Aidi Injection, Compound Kushen Injection, or Kanglaite Injection: Which Is the Best Partner with Systemic Chemotherapy for Patients with HCC? A Network Meta-Analysis.

OBJECTIVE: The aim of this network meta-analysis (NMA) was to explore the effectiveness of different traditional Chinese medicine injections (TCMIs) combined with systemic chemotherapy for the treatment of hepatocellular carcinoma (HCC). METHODS: A comprehensive search for randomized controlled trials (RCTs) was performed with regard to different TCMIs for treating HCC in seven electronic databases up to November 2019. The quality assessment of the included RCTs was conducted according to the Cochrane risk of bias tool. The objective response rate (ORR), clinical benefit rate (CBR), and Karnofsky performance score (KPS) data were extracted. The network meta-analysis used the network package in Stata software to analyse the data and draw a map of the evidence summarizing the direct and indirect comparisons. RESULTS: A total of 1697 articles were retrieved through the comprehensive search. Twenty RCTs focusing on Aidi injection, compound Kushen injection, and Kanglaite injection as adjuvant therapies to chemotherapy were included, involving a total of 1418 patients. The NMA statistics showed that all three indicators (ORR, CBR, and KPS) were better in the combined treatment group of TCMIs with chemotherapy than that in the single treatment group of chemotherapy alone. Kanglaite injection tended to be better than the other two in terms of primary outcome, but there was not a significant difference. The combined treatment group had fewer adverse reactions than the single treatment group. Moreover, several articles reported that TCMIs combined with chemotherapy could increase the number of CD3+ and CD4+ T lymphocytes and the ratio of CD4+/CD8+ T lymphocytes. CONCLUSIONS: TCMIs combined with systemic chemotherapy could be an effective and safe treatment option for patients with HCC. Kanglaite injection showed a tendency to be better than the other two kinds of injections in terms of ORR. Nevertheless, additional results from multicentre trials and high-quality studies will be pivotal for supporting our findings.

Anti-inflammatory effects of Z23 on LPS-induced inflammatory responses in RAW264.7 macrophages.

AIM OF THE STUDY: Fissistigma oldhamii (Hemsl.) Merr, a traditional Chinese herb medicine, is used for treating rheumatoid arthritis in China. In our previous study, an effective compound, 7'-(3',4'-dihydroxyphenyl)-N-[(4-methoxyphenyl) ethyl] propenamide (Z23), from this herb has showed potent immunosuppressive effects both in vitro and in vivo. However, its anti-inflammatory effect and mechanism is still need to explore. MATERIALS AND METHODS: We examined the in vitro effects of Z23 on the production of nitric oxide (NO), prostaglandin E2 (PGE2) and cytokines by lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. RESULTS: Z23 significantly decreased the production of PGE2, NO, tumour necrosis factor alpha (TNFalpha) and IL6 production. Inducible nitric oxide synthase (iNOS) and cyclooxygenase2 (COX2) gene expression were also significantly reduced. CONCLUSIONS: These results demonstrated that Z23 exerted an anti-inflammatory effect through modulating the synthesis of several mediators and cytokines involved in the inflammatory process. This study provided evidence to understand the therapeutic effects of Fissistigma oldhamii (Hemsl.) Merr and indicated that Z23 has the potential for treatment of various inflammatory diseases where the overproduction of NO, PGE2 and inflammatory cytokines has been shown to play a role, e.g. rheumatoid arthritis.

COX-2 inhibitors ameliorate experimental autoimmune encephalomyelitis through modulating IFN-gamma and IL-10 production by inhibiting T-bet expression.

The COX-2 inhibitors Rofecoxib (Rof) and Lumiracoxib (Lum) were evaluated in experimental autoimmune encephalomyelitis (EAE), the model of multiple sclerosis (MS). Administration of Rof and Lum significantly reduced the incidence and severity of EAE, which was associated with the inhibition of MOG 35-55 lymphocyte recall response, anti-MOG 35-55 T cell responses, and modulation of cytokines production. In vitro Rof and Lum inhibited primary T cells proliferation and modulated cytokine production. These findings highlight the fact that Rof and Lum likely prevents EAE by modulating Th1/Th2 response, and suggest its utility in the treatment of MS and other autoimmune diseases.

7'-(3',4'-dihydroxyphenyl)-N-[(4-methoxyphenyl)ethyl]propenamide (Z23), an effective compound from the Chinese herb medicine Fissistigma oldhamii (Hemsl.) Merr, suppresses T cell-mediated immunity in vitro and in vivo.

