Ruthenium-dihydroartemisinin complex: a promising new compound for colon cancer prevention via G1 cell cycle arrest, apoptotic induction, and adaptive immune regulation.

BACKGROUND: Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies. METHODS: To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium-dihydroartemisinin complex (D-Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties. RESULTS: Compared with its parent compound, ART, D-Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D-Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D-Ru downregulated the expressions of pro-inflammatory cytokines IL-1ß, IL-6, and IL-8. Although ART and D-Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: Our results demonstrated that D-Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound's anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D-Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity.

Utilizing the photodynamic properties of curcumin to disrupt biofilms in Cutibacterium acnes: A promising approach for treating acne.

BACKGROUND: The treatment of acne vulgaris is often challenging due to the antibiotic resistance frequently observed in Cutibacterium acnes (C.acnes), a prevalent bacterium linked to this condition. OBJECTIVE: The objective of this research was to examine the impact of curcumin photodynamic therapy (PDT) on the survival of C.acnes and activity of biofilms produced by this microorganism. METHODS: Following the Clinical and Laboratory Standards Institute (CLSI) guidelines, we assessed the drug sensitivity of 25 clinical C.acnes strains to five antibiotics (erythromycin, clindamycin, tetracycline, doxycycline, minocycline) and curcumin by implementing the broth microdilution technique. In addition, we established C.acnes biofilms in a laboratory setting and subjected them to curcumin-PDT(curcumin combined with blue light of 180 J/cm2). Afterwards, we evaluated their viability using the XTT assay and observed them using confocal laser scanning microscopy. RESULTS: The result revealed varying resistance rates among the tested antibiotics and curcumin, with erythromycin, clindamycin, tetracycline, doxycycline, minocycline, and curcumin exhibiting resistance rates of 72 %, 44 %, 36 %, 28 %, 0 %, and 100 %, respectively. In the curcumin-PDT inhibition tests against four representative antibiotic-resistant strains, it was found that the survival rate of all strains of planktonic C. acnes was reduced, and the higher the concentration of curcumin, the lower the survival rate. Furthermore, in the biofilm inhibition tests, the vitality and three-dimensional structure of the biofilms were disrupted, and the inhibitory effect became more significant with higher concentrations of curcumin. CONCLUSION: The results emphasize the possibility of using curcumin PDT as an alternative approach for the treatment of C.acnes, especially in instances of antibiotic-resistant variations and infections related to biofilms.

A third (booster) dose of the inactivated SARS-CoV-2 vaccine elicits immunogenicity and T follicular helper cell responses in people living with HIV.

Introduction: This study sought to explore the immunogenicity of a booster dose of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in people living with human immunodeficiency virus (HIV) and identify the factors affecting the magnitude of anti-SARS-CoV-2 antibody levels. Materials and methods: A total of 34 people living with HIV (PLWH) and 34 healthy donors (HD) were administered a booster dose of the same SARS-CoV-2 vaccine. Anti-SARS-CoV-2 antibody and immunoglobulin G (IgG) levels were measured using the SARS-CoV-2 S protein neutralizing antibody Enzyme-Linked Immunosorbent Assay (ELISA) and 2019-nCov IgG Chemiluminescent Immunoassay Microparticles, respectively. Spearman correlation analysis was used to measure the correlation between laboratory markers and neutralizing antibody and IgG levels. Peripheral blood mononuclear cells (PBMCs) were extracted from each subject using density gradient centrifugation and the numbers of memory T and T follicular helper (Tfh) cells were determined using flow cytometry. Results: PLWH had a marked reduction in CD4 and B cell levels that was accompanied by a lower CD4/CD8 T cell ratio. However, those who received a supplementary dose of inactivated SARS-CoV-2 vaccines exhibited antibody positivity rates that were analogous to levels previously observed. The booster vaccine led to a reduction in IgG and neutralizing antibody levels and the amplitude of this decline was substantially higher in the PLWH than HD group. Correlation analyses revealed a strong correlation between neutralizing antibody levels and the count and proportion of CD4 cells. Anti-SARS-CoV-2 IgG antibody levels followed a similar trend. The expression of memory T and Tfh cells was considerably lower in the PLWH than in the HD group. Discussion: PLWH had an attenuated immune response to a third (booster) administration of an inactivated SARS-CoV-2 vaccine, as shown by lower neutralizing antibody and IgG levels. This could be attributed to the reduced responsiveness of CD4 cells, particularly memory T and cTfh subsets. CD4 and cTfh cells may serve as pivotal markers of enduring and protective antibody levels. Vaccination dose recalibration may be critical for HIV-positive individuals, particularly those with a lower proportion of CD4 and Tfh cells.

