HSP90AB1 as the Druggable Target of Maggot Extract Reverses Cisplatin Resistance in Ovarian Cancer.

Cisplatin resistance is a crucial factor affecting ovarian cancer patient's survival rate, but the primary mechanism underlying cisplatin resistance in ovarian cancer remains unclear, and this prevents the optimal use of cisplatin therapy. Maggot extract (ME) is used in traditional Chinese medicine for patients with comas and patients with gastric cancer when combined with other drug treatments. In this study, we investigated whether ME enhances the sensitivity of ovarian cancer cells to cisplatin. Two ovarian cancer cells-A2780/CDDP and SKOV3/CDDP-were treated with cisplatin and ME in vitro. SKOV3/CDDP cells that stably expressed luciferase were subcutaneously or intraperitoneally injected into BALB/c nude mice to establish a xenograft model, and this was followed by ME/cisplatin treatment. In the presence of cisplatin, ME treatment effectively suppressed the growth and metastasis of cisplatin-resistant ovarian cancer in vivo and in vitro. RNA-sequencing data showed that HSP90AB1 and IGF1R were markedly increased in A2780/CDDP cells. ME treatment markedly decreased the expression of HSP90AB1 and IGF1R, thereby increasing the expression of the proapoptotic proteins p-p53, BAX, and p-H2AX, while the opposite effects were observed for the antiapoptotic protein BCL2. Inhibition of HSP90 ATPase was more beneficial against ovarian cancer in the presence of ME treatment. In turn, HSP90AB1 overexpression effectively inhibited the effect of ME in promoting the increased expression of apoptotic proteins and DNA damage response proteins in SKOV3/CDDP cells. Inhibition of cisplatin-induced apoptosis and DNA damage by HSP90AB1 overexpression confers chemoresistance in ovarian cancer. ME can enhance the sensitivity of ovarian cancer cells to cisplatin toxicity by inhibiting HSP90AB1/IGF1R interactions, and this might represent a novel target for overcoming cisplatin resistance in ovarian cancer chemotherapy.

Effects and central mechanism of electroacupuncture and MRI-navigated rTMS for PSD: study protocol for an fMRI-based single-center, randomized, controlled, open-label trial.

Background: Post-stroke depression (PSD) is the most common mental complication after stroke and has a serious impact on functional outcomes and quality of life for stroke patients. Antidepressants are the first-line treatment for PSD; however, many reported side effects remain. Clinical research and practice guidelines have shown that electro-acupuncture (EA) or rTMS have a positive effect on PSD. However, there are few clinical studies on EA and MRI-navigated rTMS for PSD that explore the fMRI-based central mechanism in depression. Methods: In this randomized, controlled, open-label trial, 64 patients with PSD will be randomly allocated into the experiment group (n = 32) or control group (n = 32). The experiment group will receive EA and MRI-navigated rTMS and the control group will receive MRI-navigated rTMS treatment, in 12-20 sessions over 4 weeks. In addition, 10 healthy people for fMRI scanning will be recruited as a healthy control group without any intervention. The primary outcome will be the change from baseline in the Hamilton Depression Scale-24 item (HAMD-24) scores at week 4. The primary analysis of the central mechanism will mainly involve cortical morphology, local spontaneous brain activity, and the default mode network (DMN) functional connectivity based on fMRI at 0 and 4 weeks. Secondary outcomes will include the neuro-patho-physiological and quality of life changes in cortical excitability, determined using the motor evoked potential test (MEP), National Institutes of Health Stroke Scale (NIHSS), EuroQol Five Dimensions Questionnaire (EQ-5D) Scale, Modified Barthel Index (MBI) Scale, and Health Scale of Traditional Chinese Medicine (HSTCM). Additional indicators will include the Acceptability Questionnaire and Health Economics Evaluation (cost-effectiveness analysis) to assess the acceptability and economic practicality of the treatment under study. Outcomes will be assessed at baseline and post intervention. Discussion: EA and MRI-navigated rTMS therapy could become an alternative treatment for PSD, and it is expected that this trial will provide reliable clinical evidence and a potential central mechanism for the future use of EA and MRI-navigated rTMS for PSD. Clinical trial registration: NCT05516680, ClinicalTrials.gov (registered in August 2022).

Comparison of therapeutic effects of different acupuncture and moxibustion therapies in the treatment of peripheral facial nerve paralysis: A protocol for systematic review and network meta-analysis.

