bluuebunny/crossref_metadata_2025 huggingface dataset:
Bifidobacterium infantis Maintains Genome Stability in Ulcerative Colitis via Regulating Anaphase-Promoting Complex Subunit 7
Authors: Han Taotao , Hu Xiaomin , Li Kemin , Zhang Di , Zhang Yan , Li Jingnan
Published: November 2021

Probiotics represents a promising intestinal microbiota-targeted therapeutic method for the treatment of ulcerative colitis (UC). Several lines of evidence implicate that Bifidobacterium infantis serves as a probiotic strain with proven efficacy in maintaining the remission of UC. However, the exact mechanisms underlying the beneficial effects of B. infantis on UC progression have yet to be elucidated. Herein, we provide evidence that B. infantis acts as a key predisposing factor for the maintenance of host genome stability. First, we showed that the fecal microbiota transplantation (FMT) of UC-derived feces contributes to more severely DNA damage in dextran sodium sulfate (DSS)-induced mice likely due to mucosa-associated microbiota alterations, as reflected by the rapid appearance of DNA double strand breaks (DSBs), a typical marker of genome instability. Genomic DNA damage analysis of colon tissues derived from healthy controls, patients with UC or dysplasia, and colitis associated cancer (CAC) patients, revealed an enhanced level of DSBs with aggravation in the degree of the intestinal mucosal lesions. To evaluate whether B. infantis modulates the host genome stability, we employed the DSS-induced colitis model and a TNFα-induced intestinal epithelial cell model. Following the administration of C57BL/6 mice with B. infantis via oral gavage, we found that the development of DSS-induced colitis in mice was significantly alleviated, in contrast to the colitis model group. Notably, B. infantis administration decreased DSB levels in both DSS-induced colitis and TNF-treated colonial cell model. Accordingly, our bioinformatic and functional studies demonstrated that B. infantis altered signal pathways involved in ubiquitin-mediated proteolysis, transcriptional misregulation in cancer, and the bacterial invasion of epithelial cells. Mechanistically, B. infantis upregulated anaphase-promoting complex subunit 7 (APC7), which was significantly suppressed in colitis condition, to activate the DNA repair pathway and alter the genome stability, while downregulation of APC7 abolished the efficiency of B. infantis treatment to induce a decrease in the level of DSBs in TNFα-induced colonial cells. Collectively, our results support that B. infantis orchestrates a molecular network involving in APC7 and genome stability, to control UC development at the clinical, biological, and mechanistic levels. Supplying B. infantis and targeting its associated pathway will yield valuable insight into the clinical management of UC patients.
The Impact of Mutation L138F/L210F on the Orai Channel: A Molecular Dynamics Simulation Study
Authors: Zhang Xiaoqian , Yu Hua , Liu Xiangdong , Song Chen
Published: November 2021

The calcium release-activated calcium channel, composed of the Orai channel and the STIM protein, plays a crucial role in maintaining the Ca2+ concentration in cells. Previous studies showed that the L138F mutation in the human Orai1 creates a constitutively open channel independent of STIM, causing severe myopathy, but how the L138F mutation activates Orai1 is still unclear. Here, based on the crystal structure of Drosophila melanogaster Orai (dOrai), molecular dynamics simulations for the wild-type (WT) and the L210F (corresponding to L138F in the human Orai1) mutant were conducted to investigate their structural and dynamical properties. The results showed that the L210F dOrai mutant tends to have a more hydrated hydrophobic region (V174 to F171), as well as more dilated basic region (K163 to R155) and selectivity filter (E178). Sodium ions were located deeper in the mutant than in the wild-type. Further analysis revealed two local but essential conformational changes that may be the key to the activation. A rotation of F210, a previously unobserved feature, was found to result in the opening of the K163 gate through hydrophobic interactions. At the same time, a counter-clockwise rotation of F171 occurred more frequently in the mutant, resulting in a wider hydrophobic gate with more hydration. Ultimately, the opening of the two gates may facilitate the opening of the Orai channel independent of STIM.
Positron Emission Computed Tomography Imaging of Synaptic Vesicle Glycoprotein 2A in Alzheimer’s Disease
Authors: Kong Yanyan , Zhang Shibo , Huang Lin , Zhang Chencheng , Xie Fang , Zhang Zhengwei , Huang Qi , Jiang Donglang , Li Junpeng , Zhou Weiyan , Hua Tao , Sun Bomin , Wang Jiao , Guan Yihui
Published: November 2021

