摘要:
The study uses an LMJSS‐TMT‐UPLC‐MS method to spatially map amine metabolites to brain histopathological changes including neuron loss, glial cell activation, and neurogenesis. This integrated study explains the mechanisms of posttraumatic brain injury brain damage and repair. It also uncovers the therapeutic mechanisms of traditional Chinese medicine, Xuefu Zhuyu decoction. Abstract Introduction Spatial changes of amine metabolites and histopathology of the whole brain help to reveal the mechanism of traumatic brain injury (TBI) and treatment. Methods A newly developed liquid microjunction surface sampling–tandem mass tag–ultra performance liquid chromatography–mass spectrometry technique is applied to profile brain amine metabolites in five brain regions after impact‐induced TBI at the subacute stage. H&E, Nissl, and immunofluorescence staining are performed to spatially correlate microscopical changes to metabolic alterations. Then, bioinformatics, molecular docking, ELISA, western blot, and immunofluorescence are integrated to uncover the mechanism of Xuefu Zhuyu decoction (XFZYD) against TBI. Results Besides the hippocampus and cortex, the thalamus, caudate‐putamen, and fiber tracts also show differentiated metabolic changes between the Sham and TBI groups. Fourteen amine metabolites (including isomers such as L‐leucine and L‐isoleucine) are significantly altered in specific regions. The metabolic changes are well matched with the degree of neuronal damage, glia activation, and neurorestoration. XFZYD reverses the dysregulation of several amine metabolites, such as hippocampal Lys‐Phe/Phe‐Lys and dopamine. Also, XFZYD enhances post‐TBI angiogenesis in the hippocampus and the thalamus. Conclusion This study reveals the local amine‐metabolite and histological changes in the subacute stage of TBI. XFZYD may promote TBI recovery by normalizing amine metabolites and spatially promoting dopamine production and angiogenesis.
作者机构:
[Sheng, Wen] Hunan Univ Chinese Med, Coll Tradit Chinese Med, Changsha 410000, Peoples R China.;[Lu, Baowei; Sheng, Wen; Liu, Lumei; Ding, Jin; He, Qinghu] Hunan Univ Chinese Med, Androl Lab, Changsha 410000, Peoples R China.;[Xu, Wenjing] Hunan Univ Chinese Med, Affiliated Hosp 1, Dept Dermatol, Changsha 410000, Peoples R China.;[Ding, Jin] Guangzhou Univ Tradit Chinese Med, Affiliated Baoan Hosp Tradit Chinese Med, Clin Med Coll 7, Dept Androl, Shenzhen 518000, Peoples R China.;[Lu, Baowei; Liu, Lumei] Hunan Univ Chinese Med, Coll Integrated Tradit Chinese & Western Med, Changsha 410000, Peoples R China.
通讯机构:
[Zhou, Q ; He, QH ] H;Hunan Univ Chinese Med, Androl Lab, Changsha 410000, Peoples R China.;Hunan Univ Med, Coll Tradit Chinese Med, Changsha 410000, Peoples R China.;Hunan Univ Chinese Med, Hosp 1, Dept Androl, Changsha 410000, Peoples R China.
