagen(collagen Ⅲ). Western blot was used to detect the protein expression of p62, microtubule-associated protein 1 light chain 3(LC3), beclin1, B cell lymphoma 2(Bcl-2), and Bcl-2-associated X protein(Bax). Transmission electron microscopy(TEM) was used to observe cell morphology and autophagosome formation in each group. The autophagic flux was observed after cell infection with adenovirus under double fluorescence labeling. The cell viability assay revealed that compared with the TGF-ß1 group, the curcumol groups showed significantly decreased cell viability. The apoptosis assay showed that the apoptosis rates of the curcumol groups were significantly higher than that of the TGF-ß1 group. RT-PCR indicated that the mRNA expression of α-SMA, collagenⅠ, and collagen Ⅲ in the curcumol groups was significantly lower than that of the TGF-ß1 group. Western blot showed that the expression of p62, LC3, beclin1, Bcl-2, and Bax in the curcumol groups was significantly different from that in the TGF-ß1 group. As demonstrated by TEM, compared with the TGF-ß1 group, the curcumol groups showed significantly increased autophagosomes. The detection of autophagic flow by the adenovirus under double fluorescence labeling showed that autolysosomes in the curcumol groups were significantly increased compared with those in the TGF-ß1 group. Curcumol can induce the autophagy and apoptosis of hepatic stellate cells, which may be one of its anti-liver fibrosis mechanisms.

A Novel Immunosuppressant, Luteolin, Modulates Alloimmunity and Suppresses Murine Allograft Rejection.

An allograft is rejected in the absence of any immunosuppressive treatment because of vigorous alloimmunity and thus requires extensive immunosuppression for its survival. Although there are many conventional immunosuppressants for clinical use, it is necessary to seek alternatives to existing drugs, especially in case of transplant patients with complicated conditions. Luteolin, a natural ingredient, exists in many plants. It exhibits multiple biological and pharmacological effects, including anti-inflammatory properties. In particular, luteolin has been shown to upregulate CD4+CD25+ regulatory T cells (Tregs) in the context of airway inflammation. However, it remains unknown whether luteolin regulates alloimmune responses. In this study, we demonstrated that luteolin significantly prolonged murine skin allograft survival, ameliorated cellular infiltration, and downregulated proinflammatory cytokine gene expression in skin allografts. Furthermore, luteolin increased the percentage of CD4+Foxp3+ Tregs while reducing frequency of mature dendritic cells and CD44highCD62Llow effector CD4+/CD8+ T cells posttransplantation. It also suppressed the proliferation of T cells and their production of cytokines IFN-γ and IL-17A in vitro while increasing IL-10 level in the supernatant. Moreover, luteolin promoted CD4+Foxp3+ Treg generation from CD4+CD25- T cells in vitro. Depleting Tregs largely, although not totally, reversed luteolin-mediated extension of allograft survival. More importantly, luteolin inhibited AKT/mTOR signaling in T cells. Thus, for the first time, to our knowledge, we found that luteolin is an emerging immunosuppressant as an mTOR inhibitor in allotransplantation. This finding could be important for the suppression of human allograft rejection, although it remains to be determined whether luteolin has an advantage over other conventional immunosuppressants in suppression of allograft rejection.

Small Nuclear Ribonucleoprotein Polypeptide A-Mediated Alternative Polyadenylation of STAT5B during Th1 Cell Differentiation.

T cells are activated and differentiated into Th cells depending on the rapid and accurate changes in the cell transcriptome. In addition to changes in mRNA expression, the sequences of many transcripts are altered by alternative splicing and alternative polyadenylation (APA). We profiled the APA sites of human CD4+ T cell subsets with high-throughput sequencing and found that Th1 cells harbored more genes with shorter tandem 3' untranslated regions (UTRs) than did naive T cells. We observed that STAT5B, a key regulator of Th1 differentiation, possessed three major APA sites and preferred shorter 3' UTRs in Th1 cells. In addition, small nuclear ribonucleoprotein polypeptide A (SNRPA) was found to bind directly to STAT5B 3' UTR and facilitate its APA switching. We also found that p65 activation triggered by TCR signaling could promote SNRPA transcription and 3' UTR shortening of STAT5B. Thus we propose that the APA switching of STAT5B induced by TCR activation is mediated by SNRPA.

