Objective To explore the effects of Mahuang Lianqiao Chixiaodu Decoction on IgA nephropathy model rats and its mechanism based on C3a/C3aR signaling pathway.Methods Nine rats were randomly selected from 30 male Wistar rats as control group(9 rats),the remaining 21 rats were prepared IgA nephropathy models using the bovine serum albumin-lipopolysaccharide-carbon tetrachloride complex immunization method.Finally 18 successfully modeled rats were randomly divided into model group,Chinese medicine group and Western medicine group,Chinese medicine group was treated with Mahuang Lianqiao Chixiaodou Decoction suspension by gavage,the Western medicine group was treated with losartan suspension by gavage,the control group and model group were treated with normal saline by gavage.The intervention lasted for 4 weeks.HE,PAS and Masson staining were used to observe the morphology of renal tissue,the expression of IgA in glomerular mesangial area was detected by immunofluorescence,the contents of IL-6,TNF-α and C3a in renal tissue were detected by ELISA,the protein expressions of C3/C3b/C3c,C3aR,CFB,TLR4 and NF-κBp65 in renal tissue were detected by Western blot,the positive expressions of C3,C3aR and CFB in renal tissue were detected by immunohistochemistry.Results Compared with the control group,the model group showed compensatory expansion of large glomeruli,proliferation of mesangial cells,expansion of mesangial matrix,and strong positive IgA immune complex deposition in mesangial area(P<0.01),the contents of IL-6,TNF-α and C3a in renal tissue significantly increased(P<0.01),the expressions of C3/C3b/C3c,C3aR,CFB,TLR4 and NF-κBp65 protein in renal tissue increased(P<0.05),the positive expressions of C3,C3aR and CFB in renal tissue significantly increased(P<0.01).Compared with the model group,the pathological damage of Chinese medicine group and Western medicine group was alleviated,the deposition of IgA immune complex was significantly reduced(P<0.01),the contents of IL-6 and TNF-α in renal tissue significantly decreased(P<0.01,P<0.05),and the expressions of C3/C3b/C3c,C3aR,CFB,TLR4 and NF-κBp65 protein in renal tissue decreased(P<0.01,P<0.05),the positive expressions of C3,C3aR and CFB in renal tissues decreased(P<0.01).Conclusion Mahuang Lianqiao Chixiaodou Decoction can inhibit the inflammatory response and improve renal pathological damage in IgA nephropathy rats,and the mechanism may be related to the inhibition of alternative pathway complement activation and the regulation of C3a/C3aR and TLR4/NF-κB signaling pathways.

Objective To explore the effects of Mahuang Lianqiao Chixiaodu Decoction on IgA nephropathy model rats and its mechanism based on C3a/C3aR signaling pathway.Methods Nine rats were randomly selected from 30 male Wistar rats as control group(9 rats),the remaining 21 rats were prepared IgA nephropathy models using the bovine serum albumin-lipopolysaccharide-carbon tetrachloride complex immunization method.Finally 18 successfully modeled rats were randomly divided into model group,Chinese medicine group and Western medicine group,Chinese medicine group was treated with Mahuang Lianqiao Chixiaodou Decoction suspension by gavage,the Western medicine group was treated with losartan suspension by gavage,the control group and model group were treated with normal saline by gavage.The intervention lasted for 4 weeks.HE,PAS and Masson staining were used to observe the morphology of renal tissue,the expression of IgA in glomerular mesangial area was detected by immunofluorescence,the contents of IL-6,TNF-α and C3a in renal tissue were detected by ELISA,the protein expressions of C3/C3b/C3c,C3aR,CFB,TLR4 and NF-κBp65 in renal tissue were detected by Western blot,the positive expressions of C3,C3aR and CFB in renal tissue were detected by immunohistochemistry.Results Compared with the control group,the model group showed compensatory expansion of large glomeruli,proliferation of mesangial cells,expansion of mesangial matrix,and strong positive IgA immune complex deposition in mesangial area(P<0.01),the contents of IL-6,TNF-α and C3a in renal tissue significantly increased(P<0.01),the expressions of C3/C3b/C3c,C3aR,CFB,TLR4 and NF-κBp65 protein in renal tissue increased(P<0.05),the positive expressions of C3,C3aR and CFB in renal tissue significantly increased(P<0.01).Compared with the model group,the pathological damage of Chinese medicine group and Western medicine group was alleviated,the deposition of IgA immune complex was significantly reduced(P<0.01),the contents of IL-6 and TNF-α in renal tissue significantly decreased(P<0.01,P<0.05),and the expressions of C3/C3b/C3c,C3aR,CFB,TLR4 and NF-κBp65 protein in renal tissue decreased(P<0.01,P<0.05),the positive expressions of C3,C3aR and CFB in renal tissues decreased(P<0.01).Conclusion Mahuang Lianqiao Chixiaodou Decoction can inhibit the inflammatory response and improve renal pathological damage in IgA nephropathy rats,and the mechanism may be related to the inhibition of alternative pathway complement activation and the regulation of C3a/C3aR and TLR4/NF-κB signaling pathways.