BACKGROUND: Previous evidences show that acupuncture and moxibustion therapy has positive effects on peripheral facial nerve paralysis (PFP), but there are many acupuncture treatments based on meridian theory, and there are differences in the efficacy of each program. This study will compare the clinical efficacy of different acupuncture treatments for PFP through mesh meta-analysis. METHODS: Randomized controlled trials of acupuncture therapy in the treatment of PFP are going to be retrieved from 8 Science databases including CNKI, Wanfang, VIP and Chinese Biomedical Science, PubMed, Embase, Web of Science and the Cochrane Library from establishment to January 2022. We will use the Cochrane Risk Bias Assessment Tool to assess the quality of the studies and the grading of recommendation assessment, development and evaluation method to assess the strength of the evidence. All data analyses will be performed by Revman5.3, Gemtc 0.14.3, and Stata 14.0. RESULTS: This study will evaluate the efficacy of different acupuncture treatments for PFP by evaluating clinical efficacy rate, facial nerve function score, facial disability score scale, facial electromyography, adverse reactions, etc, and further explore the mechanism of action of each therapy. CONCLUSION: This study will provide a reliable evidence-based basis for selecting the best acupuncture treatment for PFP. TRIAL REGISTRATION: Open science framework registration number: DOI 10.17605/OSF.IO/XQRK9.

[Effect of warm acupuncture at Yifeng (TE 17) on facial paralysis with periauricular pain during pregnancy].

OBJECTIVE: To compare the curative effect between the warm acupuncture at Yifeng (TE 17) combined with conventional acupuncture and TDP plus conventional acupuncture on facial paralysis with periauricular pain during pregnancy. METHODS: A total of 68 patients were randomized into an observation group (36 cases, 3 cases dropped off) and a control group (32 cases, 1 case dropped off). First week, TDP light was used on the affected side in the control group, and warm acupuncture at Yinfeng (TE 17) on the affected side was used in the observation group, both once a day. From the second week, both groups were given acupuncture at Chengjiang (CV 24) and the affected side of Cuanzhu (BL 2), Yangbai (GB 14), Taiyang (EX-HN 5), Yingxiang (LI 20), Dicang (ST 4), etc. and electroacupuncture (continuous wave, 2 Hz in frequency) was connected at Cuanzhu (BL 2) and Taiyang (EX-HN 5), Jiache (ST 6) and Dicang (ST 4). Both treatments were given every other day for 4 weeks totally. The visual analogue scale (VAS) score of the periauricular pain degree before treatment and after 1 week of treatment, the House-Brackmann (H-B) facial nerve function grading scale and facial disability index (FDI) score before treatment and after 2, 4 weeks of treatment were compared between the two groups. RESULTS: After 1 week of treatment, the VAS scores of both groups decreased (P<0.001), and the variation in the observation group was larger than the control group (P<0.01). After 2 and 4 weeks of treatment, the H-B grading of both groups were improved (P<0.01, P<0.05), and those in the observation group were better than the control group (P<0.05). After 2 and 4 weeks of treatment, the FDI physical function (FDIP) scores of both groups were higher (P<0.01), and the FDI social life function (FDIS) scores were lower than before treatment (P<0.05, P<0.01), and the FDIP scores in the observation group were higher than those in the control group (P<0.05). CONCLUSION: Warm acupuncture at Yinfeng (TE 17) combined with conventional acupuncture can effectively improve the periauricular pain and facial nerve function in patients of facial paralysis with periauricular pain during pregnancy, and the curative effect is better than TDP plus conventional acupuncture.

[Clinical observation on time-effect of electroacupuncture for idiopathic facial paralysis].

OBJECTIVE: To observe the effect of different acupuncture frequency and duration of needle retention on idiopathic facial paralysis, and optimize the acupuncture treatment plan. METHODS: A total of 140 patients were randomized into a group A (37 cases, 3 cases dropped off), a group B (35 cases, 3 cases dropped off), a group C (34 cases, 1 case dropped off) and a group D (34 cases, 1 case dropped off). Under the same basic treatment, acupuncture intervention time (day 8 of morbidity), acupoint selection [Cuanzhu (BL 2), Yangbai (GB 14), Taiyang (EX-HN 5), Yingxiang (LI 20), Jiache (ST 6), Dicang (ST 4) on the affected side, Chengjiang (CV 24) and Hegu (LI 4) on the unaffected side] and electroacupuncture intervention, different acupuncture interval time and duration of needle retention were applied. In the group A, the treatment was given 20 min once a day, while the group B 30 min once a day, the group C 20 min once every 2 days, the group D 30 min once every 2 days. Totally 20-day treatment were required. The House-Brackmann (H-B) facial nerve function grading system was used to evaluate the improvement of clinical symptom, the situation and latency periods of the R1 wave in blink reflex and facial nerve motor conduction before and after treatment were observed in the 4 groups. RESULTS: After treatment, the cured rates in the 4 groups were 44.1% (15/34), 46.9% (15/32), 57.6% (19/33) and 51.5% (17/33), there was no significant difference among 4 groups (P>0.05). The situation and latency periods of the R1 wave in blink reflex and latency periods and amplitude of facial nerve motor conduction after treatment were improved in the 4 groups (P<0.01, P<0.05), there was no significant difference among 4 groups (P>0.05). CONCLUSION: Acupuncture 20 min once a day, 30 min once a day, 20 min once every 2 days and 30 min once every 2 days have significant effect on the recovery of idiopathic facial paralysis, and the effect is comparable.