On the spectral profile change in the Q band absorption spectra of metalloporphyrins (Mg, Zn, and Pd): A first-principles study.

We performed a systematic study of the vibrationally resolved absorption spectra in the Q band of three metalloporphyrins (Mg, Zn, and Pd) to understand the spectral changes in this series, including both the Franck-Condon (FC) and Herzberg-Teller (HT) contributions. The ground (S0) and the lowest singlet excited (S1) states were, respectively, simulated by the static and time-dependent density functional theory, with which the Duschinsky rotation effect was considered. Different functionals and basis sets were tested and compared with experiment. Results show that the long-range corrected functional CAM-B3LYP can nicely describe the spectral fingerprints of these metalloporphyrins, while the B3LYP functional significantly underestimates the FC contributions. We found that the absorption fine structures of these molecules are mainly caused by the HT vibronic couplings. The experimentally observed enhancements to the on-site 0-0 absorption peak in the series of Mg, Zn, and Pd are nicely reproduced. Enhanced absorption intensity is caused by larger FC contributions of molecules with heavier metal ions. The structure-spectroscopy relationship was analyzed, and it was found that the smaller cavity size of the porphyrin ring can significantly enhance the oscillator strength of the S0 → S1 transition.

Mangiferin Attenuates Murine Lupus Nephritis by Inducing CD4+Foxp3+ Regulatory T Cells via Suppression of mTOR Signaling.

BACKGROUND/AIMS: Lupus nephritis (LN) is an autoimmune glomerulonephritis that frequently develops secondary to systemic lupus erythematosus. Patients with LN require extensive treatments with global immunosuppressive agents. However, long-term treatment with conventional immunosuppressants may cause various side effects. Therefore, it's important to seek alternative drugs for treating LN. Here we aimed to investigate the immunoregulatory effects of mangiferin (MG), an ingredient that was originally extracted from natural herbs, including Mangifera Indica Linn. and Rhizoma Anemarrhenae. METHODS: FasL-deficient B6/ gld mice were used as a spontaneous LN model. The serum anti-dsDNA Ab and creatinine levels were analyzed via ELISA. Renal histology and immunopathology were determined using H&E and PAS staining, immunofluorescence (IgG and C3), and IHC staining (CD3 and a-SMA). Cytokine gene expression was measured by RT-PCR assays while effector T cells and Tregs were enumerated by flow analysis. Finally, the proliferation and apoptosis of T cells were measured by CFSE staining and flow analysis while their mTOR signaling was detected through Western blotting. RESULTS: We found that administration of MG ameliorated LN in lupus-prone B6/gld mice by reducing the urinary protein and serum creatinine levels, diminishing T cell infiltration in kidneys and improving renal immunopathology. MG also significantly lowered the percentages of CD44highCD62Llow effector T cells in B6/gld mice. Importantly, treatments with MG augmented CD4+FoxP3+ Treg frequencies in spleens, lymph nodes and kidneys of B6/gld mice. It also induced CD4+FoxP3+ Tregs from CD3+ T cells in vitro and promoted Treg proliferation. Furthermore, it inhibited CD3+ T cell proliferation in vitro and suppressed their phosphorylation of mTOR and its downstream P70S6K. However, MG did not promote T cell apoptosis, implying that it is not cytotoxic. Depletion of CD4+CD25+FoxP3+ Tregs in B6/gld mice abrogated its therapeutic effects on LN. CONCLUSION: MG exerts a novel therapeutic effect on murine LN via upregulating CD4+FoxP3+ Tregs, downregulating mTOR/p70S6K pathway and improving renal immunopathology. It may be useful for treating LN in clinic.

First-principles study on vibrationally resolved fluorescence of fused 5,15-(diphenyl)-10,20-(dibromo)porphyrin molecule.