Astragaloside IV reduces lung injury in lethal sepsis via promoting treg cells expansion and inhibiting inflammatory responses.

Sepsis is a systemic inflammatory response syndrome caused by an infection progressing to sepsis-associated organ failure (such as lung injury). Our previous review revealed that Astragaloside IV (ASI-IV), one of the primary bioactive ingredients in Astragalus membranaceus (Fisch) Bge (Huang-Qi), had been shown to exert anti-inflammatory and immunomodulatory effects. Nevertheless, it is still unclear whether ASI-IV could attenuate septic lung injury via activating regulatory T-cells (Tregs). This study was designed to evaluate the therapeutic potential of ASI-IV on sepsis-induced lung injury and to further explore its underlying mechanism. In the murine models of cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) induced sepsis, ASI-IV can markedly improve the survival rate and reduce inflammatory lung injury, protect mice against exacerbated inflammatory responses by decreasing myeloid cell infiltration and down-regulating IL-6 and TNF-α in lung tissue. Meanwhile, Treg cell-related gene expression, including Foxp3 and IL-10, significantly increased after ASI-IV treatment. Furthermore, ASI-IV notably promoted the differentiation of naïve CD4+ T cells into T regulatory cells without obviously affecting Th1 and Th17 differentiation. Our results indicated that ASI-IV could attenuate septic lung injury by promoting Treg cell expansion and inhibiting inflammatory responses. It represents a promising agent for the treatment of sepsis.

Effects of Curcuminoids and Surfactant-Formulated Curcumin on Chemo-Resistant Colorectal Cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related death in the United States, and chronic gut inflammation is a risk factor for CRC initiation and development. Curcuma longa L., or turmeric, has become one of the most studied herbal medicines in recent years due to its anticancer potentials. It is generally accepted that the major component in turmeric is curcuminoids, and the active constituent in curcuminoids is curcumin. However, unprocessed curcumin is characterized by poor water solubility, which means low bioavailability in humans. To increase the bioavailability of curcumin, in this study, we utilized a novel surfactant-formulated curcumin (CuminUP60[Formula: see text]) and evaluated its CRC chemopreventive activities. Compared with the chemo-sensitive CRC cell line HCT-116, the management of the CRC SW-480 cell line is a challenge, since the latter is chemo-resistant. In other words, these cancer cells resist the effects of the chemotherapy. Using the newly formulated CuminUP60[Formula: see text] water solution, this study demonstrated its strong antiproliferative effects on the SW-480 cells in a dose- and time-dependent manner. This new formulation induced early apoptosis and arrested the cell cycle in the G2/M phase via the upregulation of cyclin B1. We also observed that this new formulation possessed inhibitory effects on Th17 cell differentiation, which regulates the body's immune response against gut malignancies. In summary, our results exhibited a potential clinical utility of the surfactant-formulated curcumin in chemo-resistant colorectal cancer management.

Anticancer evaluation of benzofuran derivatives linked to dipiperazine moiety.

In this work, a series of novel benzofuran derivatives linked to dipiperazine moiety have been prepared, and in vitro anticancer activity against Hela and A549 was investigated. The results demonstrated that benzofuran derivatives exerted potent antitumor effect. Especially, compounds 8c and 8d showed better antitumor activity against A549 (IC50 = 0.12 µM and 0.43 µM). Further mechanism study indicated that compound 8d could significantly induce cell apoptosis in A549 by FACs analysis.