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

AIM:To study the in vivo material ba-sis that is involved in the rapid antidepressant ef-fects of saffron glycoside-Ⅰ,so as to provide evi-dences to facilitate the interpreting the inconsis-tency of PK-PD,and the exploring the underlying mechanism.METHODS:The antidepressant effica-cy of saffron glycoside-Ⅰ and saffron aglycone was evaluated by investigating depressive-like behaviors such as Sucrose Preference Test(SPT),Social Inter-action Test(SIT),Tail Suspension test(TST),and the Forced Swim Test(FST)in mice induced by Chronic Unpredictable Stress(CUMS)and Chronic Social De-feat Stress(CSDS).The LPS-induced model of in-flammation was used to investigate the regulatory effect of saffron glycoside-Ⅰ on primary inflammato-ry factors.The regulation of saffron glycoside-Ⅰ and saffron aglycone on small molecules and neu-rotransmitters in blood and intestine were further studied by non-targeting metabolomics and target-ing metabolites of neural transmitters based on HPLC-qTOF/MS and LC/MS-MS techniques.RE-SULTS:Saffron glycoside-Ⅰ and its aglycone showed rapid and efficient antidepressant effects,and they significantly improved the performance of CSDS mice on SIT,TST,and FST.Saffron glycoside-Ⅰ did not show obvious effect on reducing LPS-induced inflammatory factors of IL-6 and TNF-α.On the con-trary,typical anti-inflammatory drug components of paeoniflorin,silybin and magnesium isoglycyrrhi-zinate significantly reversed the elevation of IL-6 and TNF-α induced by LPS,but they could not res-cue the depressant behaviors of CSDS mice.Metab-olomic study revealed perturbation of metabolic phenotype,small molecules and neural transmit-ters in plasma and gut contents of both CUMS and CSDS mice.To a large content,and Saffron glyco-side-Ⅰ and saffron aglycone modulated metabolic phenotype,similar to the normal controls.Saffron aglycone successfully regulated a variety of metab-olites,metabolites associated in purine pathway,and transmitters,such as 5-HT,y-GABA,glutamic acid and norepinephrine that were perturbed in plasma and gut contents in CSDS mice.CONCLU-SION:Saffron aglycone shows a rapid antidepres-sant effect similar to saffron glycoside-Ⅰ,the anti-depressant effect of saffron glycoside-Ⅰ is closely as-sociated with its primary metabolite saffron agly-cone in vivo.The antidepressant effect of saffron aglycone is involved in its regulation effects on en-dogenous small molecules and neurotransmitters in the circulatory system and intestinal tract of de-pression model mice,instead of that on inhibition on inflammatory factors.