The vibrationally resolved fluorescence spectrum of a narrow-line single-molecule transducer, fused 5,15-(diphenyl)-10,20-(dibromo)porphyrin (fused-H2P) molecule, has been calculated by time-dependent density functional theory with the inclusion of both Franck-Condon and Herzberg-Teller contributions. Analytical transition dipole derivatives are used for the calculations of Herzberg-Teller terms to eliminate the possible errors caused by numerical differentials. The performance of different exchange-correlation functionals including B3LYP, ωB97X-D, and M06-2X has been examined. The comparison with the high-resolution experimental emission spectrum indicates that all three functionals can satisfactorily describe the fluorescence spectral profile, while ωB97X-D and M06-2X give slightly better excitation energy than B3LYP. Detailed analysis shows that the fluorescence spectrum is dominated by the Franck-Condon contribution, while the Herzberg-Teller term contributes mostly to its low energy tail. It is found that the size of the basis set has limited influence on the fluorescence spectrum, and a standard 6-31G(d, p) basis set is adequate for the purpose. The substitution of terthiophene side chains is found to have minor effects on the fluorescence spectrum. Our study provides unambitious assignments for all the vibronic structures in the experimental spectrum.

Methotrexate and electrostimulation cooperate to alleviate the relapse of psoriasiform skin inflammation by suppressing memory T cells.

Methotrexate (MTX) is an immunosuppressant used to treat autoimmune diseases, including psoriasis. However, like other immunosuppressants, MTX alone does not prevent their recurrence. Electrostimulation (ES) has been utilized to treat some inflammatory disorders without any major side-effect. But it remains unknown if ES alone, or together with MTX, ameliorates autoimmune disease relapse: a sticky medical problem. In particular, the mechanisms underlying ES action remain unclear. The objective of this study was to determine an impact of ES and/or MTX on psoriasis relapse and their potential cooperation. We found that regional ES, but not MTX, ameliorated psoriasiform skin inflammation recurrence. Interestingly, treatment with both MTX and ES further prevented psoriasis recurrence compared to ES alone. Moreover, ES downregulated potassium channel Kv1.3 on T-cells and reduced CD4+/CD8+ effector memory (TEM) and CD8+ skin-resident memory T (TRM) cells, while ES plus MTX further decreased CD8+ TEM/TRM cells compared to ES alone. However, ES failed to further attenuate psoriasis recurrence or suppress T cell memory in Kv1.3-deficient mice, whereas lack of Kv1.3 itself ameliorated psoriasis relapse by shrinking T cell memory pool. Importantly, ES moderately inhibited T-cell proliferation in vitro. ES also reduced human CD8+ TRM cells and attenuated human skin lesions in humanized mice grafted with lesional skin from patients with recurrent psoriasis, with an enhanced efficacy in mice treated with both ES and MTX. Thus, ES and MTX cooperated to prevent psoriasis relapse by reducing T-cell memory via targeting potassium channel Kv1.3. Our studies may be implicated for treating human psoriasis.

The TOPK Inhibitor HI-TOPK-032 Enhances CAR T-cell Therapy of Hepatocellular Carcinoma by Upregulating Memory T Cells.

Chimeric antigen receptor (CAR) T cells are emerging as an effective antitumoral therapy. However, their therapeutic effects on solid tumors are limited because of their short survival time and the immunosuppressive tumor microenvironment. Memory T cells respond more vigorously and persist longer than their naïve/effector counterparts. Therefore, promoting CAR T-cell development into memory T cells could further enhance their antitumoral effects. HI-TOPK-032 is a T-LAK cell-originated protein kinase (TOPK)-specific inhibitor that moderately represses some types of tumors. However, it is unknown whether HI-TOPK-032 works on hepatocellular carcinoma (HCC) and whether it impacts antitumoral immunity. Using both subcutaneous and orthotopic xenograft tumor models of two human HCC cell lines, Huh-7 and HepG2, we found that HI-TOPK-032 significantly improved proliferation/persistence of CD8+ CAR T cells, as evidenced by an increase in CAR T-cell counts or frequency of Ki-67+CD8+ cells and a decrease in PD-1+LAG-3+TIM-3+CD8+ CAR T cells in vivo. Although HI-TOPK-032 did not significantly suppress HCC growth, it enhanced the capacity of CAR T cells to inhibit tumor growth. Moreover, HI-TOPK-032 augmented central memory CD8+ T cell (TCM) frequency while increasing eomesodermin expression in CD8+ CAR T cells in tumor-bearing mice. Moreover, it augmented CD8+ CAR TCM cells in vitro and reduced their expression of immune checkpoint molecules. Finally, HI-TOPK-032 inhibited mTOR activation in CAR T cells in vitro and in tumors, whereas overactivation of mTOR reversed the effects of HI-TOPK-032 on CD8+ TCM cells and tumor growth. Thus, our studies have revealed mechanisms underlying the antitumoral effects of HI-TOPK-032 while advancing CAR T-cell immunotherapy.