Alzheimer’s disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Early diagnosis of AD is of great significance to control the development of the disease. Synaptic loss is an important pathology in the early stage of AD, therefore the measurement of synaptic density using molecular imaging technology may be an effective way to early diagnosis of AD. Synaptic vesicle glycoprotein 2A (SV2A) is located in the presynaptic vesicle membrane of virtually all synapses. SV2A Positron Emission Computed Tomography (PET) could provide a way to measure synaptic density quantitatively in living humans and to track changes in synaptic density in AD. In view of the fact that synaptic loss is the pathology of both epilepsy and AD, this review summarizes the potential role of SV2A in the pathogenesis of AD, and suggests that SV2A should be used as an important target molecule of PET imaging agent for the early diagnosis of AD.
Does Prior Stroke Predict Long-Term Recurrent Stroke After Percutaneous Coronary Intervention? Five-Year Results From a Large Cohort Study
Authors: Xu Jing-jing , Jia Si-da , Zhu Pei , Jiang Lin , Jiang Ping , Song Ying , Zhao Xue-yan , Li Jian-xin , Chen Jue , Yang Yue-jin , Gao Run-lin , Qiao Shu-bin , Xu Bo , Yuan Jin-qing
Published: November 2021

Background: We found a positive correlation between the prior stroke history and recurrent stroke in patients who underwent percutaneous coronary intervention (PCI) in our previous study, which indicated the close interaction of stroke and cardiovascular diseases. However, it is unclear whether prior stroke is still associated with worse prognosis at a longer follow-up period.

Methods: A total of 10,724 coronary heart disease (CHD) patients who received PCI from January to December 2013 were prospectively enrolled and were subsequently divided into the prior stroke (n = 1,150) and non-prior stroke (n = 9,574) groups according to their history. Baseline characteristics and 5-year outcomes were recorded.

Results: Patients with prior stroke had more clinical risk factors, as well as more extensive coronary artery lesions. Although in-hospital outcomes were similar between patients from the two groups, the 5-year follow-up result revealed that patients with prior stroke experienced higher incidence of stroke, major adverse cardiac and cerebrovascular events (MACCEs), all-cause death, and cardiac death (7.0 vs. 3.0%, p < 0.001; 25.9 vs. 20.3%, p < 0.001; 5.3 vs. 3.5%, p = 0.002; 3.1 vs. 2.1%, p = 0.032, respectively). After the propensity score matching, the 5-year stroke rate was still higher in the prior stroke group (6.8 vs. 3.4%, p = 0.001). The multivariable regression analysis also identified the prior stroke as a risk predictor of the 5-year stroke (HR = 2.011, 95% CI: 1.322–3.059, p = 0.001).

Conclusions: Coronary heart disease patients with prior stroke who received PCI had a higher incidence of 5-year long-term adverse cardiovascular and cerebrovascular events, especially recurrent stroke. Prior stroke was a strong risk predictor of future stroke events.
Frequency-Specific Effects of Galvanic Vestibular Stimulation on Response-Time Performance in Parkinson's Disease
Authors: Lee Soojin , Smith Paul F. , Lee Won Hee , McKeown Martin J.
Published: November 2021

Background: Galvanic vestibular stimulation (GVS) is being increasingly explored as a non-invasive brain stimulation technique to treat symptoms in Parkinson's disease (PD). To date, behavioral GVS effects in PD have been explored with only two stimulus types, direct current and random noise (RN). The interaction between GVS effects and anti-parkinsonian medication is unknown. In the present study, we designed multisine (ms) stimuli and investigated the effects of ms and RN GVS on motor response time. In comparison to the RN stimulus, the ms stimuli contained sinusoidal components only at a set of desired frequencies and the phases were optimized to improve participants' comfort. We hypothesized GVS motor effects were a function of stimulation frequency, and specifically, that band-limited ms-GVS would result in better motor performance than conventionally used broadband RN-GVS.