AIM:To study the in vivo material ba-sis that is involved in the rapid antidepressant ef-fects of saffron glycoside-Ⅰ,so as to provide evi-dences to facilitate the interpreting the inconsis-tency of PK-PD,and the exploring the underlying mechanism.METHODS:The antidepressant effica-cy of saffron glycoside-Ⅰ and saffron aglycone was evaluated by investigating depressive-like behaviors such as Sucrose Preference Test(SPT),Social Inter-action Test(SIT),Tail Suspension test(TST),and the Forced Swim Test(FST)in mice induced by Chronic Unpredictable Stress(CUMS)and Chronic Social De-feat Stress(CSDS).The LPS-induced model of in-flammation was used to investigate the regulatory effect of saffron glycoside-Ⅰ on primary inflammato-ry factors.The regulation of saffron glycoside-Ⅰ and saffron aglycone on small molecules and neu-rotransmitters in blood and intestine were further studied by non-targeting metabolomics and target-ing metabolites of neural transmitters based on HPLC-qTOF/MS and LC/MS-MS techniques.RE-SULTS:Saffron glycoside-Ⅰ and its aglycone showed rapid and efficient antidepressant effects,and they significantly improved the performance of CSDS mice on SIT,TST,and FST.Saffron glycoside-Ⅰ did not show obvious effect on reducing LPS-induced inflammatory factors of IL-6 and TNF-α.On the con-trary,typical anti-inflammatory drug components of paeoniflorin,silybin and magnesium isoglycyrrhi-zinate significantly reversed the elevation of IL-6 and TNF-α induced by LPS,but they could not res-cue the depressant behaviors of CSDS mice.Metab-olomic study revealed perturbation of metabolic phenotype,small molecules and neural transmit-ters in plasma and gut contents of both CUMS and CSDS mice.To a large content,and Saffron glyco-side-Ⅰ and saffron aglycone modulated metabolic phenotype,similar to the normal controls.Saffron aglycone successfully regulated a variety of metab-olites,metabolites associated in purine pathway,and transmitters,such as 5-HT,y-GABA,glutamic acid and norepinephrine that were perturbed in plasma and gut contents in CSDS mice.CONCLU-SION:Saffron aglycone shows a rapid antidepres-sant effect similar to saffron glycoside-Ⅰ,the anti-depressant effect of saffron glycoside-Ⅰ is closely as-sociated with its primary metabolite saffron agly-cone in vivo.The antidepressant effect of saffron aglycone is involved in its regulation effects on en-dogenous small molecules and neurotransmitters in the circulatory system and intestinal tract of de-pression model mice,instead of that on inhibition on inflammatory factors.

We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 stage IB-IIA) cervical cancer having risk factors after surgery. The condition was assessed in terms of prognosis, adverse effects, and quality of life. This randomized trial involved nine centers across China. Eligible patients were randomized to receive adjuvant chemotherapy or CCRT after surgery. The primary end-point was progression-free survival (PFS). From December 2012 to December 2014, 337 patients were subjected to randomization. Final analysis included 329 patients, including 165 in the adjuvant chemotherapy group and 164 in the adjuvant CCRT group. The median follow-up was 72.1 months. The three-year PFS rates were both 91.9%, and the five-year OS was 90.6% versus 90.0% in adjuvant chemotherapy and CCRT groups, respectively. No significant differences were observed in the PFS or OS between groups. The adjusted HR for PFS was 0.854 (95% confidence interval 0.415-1.757; P = 0.667) favoring adjuvant chemotherapy, excluding the predefined non-inferiority boundary of 1.9. The chemotherapy group showed a tendency toward good quality of life. In comparison with post-operative adjuvant CCRT, adjuvant chemotherapy treatment showed non-inferior efficacy in patients with early-stage cervical cancer having pathological risk factors. Adjuvant chemotherapy alone is a favorable alternative post-operative treatment.
Female ; Humans ; Uterine Cervical Neoplasms/drug therapy* ; Prospective Studies ; Quality of Life ; Neoplasm Staging ; Chemoradiotherapy ; Chemotherapy, Adjuvant/adverse effects* ; Adjuvants, Immunologic ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Retrospective Studies