Electroacupuncture and methotrexate cooperate to ameliorate psoriasiform skin inflammation by regulating the immune balance of Th17/Treg.

Psoriasis is an autoinflammatory dermatosis, while methotrexate (MTX) is an immunosuppressant used to treat psoriasis. However, conventional immunosuppressants may cause various side effects. Acupuncture has potential benefits in treating psoriasis based on its anti-inflammatory effects. However, the immune mechanisms underlying its effects remain unclear. In this study, imiquimod-induced psoriatic mice were used to investigate the effects and mechanisms of electroacupuncture (EA) and, in particular, its joint treatment with MTX. We found that treatment with either EA or MTX ameliorated psoriasiform skin lesions, improved skin pathology and reduced proinflammatory cytokines in the skin, while joint treatment with both EA and MTX further alleviated the skin lesions and inflammation compared to either one alone. Moreover, percentages of CD4+ IL-17A+ Th17 cells in the skin and lymph nodes were decreased by EA or MTX and further lowered by combined EA+MTX treatment. Similarly, EA or MTX also reduced their RORγt expression. On the contrary, CD4+ FoxP3+ Treg frequency in psoriatic mice was augmented by EA or MTX and further increased by the joint treatment. However, depleting Tregs mostly reversed the therapeutic effects of EA or EA plus MTX. Additionally, the phosphorylated NF-κB (p65) expression was suppressed by treatment with EA, MTX or better with EA+MTX. Meanwhile, the anti-inflammatory effects of EA plus MTX were offset by an NF-κB agonist. Thus, this study has revealed that EA cooperates with MTX to balance Th17/Treg responses and to ameliorate psoriasiform skin inflammation through suppressing NF-κB activation. Our findings may be implicated for treating human psoriasis.

Zhen-Wu-Tang ameliorates lupus nephritis by diminishing renal tissue-resident memory CD8+ T cells via suppressing IL-15/STAT3 pathway.

Zhen-Wu-Tang (ZWT), a conventional herbal mixture, has been recommended for treating lupus nephritis (LN) in clinic. However, its mechanisms of action remain unknown. Here we aimed to define the immunological mechanisms underlying the effects of ZWT on LN and to determine whether it affects renal tissue-resident memory T (TRM) cells. Murine LN was induced by a single injection of pristane, while in vitro TRM cells differentiated with IL-15/TGF-ß. We found that ZWT or mycophenolate mofetil treatment significantly ameliorated kidney injury in LN mice by decreasing 24-h urine protein, Scr and anti-dsDNA Ab. ZWT also improved renal pathology and decreased IgG and C3 depositions. In addition, ZWT down-regulated renal Desmin expression. Moreover, it lowered the numbers of CD8+ TRM cells in kidney of mice with LN while decreasing their expression of TNF-α and IFN-γ. Consistent with in vivo results, ZWT-containing serum inhibited TRM cell differentiation induced by IL-15/TGF-ß in vitro. Mechanistically, it suppressed phosphorylation of STAT3 and CD122 （IL2/IL-15Rß）expression in CD8+ TRM cells. Importantly, ZWT reduced the number of total F4/80+CD11b+ and CD86+, but not CD206+, macrophages in the kidney of LN mice. Interestingly, ZWT suppressed IL-15 protein expression in macrophages in vivo and in vitro. Thus, we have provided the first evidence that ZWT decoction can be used to improve the outcome of LN by reducing CD8+ TRM cells via inhibition of IL-15/IL-15R /STAT3 signaling.

Corrigendum: Polyphyllin I suppresses the gastric cancer growth by promoting cancer cell ferroptosis.