关键词:
Colla Carapacis et Plastri;Fecal microbiota transplantation;Male infertility;Gut microbiota;Spermatogenesis ability
摘要:
[ABSTRACT] Male infertility is a significant cause of psychosocial and marital distress in approximately 50% of couples who are unable to conceive, with male factors being the underlying cause. Guijiajiao (Colla Carapacis et Plastri, CCP) is a Traditional Chinese Medicine commonly used to treat male infertility. The present study aimed to investigate the potential mechanisms underlying the preventive effects of CCP on male infertility. An infertile male rat model was established using cyclophosphamide (CTX), and CCP was administered for both treatment and prevention. Fecal microbiota transplantation (FMT) was also performed to explore the role of gut microbiota in the CCP-mediated prevention of male infertility in rats. Sperm motility and concentration were determined using a semiautomatic sperm classification analyzer. Subsequently, histopathological analysis using HE staining was performed to examine the changes in the small intestine and testis. Moreover, the serum levels of lipopolysaccharide (LPS) and testosterone were measured by ELISA. In addition, immunohistochemistry was conducted to detect CD3 expression in the small intestine, while RT-qPCR was employed to assess the expressions of interleukin-1 beta (IL-10), cluster of differentiation 3 (CD3), Monocyte chemoattractant protein-1 (MCP-1), and C-X-C motif chemokine ligand 10 (CXCL-10) in the small intestine and epididymis. Finally, gut microbiota was analyzed by 16S rRNA sequencing. CCP improved sperm motility, number, and concentration in CTX-induced infertile male rats. CCP increased the serum testosterone level, inhibited the immune cell infiltration of the intestinal lamina propria, and promoted the aggregation of CD3+ T cells in CTX-induced male infertility rats. CCP also inhibited the expressions of MCP-1, CXCL-10, and IL-10 in the epididymis of male infertility rats. At the genus level, CTX led to a reduction in the abundance of Lactobacillus, Clostridia_UCG.014, and Romboutsia in the intestinal tract of rats. In contrast, CCP decreased the abundance of Ruminococcus and increased the abundance of Romboutsia in infertile male rats. Additionally, FMT experiments proved that the gut microbiota of CCP-treated rats facilitated testicular tissue recovery and spermatogenesis while also reducing the serum LPS level in infertile male rats. CCP improves the spermatogenic ability of infertile male rats by restoring gut microbiota diversity and inhibiting epididymal inflammation.
摘要:
BACKGROUND: The motor symptoms in patients with Parkinson's disease (PD) are commonly preceded by gastrointestinal (GI) symptoms. The enteric nervous system (ENS) has also been reported to exhibit neuropathological characteristics of PD. OBJECTIVES: To evaluate the relationship between the incidence of parkinsonism and alteration in gut microbiota and pathogens. MATERIAL AND METHODS: Studies in different languages that evaluate the relationship between gut microorganisms and PD were included into this meta-analysis. The outcomes of these studies were analyzed using a random effects model; it was also used to calculate the mean difference (MD) with 95% confidence interval (95% CI) in order to quantify the impact of different rehabilitation techniques on clinical parameters. Dichotomous and continuous models were used for the analysis of extracted data. RESULTS: A total of 28 studies were included in our analysis. The analysis of small intestinal bacterial overgrowth showed a significant correlation with Parkinson's subjects compared with controls (p < 0.001). In addition, the presence of Helicobacter pylori (HP) infection was significantly related to the Parkinson's group (p < 0.001). On the other hand, there was a significantly higher abundance level of Bifidobacteriaceae (p = 0.008), Verrucomicrobiaceae (p < 0.001) and Christensenellaceae (p = 0.003) in Parkinson's subjects. In contrast, a significantly lower abundance levels in Parkinson's subjects were found in Faecalibacterium (p = 0.03), Lachnospiraceae (p = 0.005) and Prevotellaceae (p = 0.005). No significant difference was related to Ruminococcaceae. CONCLUSION: Parkinson's subjects showed a higher degree of alteration of gut microbiota and pathogens compared with normal human subjects. Future multicenter randomized trials are needed.
期刊:
Frontiers in Pharmacology,2023年13:4847 ISSN:1663-9812
作者机构:
[Peng, Xiwen; Shang, Hongcai; She, Ruining; Ge, Jinwen; Meng, Pan; Cheng, Shaowu; Wang, Shanshan; Fang, Rui; Wang, Xiangyuan; Lin, Hongyuan; Mei, Zhigang; Zhou, Yue] Hunan Univ Chinese Med, Sch Integrated Chinese & Western Med, Changsha, Hunan, Peoples R China.;[Ge, Jinwen; Fang, Rui] Hunan Acad Chinese Med, Inst Clin Pharmacol Chinese Mat Med, Changsha, Hunan, Peoples R China.;[Hu, Hua] Hunan Univ Chinese Med, Neurol Dept, Hosp 1, Changsha, Hunan, Peoples R China.;[Jiang, Qiling; Liu, Litao] Shaoyang Univ, Sch Food & Chem Engn, Shaoyang, Hunan, Peoples R China.;[Wu, Dahua; Xie, Yao; Xie, Le] Hunan Prov Hosp Integrated Chinese & Western Med, Hunan Acad Chinese Med Affiliated Hosp, Neurol Dept, Changsha, Hunan, Peoples R China.