Fissistigma oldhamii (Hemsl.) Merr [F. oldhamii], a traditional Chinese herb medicine, is widely used for treating rheumatoid arthritis (RA) in China. Following bioactivity-guided isolation, a representative immunosuppressive compound with low cytotoxicity, 7'-(3',4'-dihydroxyphenyl)-N-[(4-methoxyphenyl)ethyl]propenamide (Z23), was been identified in this herb medicine. We investigated the immunosuppressive effects of Z23 on T cells in vitro and in vivo. The results showed that Z23 in a dose-dependent manner significantly inhibited the proliferation of splenocytes induced by concanavalin A (ConA) and by the mixed lymphocyte culture reaction (MLR), with half inhibitive concentration (IC(50)) values of 6.22 microM and 0.78 microM, respectively. Z23 also dose-dependently inhibited the proliferation and type 1 cytokine (IFN-gamma and IL-2) production of primary T cells stimulated by anti-CD3/CD28 mAbs, but did not affect IL-12 production by mouse peritoneal macrophages (pMphi) stimulated with LPS plus IFN-gamma in vitro. Administration of Z23 (6.25 mg/kg, 12.5 mg/kg, 25 mg/kg, i.p.) dose-dependently suppressed 2,4-dinitrofluorobenzene (DNFB)-induced delayed-type hypersensitivity (DTH) reactions. Furthermore, administration of Z23 (25 mg/kg, i.p.) significantly reduced the incidence and severity of type II bovine collagen (CII)-induced arthritis (CIA), which was associated with the inhibition of CII-specific T cell proliferation and type 1 cytokine (IFN-gamma and IL-2) production. In this study, we report that a representative immunosuppressive compound from F. oldhamii, Z23, effectively inhibits murine immune responses in vitro and in vivo, and that the immunosuppressive effects of Z23 might be attributed to suppression of T cell activation and function and Th1 type cytokine production.

(5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, prevents experimental autoimmune encephalomyelitis via inhibiting T cell activation.

A novel triptolide derivative (5R)-5-hydroxytriptolide (LLDT-8) has been shown to have potent immunosuppressive activities. Here LLDT-8 was evaluated in experimental autoimmune encephalomyelitis (EAE), the model of multiple sclerosis (MS). LLDT-8 reduced the incidence and severity of EAE, which was associated with the inhibition of the MOG 35-55 lymphocyte recall response, anti-MOG 35-55 T cell responses, interleukin (IL)-2 and interferon (IFN)-gamma production. In vitro, LLDT-8 inhibited primary T cells proliferation, division, IL-2 and IFN-gamma production stimulated with anti-CD3/28. These findings highlight the fact that LLDT-8 prevents EAE by suppressing T cell proliferation and activation, with a potential for treatment of MS.

Protective effect of emodin against airway inflammation in the ovalbumin-induced mouse model.

OBJECTIVE: To investigate whether emodin exerts protective effects on mouse with allergic asthma. METHODS: A mouse model of allergic airway inflflammation was employed. The C57BL/6 mice sensitized and challenged with ovalbumin (OVA) were intraperitoneally administered 10 or 20 mg/kg emodin for 3 days during OVA challenge. Animals were sacrificed 48 h after the last challenge. Inflammatory cell count in the bronchoalveolar lavage fluid (BALF) was measured. The levels of interleukin (IL)-4, IL-5, IL-13 and eotaxin in BALF and level of immunoglobulin E (IgE) in serum were measured with enzyme-linked immuno sorbent assay kits. The mRNA expressions of IL-4, IL-5, heme oxygenase (HO)-1 and matrix metalloproteinase-9 (MMP-9) were determined by real-time quantitative polymerase chain reaction. RESULTS: Emodin induced significant suppression of the number of OVA-induced total inflammatory cells in BALF. Treatment with emodin led to significant decreases in the levels of IL-4, IL-5, IL-13 and eotaxin in BALF and total IgE level in serum. Histological examination of lung tissue revealed marked attenuation of allergen-induced lung eosinophilic inflammation. Additionally, emodin suppressed IL-4, IL-5 and MMP-9 mRNA expressions and induced HO-1 mRNA expression. CONCLUSION: Emodin exhibits anti-inflammatory activity in the airway inflammation mouse model, supporting its therapeutic potential for the treatment of allergic bronchial asthma.

Synergistic anti-inflammatory effect of Radix Platycodon in combination with herbs for cleaning-heat and detoxification and its mechanism.