Synthesis and Cytotoxic Activity of Quinazoline-Benzofuran Conjugates.

AIMS: In order to study on structure-activity relationships of benzofurans. BACKGROUND: Benzofuran is a kind of natural compound widely existing in nature with pharmacological effects. The development of new anticancer benzofuran derivatives has attracted more and more attention. METHOD: We have introduced an active quinazoline unit into piperazine-substituted benzofuran, prepared a series of quinazoline-benzofuran compounds, and evaluated cytotoxic activity against a panel of human tumor cell lines by MTT assay. RESULT: 48 novel quinazoline-substituted benzofuran derivatives have been prepared, and in vitro, cytotoxic activity against five human tumor cell lines was evaluated. The results indicated that some quinazoline-benzofuran conjugates showed selective inhibitory activity against tumor cell lines. CONCLUSION: We have found that compound 14x displayed excellent cytotoxic activity, which could be considered a potential anticancer agent.

The Small-Molecule compound baicalein alleviates experimental autoimmune encephalomyelitis by suppressing pathogenetic CXCR6+ CD4 cells.

CXC chemokine receptor6 (CXCR6)-based immunotherapy plays a significant role in autoimmune diseases, however, little is known about possible small compounds that inhibit pathogenic CXCR6+ T cells for treating multiple sclerosis (MS). Baicalein, a flavonoid isolated from Scutellarin baicalensis (Huang Qin), was shown to exert therapeutic effects on MS, but the underlying mechanisms are largely unknown. In the current study, we found that baicalein inhibited Th1 and Th17 differentiation in vitro. Oral administration of baicalein (25 mg/kg) significantly reduced the disease severity and the infiltration process, decreased the extent of demyelination in EAE, and selectively blocked IL-17A production and specific antibodies (IgG and IgG3) in MOG35-55-induced specific immune responses. In addition, the expression of CD4 cell effectors (CD44hiCD62Llow) and pathogenic Th17 cells was decreased by baicalein treatment. Furthermore, baicalein treatment largely decreased CXCR6+ CD4 and CD8 cells and prominently inhibited CXCR6+ Th17 cells in EAE. Taken together, the findings of this study suggest for the first time that baicalein may ameliorate EAE by suppressing pathogenetic CXCR6+ CD4 cells.

Jian Pi Shen Shi formula alleviates hyperuricemia and related renal fibrosis in uricase-deficient rats via suppression of the collagen-binding pathway.

AIM: Jian Pi Shen Shi Formula (JPSSF) is a beneficial treatment for hyperuricemia and related tissue damage in the clinical setting. This study was designed to investigate its therapeutic potential and underlying mechanisms in uricase-deficient rats (Uox-/- rats). METHODS: Uox-/- rats were used to assess the therapeutic potential of JPSSF on hyperuricemia. Protein extracts from renal tissues of a Uox-/- group and a JPSSF group were analyzed using tandem mass tag labeling quantitative proteomic workflow. Collagen deposition in Uox-/- rat kidneys was analyzed by Masson trichromatic staining. The gene expression associated with collagen-binding-related signaling pathways in the kidneys was further explored using quantitative polymerase chain reaction assay. The protein expressions of collagen 1a1 (col1a1), col6a1, and α-smooth muscle actin were measured by Western blotting and immunohistochemistry. RESULTS: JPSSF significantly decreased renal function indices and alleviated renal injuries. The action of JPSSF was manifested by down-regulation of col6a1 and interleukin-1 receptor-associated kinase-like 2, which blocked the binding sites on collagen and further prevented kidney injury. The anti-renal fibrosis effect of JPSSF was confirmed by reducing the collagen deposition and hydroxyproline concentrations. JPSSF treatment also intensely down-regulated the mRNA and protein expressions of col6a1, col1a1, and α-smooth muscle actin, which inhibited the function of the collagen-binding-related signaling pathway. CONCLUSION: Our results indicated that JPSSF notably ameliorated hyperuricemia and related renal fibrosis in Uox-/- rats through lowering uric acid and down-regulating the function of the collagen-binding pathway. This suggested that JPSSF is a potential empirical formula for treating hyperuricemia and accompanying renal fibrosis.