关键词:
Hypertensive cerebral small vessel disease;randomized controlled trial;Chinese medicine;Naotaifang capsule;Treatment
摘要:
Background: Hypertensive cerebral small vessel disease (HT-CSVD) is a cerebrovascular clinical, imaging and pathological syndrome caused by hypertension (HT). The condition manifests with lesions in various vessels including intracranial small/arterioles, capillaries, and small/venules. Hypertensive cerebral small vessel disease has complex and diverse clinical manifestations. For instance, it can present as an acute stroke which progresses to cause cognitive decline, affective disorder, unstable gait, dysphagia, or abnormal urination. Moreover, hypertensive cerebral small vessel disease causes 25-30% of all cases of ischemic strokes and more than 50% of all cases of single or mixed dementias. The 1-year recurrence rate of stroke in cerebral small vessel disease patients with hypertension is 14%. In the early stage of development, the symptoms of hypertensive cerebral small vessel disease are concealed and often ignored by patients and even clinicians. Patients with an advanced hypertensive cerebral small vessel disease manifest with severe physical and mental dysfunction. Therefore, this condition has a substantial economic burden on affected families and society. Naotaifang (NTF) is potentially effective in improving microcirculation and neurofunction in patients with ischemic stroke. In this regard, this multicenter randomized controlled trial (RCT) aims to furtherly evaluate the efficacy and safety of naotaifang capsules on hypertensive cerebral small vessel disease. Methods: This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 388 eligible subjects were recruited from the First Hospital of Hunan University of Chinese Medicine, Hunan Academy of Chinese Medicine Affiliated Hospital, the First Hospital of Shaoyang University, the First Traditional Chinese Medicine Hospital of Changde, and Jiangmen Wuyi Hospital of Traditional Chinese Medicine from July 2020 to April 2022. After a 4-week run-in period, all participants were divided into the intervention group (represented by Y-T, N-T) and control group (represented by Y-C, N-C); using a stratified block randomized method based on the presence or absence of brain damage symptoms in hypertensive cerebral small vessel disease (represented by Y and N). The Y-T and N-T groups were administered different doses of naotaifang capsules, whereas Y-C and N-C groups received placebo treatment. These four groups received the treatments for 6 months. The primary outcome included Fazekas scores and dilated Virchow-robin spaces (dVRS) grades on magnetic resonance imaging (MRI). The secondary outcomes included the number of lacunar infarctions (LI) and cerebral microbleeds (CMB) on magnetic resonance imaging, clinical blood pressure (BP) level, traditional Chinese medicine (TCM) syndrome scores, mini-mental state examination (MMSE) scale, and safety outcomes. Fazekas scores, dilated Virchow-robin spaces grades, and the number of lacunar infarctions and cerebral microbleeds on magnetic resonance imaging were tested before enrollment and after 6 months of treatment. The clinical blood pressure level, traditional Chinese medicine syndrome scores, mini-mental state examination scale and safety outcomes were tested before enrollment, after 3-month, 6-month treatment and 12th-month follow-up respectively. Conclusion: The protocol will comfirm whether naotaifang capsules reduce Fazekas scores, dilated Virchow-robin spaces grades, and the number of lacunar infarctions and cerebral microbleeds, clinical blood pressure, increase mini-mental state examination scores, traditional Chinese medicine syndrome scores of Qi deficiency and blood stasis (QDBS), and improve the quality of life of subjects. The consolidated evidence from this study will shed light on the benefits of Chinese herbs for hypertensive cerebral small vessel disease, such as nourishing qi, promoting blood circulation and removing blood stasis, and dredging collaterals. However, additional clinical trials with large samples and long intervention periods will be required for in-depth research.