[This corrects the article DOI: 10.3389/fphar.2023.1145407.].

Polyphyllin I suppresses the gastric cancer growth by promoting cancer cell ferroptosis.

Background: Ferroptosis is a new form of regulated cell death characterized by the accumulation of iron-dependent lipid peroxides and membrane damages. Recent studies have identified an important role for cancer cell ferroptosis in antitumor therapy. On the other hand, polyphyllin I (PPI) has been reported to exert antitumor effects on some types of cancers. However, it remains unknown whether or not PPI regulates cancer cell ferroptosis. Methods: Two types of human gastric cancer cells (AGS and MKN-45) were used to establish tumor xenograft models in nude mice that were treated with polyphyllin I (PPI) to observe tumor growth, while cells also were cultured for in vitro studies. Ferroptosis, based on the intracellular ROS/lipid ROS production and accumulation of ferrous ions, was detected using a fluorescence microscope and flow cytometer, while the expression of NRF2/FTH1 was measured using Western blotting assays. Results: Here we found that PPI inhibited the gastric cancer growth in vivo and in vitro while increasing the intracellular reactive oxygen species (ROS)/lipid peroxides and ferrous ions in the gastric cancer cells. PPI also decreased the levels of nuclear factor erythroid 2-related factor 2 (NRF2) and ferritin heavy chain 1 (FTH1) in gastric cancer cells in vitro. Moreover, liproxstain-1, an inhibitor of cell ferroptosis, mostly reversed the cell ferroptosis and tumor growth arrest induced by PPI. Finally, the effects of PPI on cancer cell ferroptosis were diminished by the overexpression of NRF2. Conclusion: For the first time, our results have demonstrated that PPI exerts its antitumor activity on the gastric cancer by, at least partially, inducing cancer cell ferroptosis via regulating NRF2/FTH1 pathway. These findings may be implicated for clinical replacement therapy of the gastric cancer.

Nursing of Vulvar Cancer Radical Operation Combined with Laparoscopic Inguinal Lymph Node Dissection.

Purpose: The application, development, and care of radical surgery combined with laparoscopic inguinal lymph node dissection for vulvar cancer. Methods: We searched the PubMed, Web of Science, the Cochrane Library, and EMBASE databases for published literature on the care of radical surgery combined with laparoscopic inguinal lymph node dissection for vulvar cancer up to June 2022. We used the following search terms and terms: "vulvar cancer," "injury," "radical vulvar cancer surgery," "laparoscopic inguinal lymph node dissection," and "care." Results: Laparoscopic inguinal lymph node dissection has become a new surgical method for the treatment of vulvar cancer, and it effectively avoids all the problems associated with traditional surgery. In addition, radical vulvar cancer surgery and laparoscopic inguinal lymph node dissection combined with high-quality nursing interventions can promote patients' recovery and reduce the occurrence of complications, which has important clinical significance. Conclusion: This article reviews the application, development, and nursing care of radical vulvar cancer surgery combined with laparoscopic inguinal lymph node dissection.

Optical Images of Molecular Vibronic Couplings from Tip-Enhanced Fluorescence Excitation Spectroscopy.

Tip-based photoemission spectroscopic techniques have now achieved subnanometer resolution that allows visualization of the chemical structure and even the ground-state vibrational modes of a single molecule. However, the ability to visualize the interplay between electronic and nuclear motions of excited states, i.e., vibronic couplings, is yet to be explored. Herein, we theoretically propose a new technique, namely, tip-enhanced fluorescence excitation (TEFE). TEFE takes advantage of the highly confined plasmonic field and thus can offer a possibility to directly visualize the vibronic effect of a single molecule in real space for arbitrary excited states in a given energy window. Numerical simulations for a single porphine molecule confirm that vibronic couplings originating from Herzberg-Teller (HT) active modes can be visually identified. TEFE further enables high-order vibrational transitions that are normally suppressed in the other plasmon-based processes. Images of the combination vibrational transitions have the same pattern as that of their parental HT active mode's fundamental transition, providing a direct protocol for measurements of the activity of Franck-Condon modes of selected excited states. These findings strongly suggest that TEFE is a powerful strategy to identify the involvement of molecular moieties in the complicated electron-nuclear interactions of the excited states at the single-molecule level.