Third dose of anti-SARS-CoV-2 inactivated vaccine for patients with RA: Focusing on immunogenicity and effects of RA drugs.

Objectives: To evaluate the immunogenicity of the third dose of inactivated SARS-CoV-2 vaccine in rheumatoid arthritis (RA) patients and explore the effect of RA drugs on vaccine immunogenicity. Methods: We recruited RA patients (n = 222) and healthy controls (HC, n = 177) who had been injected with a third dose of inactivated SARS-CoV-2 vaccine, and their neutralizing antibody (NAb) titer levels were assessed. Results: RA patients and HC were age- and gender-matched, and the mean interval between 3rd vaccination and sampling was comparable. The NAb titers were significantly lower in RA patients after the third immunization compared with HC. The positive rate of NAb in HC group was 90.4%, while that in RA patients was 80.18%, and the difference was significant. Furthermore, comparison of NAb titers between RA treatment subgroups and HC showed that the patients in the conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) group exhibited no significant change in NAb titers, while in those receiving the treatment of biological DMARDs (bDMARDs), Janus Kinase (JAK) inhibitors, and prednisone, the NAb titers were significantly lower. Spearman correlation analysis revealed that NAb responses to SARS-CoV-2 in HC did differ significantly according to the interval between 3rd vaccination and sampling, but this finding was not observed in RA patients. In addition, NAb titers were not significantly correlated with RA-related laboratory indicators, including RF-IgA, RF-IgG, RF-IgM, anti-CCP antibody; C-RP; ESR; NEUT% and LYMPH%. Conclusion: Serum antibody responses to the third dose of vaccine in RA patients were weaker than HC. Our study will help to evaluate the efficacy and safety of booster vaccination in RA patients and provide further guidance for adjusting vaccination strategies.

MW­9, a chalcones derivative bearing heterocyclic moieties, attenuates experimental autoimmune encephalomyelitis via suppressing pathogenic TH17 cells.

Previous studies have indicated that MW­9, a chalcones derivative bearing heterocyclic moieties, has considerable anti­inflammatory activity in vitro. Whether MW­9 may be used to treat inflammation­based diseases, such as multiple sclerosis, remains unknown. The present study was designed to determine the effect and underlying mechanism of MW­9 in experimental autoimmune encephalomyelitis (EAE). Female C57BL/6 mice immunized with MOG35­55 were treated with or without MW­9, then the clinical scores and other relevant parameters were investigated. Production of cytokines and specific antibodies were monitored by ELISA assays. Surface marker, Treg cell, and intracellular cytokines (IL­17A and IFN­Î³) were detected by flow cytometry, and mRNA expression in the helper­T (TH)17 cell­related signaling pathway was examined by reverse transcription­quantitative (RT­q) PCR analysis. TH17 cell differentiation assay was performed. Herein, the present results demonstrated that oral administration of MW­9 reduced the severity of disease in EAE mice through slowing down infiltration process, inhibiting the demyelination, blocking anti­MOG35­55 IgG antibody production (IgG, IgG2a and IgG3), and decreasing accumulation of CD11b+Gr­1+ neutrophils from EAE mice. MW­9 treatments also led to significantly decreased IL­17A production and IL­17 expression in CD4+ T­cells, but had no detectable influence on development of TH1 and T­regulatory cells ex vivo. RT­qPCR analysis showed that within the spinal cords of the mice, MW­9 blocked transcriptional expression of TH17­associated genes, including Il17a, Il17f, Il6 and Ccr6. In TH17 cell differentiation assay, MW­9 inhibited differentiation of 'naïve' CD4+ T­cells into TH17 cells and reduced the IL­17A production. The data demonstrated that MW­9 could attenuate EAE in part through suppressing the formation and activities of pathogenic TH17 cells.

Bioactive Components and Potential Mechanism Prediction of Kui Jie Kang against Ulcerative Colitis via Systematic Pharmacology and UPLC-QE-MS Analysis.