摘要:
Ischemic stroke, a primary cause of disability and the second leading cause of mortality, has emerged as an urgent public health issue. Growing evidence suggests that the Cyclic GMP-AMP synthase (cGAS)- Stimulator of interferon genes (STING) pathway, a component of innate immunity, is closely associated with microglia activation, neuroinflammation, and regulated cell death in ischemic stroke. However, the mechanisms underlying this pathway remain inadequately understood. This article comprehensively reviews the existing literature on the cGAS-STING pathway and its multifaceted relationship with ischemic stroke. Initially, it examines how various risk factors and pre-disease mechanisms such as metabolic dysfunction and senescence (e.g., hypertension, hyperglycemia, hyperlipidemia) affect the cGAS-STING pathway in relation to ischemic stroke. Subsequently, we explore in depth the potential pathophysiological relationship between this pathway and oxidative stress, endoplasmic reticulum stress, neuroinflammation as well as regulated cell death including ferroptosis and PANoptosis following cerebral ischemia injury. Finally, it suggests that intervention targeting the cGAS-STING pathway may serve as promising therapeutic strategies for addressing neuroinflammation associated with ischemic stroke. Taken together, this review concludes that targeting the microglia cGAS-STING pathway may shed light on the exploration of new therapeutic strategies against ischemic stroke.
作者机构:
[赵梦竹; 商洪才; 张心怡; 关之玥; 尤良震; 许倩倩] Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China;[林宏远] College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China;[赵晨] Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
通讯机构:
[Zhao, C.] I;[Shang, H.] D;Institute of Basic Research in Clinical Medicine, China;Dongzhimen Hospital, China
期刊:
Ageing Research Reviews,2023年91:102063 ISSN:1568-1637
通讯作者:
Yang, Kailin;Ge, JW;Zeng, LT
作者机构:
[Wang, Shanshan; He, Qi; Yang, Kailin; Ge, Jinwen] Hunan Univ Chinese Med, Sch Integrated Chinese & Western Med, Key Lab Hunan Prov Integrated Tradit Chinese & Wes, Changsha, Peoples R China.;[Yang, Kailin; Ge, Jinwen] Hunan Acad Chinese Med, Changsha, Hunan, Peoples R China.;[Zeng, Liuting; Zeng, LT] Chinese Acad Med Sci & Peking Union Med Coll, Nanjing Drum Tower Hosp, Grad Sch, Peking Union Med Coll,Dept Rheumatol & Immunol, Nanjing, Peoples R China.;[Zeng, Jinsong; Ge, Anqi] Hunan Univ Chinese Med, Hosp 1, Changsha, Hunan, Peoples R China.;[He, Qi; Deng, Ying] Peoples Hosp Ningxiang City, Ningxiang, Peoples R China.
通讯机构:
[Zeng, LT ] C;[Yang, KL; Ge, JW ] H;Hunan Univ Chinese Med, Sch Integrated Chinese & Western Med, Key Lab Hunan Prov Integrated Tradit Chinese & Wes, Changsha, Peoples R China.;Chinese Acad Med Sci & Peking Union Med Coll, Nanjing Drum Tower Hosp, Grad Sch, Peking Union Med Coll,Dept Rheumatol & Immunol, Nanjing, Peoples R China.
摘要:
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder of the central nervous system after Alzheimer's disease. The current understanding of PD focuses mainly on the loss of dopamine neurons in the substantia nigra region of the midbrain, which is attributed to factors such as oxidative stress, alpha-synuclein aggregation, neuroinflammation, and mitochondrial dysfunction. These factors together contribute to the PD phenotype. Recent studies on PD pathology have introduced a new form of cell death known as ferroptosis. Pathological changes closely linked with ferroptosis have been seen in the brain tissues of PD patients, including alterations in iron metabolism, lipid peroxidation, and increased levels of reactive oxygen species. Preclinical research has demonstrated the neuroprotective qualities of certain iron chelators, antioxidants, Fer-1, and conditioners in Parkinson's disease. Natural plant products have shown significant potential in balancing ferroptosis-related factors and adjusting their expression levels. Therefore, it is vital to understand the mechanisms by which natural plant products inhibit ferroptosis and relieve PD symptoms. This review provides a comprehensive look at ferroptosis, its role in PD pathology, and the mechanisms underlying the therapeutic effects of natural plant products focused on ferroptosis. The insights from this review can serve as useful references for future research on novel ferroptosis inhibitors and lead compounds for PD treatment.