OBJECTIVE: To investigate the synergistic anti-inflammatory effect of Radix Platycodon in combination with herbs for cleaning-heat and detoxification and its mechanism for Fel-targeting. METHODS: Forty Wistar rats were randomly divided into five groups (8 per group): the sham-operated group, model group, Radix Platycodon group, Flos Lonicera and Fructus Forsythia (LF) group, and Radix Platycodon, Flos Lonicera and Fructus Forsythia combination (PLF) group, using a random number table. A rat chronic obstructive pulmonary disease (COPD) model was established by passive smoking and intratracheal instillation of lipopolysaccharide (LPS). The treatments started from the 15th day of passive smoking for a total duration of 14 days. At the end of the treatment, changes in the following measurements were determined: lung histopathology, inflammatory cytokines including tumor necrosis factor α (TNF-α), transforming growth factor ß (TGF-ß) and interleukin IL-1ß (IL-1ß) in bronchoalveolar lavage fluid (BALF), and mRNA expression of endogenous active substance intestinal trefoil factor 3 (TFF3) in the lung tissue. RESULTS: Light microscopy showed that compared with the sham-operated group, rats in the COPD model group had disrupted alveolar structure, collapsed local alveoli, significantly widened or even fused alveolar septa, and massive infiltration of inflammatory cells in the alveolar wall and interstitium. In addition, significant bronchial epithelium hyperplasia, partially shed epithelia, and marked inflammatory cell infiltration in the bronchial wall and its surrounding tissues were noticed. Electron microscopy showed that rats in the model group had degeneration of alveolar type II epithelial cell; reduction, breakage or even loss of cell surface microvilli; swollen mitochondria with disappearing cristae and vacuole-like structure; and, increased secondary lysosomes in alveolar macrophages. The TNF-α, TGF-ß and IL-1ß levels and white blood cell (WBC) count in BALF were significantly increased (P < 0.01 or P < 0.05) and TFF3 mRNA expression in the lung tissue was significantly reduced (P < 0.01). After treatment, the pathological morphology of lung injury was less severe in all three treatment groups. In addition, TGF-ß and IL-1ß and WBC count in BALF were decreased (P < 0.01 or P < 0.05), and TFF3 mRNA expression in the lung tissue was significantly increased in the PLF group (P < 0.01). Compared with the LF group, the IL-1ß in BALF was significantly decreased P < 0.05), and TFF3 mRNA expression was significantly increased (P < 0.05) in the PLF group. CONCLUSIONS: Radix Platycodon synergizes with herbs for cleaning-heat and detoxification in reducing inflammatory injury in a rat model of COPD. The synergistic anti-inflammatory effect is reflected in the improvement in pathological changes and in the reduction of IL-1ß levels in BALF. The mechanism of such synergistic action may be related to its effect on maintaining the TFF3 mRNA expression and Fel-targeting function.

Specific Link between Lung and Large Intestine: A New Perspective on Neuropeptide Secretion in Lung with Herbal Laxative Stimulation.

Background. To investigate the specific link between lung and large intestine. Methods. Rat COPD-like model was prepared. Mirabilite or Chinese rhubarb was administrated intragastrically to stimulate the large intestine. Histological analysis of lung inflammation was assessed. The tissues levels of SP, VIP, NK1R, VIPR1, and VIPR2 were measured by using ELISA kits. In addition, mouse model of allergic asthma was prepared. Mirabilite was administrated intragastrically to stimulate the large intestine. Airway responsiveness and lung inflammation were assessed. The tissues levels of SP, VIP, NKA, NKB, NK1R, VIPR1, and VIPR2 were measured by using ELISA kits. Results. Stimulating the intestine with Mangxiao or Dahuang, SP, NK-1R, VIP, VIPR1, and VIPR2 were significantly increased in intestine tissues of rats with COPD and mice with asthma. Meanwhile, the SP and NK1R were significantly decreased, while VIP, VIPR1, and VIPR2 were significantly increased in lung tissues. An abnormal secretion of SP and VIP can be observed in other tissues; however, no marked changes were found in the receptors. The NKA and NKB levels were similar in lung tissues of mice with asthma among groups. Conclusions. Stimulating intestine with Mangxiao or Dahuang can specifically regulate the secretion of SP, VIP, and the receptors in lung tissues.

The chemokine receptor antagonist, TAK-779, decreased experimental autoimmune encephalomyelitis by reducing inflammatory cell migration into the central nervous system, without affecting T cell function.