Kui Jie Kang (KJK)-a traditional Chinese medicine-has demonstrated clinical therapeutic efficacy against ulcerative colitis (UC). However, the active compounds and their underlying mechanisms have not yet been fully characterized. Therefore, the current study sought to identify the volatile compounds in KJK responsible for eliciting the therapeutic effect against UC, while also analyzing key targets and potential mechanisms. To this end, systematic network pharmacology analysis was employed to obtain UC targets by using GeneCards, DisGeNET, OMIM, among others. A total of 145 candidate ingredients, 412 potential targets of KJK (12 herbs), and 1605 UC targets were identified. Of these KJK and UC targets, 205 intersected and further identified AKT1, JUN, MAPK, ESR, and TNF as the core targets and the PI3K/AKT signaling pathway as the top enriched pathway. Moreover, molecular docking and ultra-performance liquid chromatography Q Exactive-mass spectrometry analysis identified quercetin, kaempferol, luteolin, wogonin, and nobiletin as the core effective compounds of KJK. In vivo murine studies revealed that KJK exposure increases the body weight and colon length, while reducing colonic epithelial injury, and the expression of inflammatory factors in colitis tissues such as TNF-α, IL-6, and IL-1ß. Furthermore, KJK treatment downregulates the expression of pi3k and akt genes, as well as p-PI3K/PI3K and p-AKT/AKT proteins. Collectively, these findings describe the therapeutic effects and mechanisms of KJK in UC and highlight KJK as a potentially valuable therapeutic option for UC via modulation of the PI3K/AKT signaling pathway, thus providing a theoretical reference for the broader application of KJK in the clinical management of UC.

The discovery of potentially active diterpenoids to inhibit the pyroptosis from Callicarpa arborea.

Pyroptosis is a programmed-inflammatory cell death, which leads to release of inflammatory cellular contents and formation of inflammation. Uncontrollable pyroptosis can result in serious immune diseases, such as cytokine release syndrome (CRS), sepsis, disseminated intravascular coagulation (DIC), and acute organ damage, including acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). Members of the Callicarpa genus are significant raw materials for traditional Chinese medicine, widely used for analgesia, hemostasis, and anti-inflammation. Previously, we have reported some ent-clerodane diterpenoids from Callicarpa arborea, shown potent inhibitory effects against pyroptosis. In this study, we went on investigating this kind of diterpenoids, and yielded 66 ent-clerodane diterpenoids, including 52 new compounds, from Callicarpa arborea. Their structures featured with a 5/6- (1-25) or a 6/6- (26-66)-fused double-ring scaffolds, were elucidated using spectroscopic data, electrostatic circular dichroism (ECD) and X-ray diffraction analyses. Screening for the inhibitory activity against pyroptosis by detecting of IL-1ß secretion in J771A.1 cells, revealed 28 compounds with an IC50 below 10.5 µM. Compound 1 was the most potent with an IC50 of 0.68 µM and inhibited the J774A.1 macrophage pyroptosis by blocking the NLR pyrin domain containing 3 (NLRP3) inflammasome activation. An in vivo study further revealed that compound 1 decreased infiltration of CD11b + F4/80 + macrophages into lung and attenuated the lipopolysaccharide (LPS)-induced lung injury. Taken together, this study indicated the potential of compound 1 as a candidate for pyroptosis-related inflammation treatment, as well as provided the chemical and pharmacological basis for the further development of Callicarpa genus as a herbal medicine.

Immunogenicity of Inactivated SARS-CoV-2 Vaccines in Patients With Rheumatoid Arthritis: A Case Series.