摘要:
目的:对中医适宜技术治疗围绝经期失眠的研究进行可视化分析,以了解目前的研究热点、趋势,为临床研究提供参考。方法:检索中国知网、万方、维普、中国生物医学文献数据库2000年1月1日至2021年12月31日发表的相关文献,应用Cite Space 5.8软件对文献作者、机构、关键词进行可视化分析并绘制网络图谱。结果:共纳入530篇文献,近二十余年应用中医适宜技术治疗围绝经期失眠的研究形成了以孟方、于心同、任秀亚、吕梦亮等为核心的多个合作团体,以及以成都中医药大学、黑龙江中医药大学、南京中医药大学等科研院校为核心机构。该领域的研究热点为针灸、耳穴压豆、艾灸等方法治疗围绝经期失眠的临床观察,注重从肝论治进行辨证施护、改善睡眠质量。结论:治疗围绝经期失眠的中医适宜技术干预方式多样,研究方式以临床观察为主;基础研究、临床创新能力、学科间交流与合作有待提高,以促进中西医多学科融合发展。
作者机构:
[Yang, Kailin; Ge, Jinwen] Hunan Univ Chinese Med, Sch Integrated Chinese & Western Med, Key Lab Hunan Prov Integrated Tradit Chinese & Wes, Changsha, Peoples R China.;[Zeng, Liuting] Chinese Acad Med Sci & Peking Union Med Coll, Nanjing Drum Tower Hosp, Peking Union Med Coll, Grad Sch,Dept Rheumatol & Immunol, Nanjing, Peoples R China.;[Ge, Jinwen] Hunan Acad Chinese Med, Changsha, Hunan, Peoples R China.;[Long, Zhiyong; Zhen, Huang] Guangzhou Panyu Cent Hosp, Dept Rehabil Med, Guangzhou, Peoples R China.;[Xiao, Wei] Peoples Hosp Ningxiang City, Ningxiang, Peoples R China.
通讯机构:
[Ge, JW ] H;Hunan Univ Chinese Med, Sch Integrated Chinese & Western Med, Key Lab Hunan Prov Integrated Tradit Chinese & Wes, Changsha, Peoples R China.
关键词:
Total glucosides of paeony;Inflammatory arthritis;Rheumatoid arthritis;Ankylosing spondylitis;Osteoarthritis;Juvenile idiopathic arthritis;Psoriatic arthritis
摘要:
OBJECTIVE: To evaluate efficacy and safety of total glucosides of paeony in the treatment of 5 types of inflammatory arthritis METHODS: Databases such as Pubmed, Cochran Library, Embase were searched to collect RCTs about TGP in the treatment of inflammatory arthritis. Then, the RCTs were assessed for risk of bias and RCT data were extracted. Finally, RevMan 5.4 was used for the meta-analysis. RESULTS: A total of 63 RCTs were finally included, involving 5293 participants and 5 types of types of inflammatory arthritis: rheumatoid arthritis (RA), ankylosing spondylitis (AS), osteoarthritis (OA), juvenile idiopathic arthritis (JIA), psoriatic arthritis. For AS, TGP may improve AS disease activity score (ASDAS), decrease erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tumor necrosis factor (TNF)- α and interleukin (IL)-6; for RA, TGP may improve disease activity of 28 joints (DAS28), decrease ESR, CRP, rheumatoid factor (RF), TNF-α and IL-6; for psoriatic arthritis, TGP may improve psoriasis area and severity index (PASI) and decrease ESR; for OA, TGP may improve visual analogue scale (VAS) and decrease nitric oxide (NO); for JIA, TGP may increase total efficiency rate, decrease ESR, CRP and TNF-α. For safety, RCTs showed that the addition of TGP did not increase adverse events, and may even reduce adverse events. CONCLUSION: TGP may improve symptoms and inflammation levels in patients with inflammatory arthritis. However, due to the low quality and small number of RCTs, large-sample, multi-center clinical trials are still needed for revision or validation.