BACKGROUND AND PURPOSE: The C-C chemokine receptor CCR5, and the C-X-C chemokine receptor CXCR3 are involved in the regulation of T cell-mediated immune responses, and in the migration and activation of these cells. To determine whether blockade of these chemokine receptors modulated inflammatory responses in the central nervous sytem (CNS), we investigated the effect of a non-peptide chemokine receptor antagonist, TAK-779, in mice with experimental autoimmune encephalomyelitis (EAE). EXPERIMENTAL APPROACH: EAE was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG) 35-55. TAK-779 was injected s.c. once a day after immunization. Disease incidence and severity (over 3 weeks) were monitored by histopathological evaluation and FACS assay of inflammatory cells infiltrating into the spinal cord, polymerase chain reaction quantification of mRNA expression, assay of T cell proliferation, by [3H]-thymidine incorporation and cytokine production by enzyme-linked immunosorbent assay. KEY RESULTS: Treatment with TAK-779 reduced incidence and severity of EAE. It strongly inhibited migration of CXCR3/CCR5 bearing CD4+, CD8+ and CD11b+ leukocytes to the CNS. TAK-779 did not reduce proliferation of anti-MOG T cells, the production of IFN-gamma by T cells or CXCR3 expression on T cells. In addition, TAK-779 did not affect production of IL-12 by antigen-presenting cells, CCR5 induction on T cells and the potential of MOG-specific T cells to transfer EAE. CONCLUSIONS AND IMPLICATIONS: TAK-779 restricted the development of MOG-induced EAE. This effect involved reduced migration of inflammatory cells into the CNS without affecting responses of anti-MOG T cells or the ability of MOG-specific T cells to transfer EAE.

Discovery and synthesis of new immunosuppressive alkaloids from the stem of Fissistigma oldhamii (Hemsl.) Merr.

Three new alkaloids (1-3) and twenty-one known compounds were isolated from the stem of Fissistigma oldhamii (Hemsl.) Merr. which was the ruler herb in an approved Traditional Chinese herbal formula used for treatment of rheumatoid arthritis in China and synthesis of one new immunosuppressive alkaloid was achieved. These compounds, including the crude extracts of this herb, exhibited strong activities in the inhibition of T and B cell proliferation.

Differential expression of inducible nitric oxide synthase and IL-12 between peritoneal and splenic macrophages stimulated with LPS plus IFN-gamma is associated with the activation of extracellular signal-related kinase.

Resident peritoneal macrophages (pMphi) are found deficient in T cell-stimulating capacity compared with the competent splenic macrophages (sMphi). Macrophages (Mphi)-derived nitric oxide (NO) and IL-12 have been shown to play crucial roles in the interaction between Mphi and T cells. To further understand differential functions between pMphi and sMphi, we focused on the production of NO and IL-12 from LPS plus IFN-gamma-activated Mphi. We demonstrated the differential expression of inducible nitric oxide synthase (iNOS) and IL-12 in pMphi and sMphi with LPS plus IFN-gamma stimulation. pMphi produced high level of NO but low level of IL-12, whereas sMphi produced high level of IL-12 but no NO. Furthermore, we demonstrated that there were no differences in IFN-gamma-induced signal transducer and activator of transcription-1 activation and consequent interferon regulatory factor-1 and interferon consensus sequence-binding protein up-regulation between pMphi and sMphi. Likewise, p38 mitogen-activated protein kinase was activated by LPS with identical kinetics in both pMphi and sMphi. However, LPS-induced extracellular signal-regulated kinase (ERK) activation was prolonged in pMphi comparing with sMphi. Moreover, we demonstrated, using inhibitor selective for ERK cascade (PD98059), that the prolonged ERK activation contributed a positive signal for iNOS expression and a negative signal for IL-12p40 expression in resident pMphi. In addition, anti-IL-10-neutralizing antibody plus indomethacin could abrogate the inhibitory effects of endogenous IL-10 and prostaglandin E2 on the production of IL-12 by resident pMphi possibly through suppressing ERK activation. Taken together, profound difference in ERK activation may account for differential LPS plus IFN-gamma responsiveness between pMphi and sMphi. High production of NO and low production of IL-12 by pMphi may contribute to its deficiency in T cell-stimulating capacity.

Periplocoside E inhibits experimental allergic encephalomyelitis by suppressing interleukin 12-dependent CCR5 expression and interferon-gamma-dependent CXCR3 expression in T lymphocytes.