Objectives: Attenuated humoral response to mRNA SARS-CoV-2 vaccines has been reported in some patients with autoimmune disease, e.g., rheumatoid arthritis (RA). However, data of immune responses to inactivated SARS-CoV-2 vaccine in the RA population are still unknown. Herein, the safety and immunogenicity of inactivated SARS-CoV-2 vaccines in RA patients were analyzed. Methods: Seventy five RA patients and 26 healthy controls (HC) were respectively recruited from Yunnan Provincial Hospital of Traditional Chinese Medicine and the community in Kunming city. Neutralizing Antibody (NAb) Test ELISA kit was used to measure the percentage of inhibition. AKA (anti-keratin antibody) positivity was detected using indirect immunofluorescence. Rheumatoid factor (RF)-IgA was detected by ELISA. RF-IgG, RF-IgM, and anti-cyclic citrullinated peptide (CCP) antibodies were measured by chemiluminescence. ESR (erythrocyte sedimentation rate) was detected by ESR analyzer. C-RP (c-reactive protein) was detected by immunoturbidimetry. NEUT% (percentage of neutrophils) and LYMPH% (percentage of percentage) were calculated by a calculation method. Results: Compared with the HC group, the percentage of inhibition was significantly lower in RA patients receiving two doses of vaccines. Vaccines-induced percentage of inhibition was the lowest in RA patients who had not been vaccinated. In total 80.77% of the HC group had a percentage of inhibition ≧20%, compared with 45.24% of vaccinated RA patients and 6.06% of unvaccinated RA patients. Spearman correlation analysis revealed that antibody responses to SARS-CoV-2 did not differ between RA patients according to their age and disease duration. Furthermore, the results showed that no correlation was found between the percentage of inhibition and indices for RA, including RF-IgA, IgG, IgM; anti-CCP antibody; ESR; C-RP; NEUT% and LYMPH%. Conclusion: Our study showed inactivated vaccine-induced SARS-COV-2 antibody responses differ in RA patients and healthy subjects, emphasizing the importance of a third or fourth vaccination in RA patients.

Effects of dihydroartemisinin, a metabolite of artemisinin, on colon cancer chemoprevention and adaptive immune regulation.

BACKGROUND: Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared. METHODS: Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4+ T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17. RESULTS: Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24 h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects.

Inactivated SARS-CoV-2 vaccines elicit immunogenicity and T-cell responses in people living with HIV.

BACKGROUNDS: To date, the effects of SARS-CoV-2 vaccines on people living with HIV (PLWH) were mainly focused on messenger RNA (mRNA) and adenovirus vector-based vaccines, and little is known about the effects of inactivated virus-based vaccine. This study was designed to determine the effects of inactivated SARS-CoV-2 vaccines on PLWH. METHODS: Twenty-four HIV-positive individuals and 24 healthy donors (HD) were respectively recruited from Malipo Country People's Hospital and community in Kunming city. Enumeration of lymphocyte and CD4+CD45RO+ memory T cells were evaluated by flow cytometry. Competitive ELISA was used to measure the level of Anti-SARS-CoV-2 neutralization antibody. Spearman or Pearson correlation analysis was used to analyze the relationship between laboratory indicators and neutralization antibodies in PLWH. T-cell responses (Th1, Th2, Th17, Treg) and intracellular expression of cytokines (IL-2 and TNF-α) in CD4 or CD8 were induced by spike protein in SARS-CoV-2 (SARS-2-S) and further measured by intracellular staining. RESULTS: CD4, B cells, CD4+CD45RO+ memory T cells in peripheral blood of PLWH are dramatically decreased in comparison with HD. Importantly, PLWH display comparable neutralizing antibody positive rate to HD after inoculation with inactivated SARS-CoV-2 vaccine. However, PLWH showed weaker responses to vaccines exhibited by lower levels of neutralizing antibodies. Correlation analysis shows that this is possibly caused by low number of CD4 and B cells. Furthermore, SARS-2-S-induced Th2 and Th17 responses are also decreased in PLWH, while no influences on Treg and other cytokines (IL-2, TNF-α and IFN-γ) observed. CONCLUSIONS: PLWH and HD have comparable neutralizing antibodies positive rates, but PLWH display weaker responses to inactivated SARS-CoV-2 vaccines in magnitude, which suggests that a booster dose or dose adjustment are required for HIV-infected individuals, especially for those with lower counts of CD4 T and B cells.

Discovery of heterocyclic substituted dihydropyrazoles as potent anticancer agents.