Multi-glycoside of Tripterygium wilfordii Hook. f. reduces proteinuria through improving podocyte slit diaphragm dysfunction in anti-Thy1.1 glomerulonephritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Multi-glycoside of Tripterygium wilfordii Hook. f. (GTW) has been proved clinically effective in reducing proteinuria in chronic kidney disease in China. However, the mechanisms involved are still unclear. In this study we examined the effects of GTW at the different dosages on proteinuria and podocyte slit diaphragm (SD) dysfunction in anti-Thy1.1 glomerulonephritis (GN). MATERIALS AND METHODS: Rats with anti-Thy1.1 GN were divided into 2 groups, a GTW group and a vehicle group, and sacrificed at 30 min, on day 7, and on day 14 in Experiments 1, 2 and 3, respectively. The administration of GTW at the moderate and high doses was started 3 days before or at the same time of antibody injection till sacrifice. Proteinuria was determined in Experiments 1, 2, and 3. After sacrifice, the staining intensity of SD-associated key functional molecules including nephrin and podocin, podocyte structure, mesangial change, macrophage infiltration, and blood biochemical parameters were examined, respectively. Protein and mRNA expressions of nephrin and podocin in glomeruli were also investigated. Besides, liver histological characteristics were analyzed. RESULTS: In Experiment 1, GTW pretreatment at the medium dose (75 mg/kg body weight) caused no influence on the induction of anti-Thy1.1 GN and the basal nephrin expression. In Experiment 2, the high dosage (100mg/kg body weight) of GTW ameliorated proteinuria, the distribution of nephrin and podocin, mesangial proliferation, and the activated macrophage accumulation, as compared with vehicle group (P<0.05). Additionally, it increased mRNA and protein expressions of nephrin and podocin in glomeruli on day 7, but had no influence on podocyte structure. In Experiment 3, the medium dosage (75 mg/kg body weight) of GTW improved proteinuria, the partial matrix expansion, and the distribution of nephrin and podocin on day 14, as compared with anti-Thy1.1 GN rats (P<0.05). GTW at the high or moderate dose did not affect hepatic function on day 7 and on day 14. CONCLUSIONS: Podocyte SD dysfunction, such as the disordered distribution and down-regulation of nephrin and podocin expression, is critically involved in the pathogenesis of anti-Thy1.1 GN induced by mAb 1-22-3. The restoration of the distribution and expression of nephrin and podocin by GTW could be an important mechanism by which GTW ameliorates proteinuria and podocyte SD dysfunction.

[Nephritic model induced by anti-Thy1.1 monoclonal antibody and its application to study on Chinese materia medica].

The anti-Thy1.1 glomerulonephritis (GN) model induced by anti-Thy1.1 monoclonal antibody (mAb) is a widely used animal model for human mesangial proliferative glomerulonephritis (MsPGN), which is characterized by significant proteinuria and acute or progressive mesangial injury following the complement-mediated mesangiolysis and glomerular inflammatory cell infiltration. In this review, it has been discussed that the pathogenesis of reversible anti-Thy1.1 GN or irreversible anti-Thy1.1 GN induced by mAb 1-22-3 injection, the mechanisms governing inflammatory cells infiltration and several injurious cytokines in glomeruli, and some of the processes involved in the resolution of mesangial lesion such as mesangial cell proliferation and matrix expansion. Using these models, it has been reported to examine the effects of Chinese materia medica, including multi-glycoside of Tripterygium wilfordii Hook. f. (GTW) and Sairei-to on mesangial damage and proteinuria, and then to clarify the mechanism of these herbs at molecular level by examining the effects on various injurious factors.