Periplocoside E (PSE) was found to inhibit primary T-cell activation in our previous study. Now we examined the effect and mechanisms of PSE on the central nervous system (CNS) demyelination in experimental allergic encephalomyelitis (EAE). C57BL/6 mice immunized with myelin oligodendrocyte glyco-protein (MOG) were treated with PSE following immunization and continued throughout the study. The effect on the progression of EAE and other relevant parameters were assessed. PSE reduced the incidence and severity of EAE. Spinal cord histopathology analysis showed that the therapeutic effect of PSE was associated with reduced mononuclear cell infiltration and CNS inflammation. As reverse transcription-polymerase chain reaction analysis showed, PSE decreased the CD4(+), CD8(+), and CD11b(+) cell infiltration. T cells from lymph nodes of MOG-immunized mice expressed enhanced levels of CCR5 and CXCR3 mRNA compared with T cells from normal mice. However, CCR5 and CXCR3 expressions were suppressed in T cells from PSE-treated mice. In vitro study also showed PSE inhibited interferon (IFN)-gamma-dependent CXCR3 expression in T cells through suppressing T-cell receptor (TCR) ligation-induced IFN-gamma production, whereas it inhibited interleukin (IL)-12-dependent CCR5 expression through suppressing IL-12 reactivity in TCR-triggered T cells. As a result, the initial influx of T cells into CNS was inhibited in PSE-treated mice. The consequent activation of macrophages/microglia cells was inhibited in spinal cord from PSE-treated mice as determination of chemokine expressions (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10). Consistently, the secondary influx of CD4(+), CD8(+), and CD11b(+) cells was decreased in spinal cords from PSE-treated mice. These findings suggest the potential therapeutic effect of PSE on multiple sclerosis.

A reversible S-adenosyl-L-homocysteine hydrolase inhibitor ameliorates experimental autoimmune encephalomyelitis by inhibiting T cell activation.

The reversible S-adenosyl-l-homocysteine hydrolase inhibitor DZ2002 [methyl 4-(adenin-9-yl)-2-hydroxybutanoate] suppresses antigen-induced-specific immune responses, particularly type 1 helper T cell (Th1)-type responses. Experimental autoimmune encephalomyelitis (EAE) is thought to be a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of human multiple sclerosis (MS). In this study, we examined the effects of DZ2002 on active EAE induced by myelin oligodendrocyte glycoprotein (MOG) 35-55 in female C57BL/6 mice. Administration of DZ2002 (50 mg/kg/day i.p.) significantly reduced the incidence and severity of EAE, which was associated with the inhibition of MOG35-55-specific T cell proliferation and Th1-type cytokine production. In vitro studies also demonstrated that DZ2002 inhibited anti-CD3/28-induced naive T cell activation concomitant with the down-regulation of cyclin-dependent kinase (CDK) 4, CDK6, cyclin D3, and the up-regulation or protection of the CDK inhibitor p27. These findings highlight the fact that DZ2002 likely prevents EAE by suppressing T cell activation and suggest its utility in the treatment of MS and other Th1-mediated inflammatory diseases.

Periplocoside E, an effective compound from Periploca sepium Bge, inhibited T cell activation in vitro and in vivo.

Periploca sepium Bge, a traditional Chinese herb medicine, is used for treating rheumatoid arthritis in China. Followed the bioactivity-guided isolation, the most potent immunosuppressive compound, periplocoside E (PSE), a pregnane glycoside, had been identified from P. sepium Bge. We investigated the immunosuppressive effects of PSE in vitro and in vivo. The results showed that PSE in a dose-dependent manner significantly inhibited the proliferation of splenocytes induced by concanavalin A and mixed lymphocyte culture reaction at no cytotoxic concentrations (<5 microM). Administration of PSE suppressed a delayed-type hypersensitivity reaction, and ovalbumin (OVA) induced antigen-specific immune responses in mice. In vivo treatment with PSE dose dependently suppressed OVA-induced proliferation and cytokine [interleukin (IL)-2 and interferon (IFN)-gamma] production from splenocytes in vitro. Purified T cells from OVA-immunized mice with PSE treatment showed its low ability for activation by OVA plus normal antigen presenting cell stimulation again in vitro. Further studies showed PSE dose dependently inhibited anti-CD3-induced primary T cell proliferation, activation for IL-2Ralpha (CD25) expression, and cytokine (IFN-gamma and IL-2) production also at the transcriptional level. PSE was highly specific and significantly inhibited the activation of extracellular signal-regulated kinase and Jun N-terminal kinase, whereas activation of p38 was not affected in T cells stimulated with anti-CD3. These results demonstrated that PSE is an immunosuppressive compound in P. sepium Bge, which directly inhibits T cell activation in vitro and in vivo. This study provided evidence to understand the therapeutic effects of P. sepium Bge and indicated that this herb is appropriate for treatment of T cell-mediated disorders, such as autoimmune diseases.