In this work, a series of novel heterocyclic substituted dihydropyrazole derivatives have been prepared, and in vitro anticancer activity against a panel of human tumor cell lines by SRB were evaluated. The results indicated that piperazine substituted dihydropyrazole derivatives exhibited superior anticancer activity than that of other compounds. Especially, compounds 4g, 4h, 4l, 4m, 4o, 6g, 6j and 6l showed potent antitumor activity. Further mechanism study demonstrated that compound 4o could induce G2/M arrest in HCC1806 cell and p21 accumulation significantly.

Synthesis and anti-inflammatory evaluation of new chalcone derivatives bearing bispiperazine linker as IL-1ß inhibitors.

In this work, a series of novel chalcone derivatives bearing bispiperazine linker have been synthesized and in vitro anti-inflammatory, cytotoxic activity and anti-inflammatory mechanism have been screened. The results indicated that most bispiperazinochalcone derivatives displayed good inhibition of NO (IC50 < 20 µM) and low cytotoxicity (CC50 > 40 µM), and selectively inhibited the production of IL-1ß via inhibiting NLRP3 inflammasome activation, as promising candidate compounds for the treatment of NLRP3 inflammasome-driven diseases.

Synthesis and Biological Evaluation of Heterocyclic Substituted Bis(indolyl)methanes.

BACKGROUND: Bis(indolyl)methane derivatives are widely found in nature with a broad range of biological and pharmacological activities. The development of techniques for the synthesis and functionalization of bis(indolyl)methanes have attracted more and more attention in recent years. OBJECTIVE: To study the synthesis and biological activity of heterocyclic substituted bis(indolyl)methanes. MATERIALS AND METHODS: A series of heterocyclic substituted bis(indolyl)methanes (3a-3p) have been prepared by condensation reaction of indole and heterocyclic aldehydes catalyzed by boron trifluoride etherate with high yields. Preliminary in vitro anti-inflammatory in lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages and cytotoxic activity against human tumor cell lines (A549, Hela and SGC7901) by MTT assay were tested. RESULTS: The result indicated that heterocyclic substituted bis(indolyl)methanes showed good antiinflammatory and selective cytotoxic activity. Especially, compounds 3o, 3p and 3q displayed similar inhibitory effect on the generation of NO to positive control dexamethasone, and compound 3q displayed similar selective cytotoxic activity to 5-FU. CONCLUSION: Heterocyclic substituted bis(indolyl)methanes may be used as potential anti-inflammatory and anticancer leads.

Comparison of chemical constitution and bioactivity among different parts of Lonicera japonica Thunb.

BACKGROUND: Lonicera japonica Thunb is a common herb in East Asia. The flower buds are usually regarded as the traditional medicinal part, while leaves and stems are considered less valuable and receive little attention. This study compared the chemical constituents and anti-inflammatory effects of the different tissues in L. japonica Thunb for the first time. RESULTS: Thirty compounds were identified by ultra-performance liquid chromatography-photodiode detector-quadrupole / time of flight-mass spectrometry (UPLC-PDA-Q/TOF-MS/MS) analysis. Hydroxycinnamic acids, flavonoids, and iridoids were identified as the major components. The flower buds (FLJ), leaves (LLJ), and stems (SLJ) of L. japonica Thunb showed strong similarities in chemical components. The LLJ contained higher levels of hydroxycinnamic acids and flavonoids than the FLJ and SLJ. Furthermore, FLJ, LLJ, and SLJ exhibited potent anti-inflammatory activity in croton oil-induced ear edema and carrageenan-induced paw edema assays in mice. Moreover, FLJ, LLJ, and SLJ showed a cytoprotective effect on lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages. Lipopolysaccharide-induced increases in nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) were suppressed by treatments of FLJ, LLJ, and SLJ, respectively. The LLJ possessed a stronger anti-inflammatory effect than the FLJ. CONCLUSION: Leaves and stems of L. japonica Thunb have chemical components and anti-inflammatory properties similar to flower buds, and may become alternative or supplementary sources of flower buds. © 2019 Society of Chemical Industry.