Electric Field Controlled Single-Molecule Optical Switch by Through-Space Charge Transfer State.

Controlling the photon emission property of a single molecule is an important goal for nano-optics. We propose here a new mechanism for a single-molecule optical switch that utilizes the in situ electric field (EF) in biased metallic nanojunctions to control photon emission of molecules with through-space charge transfer (TSCT) excited states. The EF-induced Stark effect is capable of flipping the order of the bright noncharge transfer state and dark TSCT state, resulting in the anticipated switching behavior. The proposed mechanism was theoretically verified by scanning tunneling microscope-induced electroluminescence from a naphtalenediimide cyclophane molecule under experimentally accessible conditions. Simulations show that the proposed switching effect can be obtained by changing either bias polarity, which alters the polarization of the field, or tip-height, which affects the magnitude of the field. Our finding indicates that the in situ EF could play an important role in the design of optoelectronic molecular devices.

Immunoregulation by Artemisinin and Its Derivatives: A New Role for Old Antimalarial Drugs.

Artemisinin and its derivatives (ARTs) are known as conventional antimalarial drugs with clinical safety and efficacy. Youyou Tu was awarded a Nobel Prize in Physiology and Medicine due to her discovery of artemisinin and its therapeutic effects on malaria. Apart from antimalarial effects, mounting evidence has demonstrated that ARTs exert therapeutic effects on inflammation and autoimmune disorders because of their anti-inflammatory and immunoregulatory properties. In this aspect, tremendous progress has been made during the past five to seven years. Therefore, the present review summarizes recent studies that have explored the anti-inflammatory and immunomodulatory effects of ARTs on autoimmune diseases and transplant rejection. In this review, we also discuss the cellular and molecular mechanisms underlying the immunomodulatory effects of ARTs. Recent preclinical studies will help lay the groundwork for clinical trials using ARTs to treat various immune-based disorders, especially autoimmune diseases.

Paeoniflorin ameliorates murine lupus nephritis by increasing CD4+Foxp3+ Treg cells via enhancing mTNFα-TNFR2 pathway.

Treg cells are essential for re-establishing self-tolerance in lupus. However, given that direct Treg therapies may be inadequate to control autoimmunity and inflammation, a strategy of inducing or expanding endogenous Treg cells in vivo may be a good option. Macrophages are main tissue-infiltrating cells and play a role in promoting Treg differentiation while paeoniflorin (PF), a monoterpene glycoside, exhibits anti-inflammatory and immunoregulatory effects. Here, we studied the effects of PF on CD4+FoxP3+ Treg frequency and the potential mechanisms involving M2 macrophages. We demonstrated that PF ameliorated lupus nephritis in lupus-prone B6/gld mice by reducing urinary protein, serum creatinine and anti-dsDNA levels, diminishing renal cellular infiltration, improving renal immunopathology and downregulating renal gene and protein expressions of key cytokines, including IFN-γ, IL-6, IL-12 and IL-23. PF also lowered the percentage of CD44highCD62Llow effector T cells while augmenting CD4+FoxP3+ Treg frequency in B6/gld mice. Importantly, PF increased TNFR2 expression on CD4+FoxP3+ Tregs, but not CD4+FoxP3- T cells, in vivo and in vitro. Furthermore, we found that CD206+ subset of F4/80+CD11b+ macrophages expressed a higher level of mTNF-α than their CD206- counterparts while PF increased mTNF-α expression on CD206+ macrophages in vitro and in vivo. In vitro studies showed that mTNF-α+ M2 macrophages were more potent in inducing Treg differentiation and proliferation than their mTNF-α- counterparts, whereas the effects of mTNF-α+ M2 macrophages were largely reversed by separation of M2 macrophages using a transwell or TNFR2-blocking Ab in the culture. Finally, PF also promoted in vitro Treg generation induced by M2 macrophages. Thus, we demonstrated that mTNFα-TNFR2 interaction is a new mechanism responsible for Treg differentiation mediated by M2 macrophages. We provided the first evidence that PF may be used to treat lupus nephritis.