期刊:
Frontiers in Endocrinology,2023年14:1292011 ISSN:1664-2392
通讯作者:
Tian, XF
作者机构:
[Tian, Xuefei; Tian, XF; Chen, Yating; Liu, Mengsi; Feng, Ting] Hunan Univ Chinese Med, Sch Integrated Chinese & Western Med, Changsha, Hunan, Peoples R China.;[Tian, Xuefei; Tian, XF; Chen, Yating; Liu, Mengsi; Feng, Ting] Hunan Univ Chinese Med, Hunan Key Lab Tradit Chinese Med Prescript & Syndr, Changsha, Peoples R China.;[Tian, Xuefei; Tian, XF; Chen, Yating; Liu, Mengsi; Feng, Ting] Hunan Prov Univ Key Lab Oncol Tradit Chinese Med, Changsha, Peoples R China.;[Tian, Xuefei; Tian, XF; Chen, Yating; Liu, Mengsi; Feng, Ting] Hunan Univ Chinese Med, Key Lab Tradit Chinese Med Mech Tumor Prevent & Tr, Changsha, Peoples R China.;[Zhang, Zhen] Hunan Acad Tradit Chinese Med, Dept Oncol, Affiliated Hosp, Changsha, Peoples R China.
通讯机构:
[Tian, XF ] H;Hunan Univ Chinese Med, Sch Integrated Chinese & Western Med, Changsha, Hunan, Peoples R China.;Hunan Univ Chinese Med, Hunan Key Lab Tradit Chinese Med Prescript & Syndr, Changsha, Peoples R China.;Hunan Prov Univ Key Lab Oncol Tradit Chinese Med, Changsha, Peoples R China.;Hunan Univ Chinese Med, Key Lab Tradit Chinese Med Mech Tumor Prevent & Tr, Changsha, Peoples R China.
摘要:
Recent research has emphasized the interaction between the circadian clock and lipid metabolism, particularly in relation to tumors. This review aims to explore how the circadian clock regulates lipid metabolism and its impact on carcinogenesis. Specifically, targeting key enzymes involved in fatty acid synthesis (SREBP, ACLY, ACC, FASN, and SCD) has been identified as a potential strategy for cancer therapy. By disrupting these enzymes, it may be possible to inhibit tumor growth by interfering with lipid metabolism. Transcription factors, like SREBP play a significant role in regulating fatty acid synthesis which is influenced by circadian clock genes such as BMAL1, REV-ERB and DEC. This suggests a strong connection between fatty acid synthesis and the circadian clock. Therefore, successful combination therapy should target fatty acid synthesis in addition to considering the timing and duration of drug use. Ultimately, personalized chronotherapy can enhance drug efficacy in cancer treatment and achieve treatment goals
摘要:
Cerebral ischemia-reperfusion (CIR) is a serious complication often associated with cerebral ischemia. The pur-pose of this study was to explore the therapeutic effect of nourishing qi, activating blood circulation, and inducing resuscitation (Borneol with astragaloside IV and Panax notoginseng total saponins, BAP) on CIR. Neurological function score system was used to determine the neurological function. The survival of nerve cells was detected by Nissl staining. The levels of IL-1(3, IL-18, IL-4, and IL-10 were detected by ELISA. The expression of GSDMD, GSDMD-N, Nrf2, and HO-1 proteins in hippocampus tissues was measured by immunohistochemistry (IHC). Western blot, RT-qPCR, or immunofluorescence (IF) were used to detect the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), pro-Caspase-1, Caspase-1, Nrf2, and HO-1 expression. Lactate dehy-drogenase (LDH) level was analyzed by LDH release assay. Cell viability was determined by cell counting kit-8 (CCK8). Apoptosis was detected by flow cytometry. BAP significantly promoted the recovery of nerve function, the activity of nerve cells, and the expression of Nrf2, HO-1, IL-4, and IL-10 in rat hippocampus tissues after CIR. BAP has an obvious inhibitory effect on the expression of NLRP3, pro-Caspase-1, and Caspase-1 proteins, the release of IL-1(3 and IL-18 factors, and neuronal pyroptosis in hippocampal tissues. BAP also promoted IL-4 and IL-10 levels, and the activity of SH-SY5Y cells. The IL-1(3, IL-18, NLRP3, pro-Caspase-1, Caspase-1, GSDMD, and GSDMD-N expressions were significantly inhibited by BAP in vitro, which was reversed by Nrf2 knockdown. This study confirmed that BAP alleviated rat CIR and inhibited the pyroptosis of SH-SY5Y cells by regulating the Nrf2/ HO-1 signaling pathway. This study provided new directions and ideas for the treatment of CIR.