Materials and Methods: Eighteen PD patients (PDMOFF/PDMON: off-/on-levodopa medication) and 20 healthy controls (HC) performed a simple reaction time task while receiving sub-threshold GVS. Each participant underwent nine stimulation conditions: off-stimulation, RN (4–200 Hz), ms-θ (4–8 Hz), ms-α (8–13 Hz), ms-β (13–30 Hz), ms-γ (30–50 Hz), ms-h1 (50–100 Hz), ms-h2 (100–150 Hz), and ms-h3 (150–200 Hz).

Results: The ms-γ resulted in shorter response time (RPT) in both PDMOFF and HC groups compared with the RN. In addition, the RPT of the PDMOFF group decreased during the ms-β while the RPT of the HC group decreased during the ms-α, ms-h1, ms-h2, and ms-h3. There was considerable inter-subject variability in the optimum stimulus type, although the frequency range tended to fall within 8–100 Hz. Levodopa medication significantly reduced the baseline RPT of the PD patients. In contrast to the off-medication state, GVS did not significantly change RPT of the PD patients in the on-medication state.

Conclusions: Using band-limited ms-GVS, we demonstrated that the GVS frequency for the best RPT varied considerably across participants and was >30 Hz for half of the PDMOFF patients. Moreover, dopaminergic medication was found to influence GVS effects in PD patients. Our results indicate the common “one-size-fits-all” RN approach is suboptimal for PD, and therefore personalized stimuli aiming to address this variability is warranted to improve GVS effects.
Neuromuscular Fatigue in Unimanual Handgrip Does Not Completely Affect Simultaneous Bimanual Handgrip
Authors: Hikosaka Mikito , Aramaki Yu
Published: November 2021

Simultaneous bimanual movements are not merely the sum of two unimanual movements. Here, we considered the unimanual/bimanual motor system as comprising three components: unimanual-specific, bimanual-specific, and overlapping (mobilized during both unimanual and bimanual movements). If the force-generating system controlling the same limb differs between unimanual and bimanual movements, unimanual exercise would be expected to fatigue the unimanual-specific and overlapping parts in the force-generating system but not the bimanual-specific part. Therefore, we predicted that the decrease in bimanual force generation induced by unimanual neuromuscular fatigue would be smaller than the decrease in unimanual force generation. Sixteen healthy right-handed adults performed unimanual and bimanual maximal handgrip measurements before and after a submaximal fatiguing handgrip task. In the fatigue task, participants were instructed to maintain unimanual handgrip force at 50% of their maximal handgrip force until the time to task failure. Each participant performed this task in a left-hand fatigue (LF) condition and a right-hand fatigue (RF) condition, in a random order. Although the degree of neuromuscular fatigue was comparable in both conditions, as expected, the decrease in bimanual right handgrip force was significantly smaller than those during unimanual right performance in the RF condition, but not in the LF condition. These results indicate that for the right-hand, neuromuscular fatigue in unimanual handgrip does not completely affect simultaneous bimanual handgrip. Regarding the underlying mechanisms, we propose that although neuromuscular fatigue caused by unimanual handgrip reduces the motor output of unimanual-specific and overlapping parts in the force-generating system, when simultaneous bimanual handgrip is performed, the overlapping part (which is partially fatigued) and the bimanual-specific part (which is not yet fatigued) generate motor output, thus decreasing the force reduction.
GluN2A/ERK/CREB Signaling Pathway Involved in Electroacupuncture Regulating Hypothalamic-Pituitary-Adrenal Axis Hyperactivity
Authors: Wang Yu , Han Jing , Zhu Jing , Zhang Mizhen , Ju Minda , Du Yueshan , Tian Zhanzhuang
Published: November 2021

Graphical Abstract

Surgery induced HPA axis hyperactivity, while EA intervention inhibited the activation of hypothalamic GluN2A/ERK/CREB signaling pathway, thereby reducing the synthesis and secretion of CRH, alleviating the hyperactivity of the HPA axis after surgery.
Photobiomodulation Promotes Repair Following Spinal Cord Injury by Regulating the Transformation of A1/A2 Reactive Astrocytes
Authors: Wang Xuankang , Zhang Zhihao , Zhu Zhijie , Liang Zhuowen , Zuo Xiaoshuang , Ju Cheng , Song Zhiwen , Li Xin , Hu Xueyu , Wang Zhe
Published: November 2021

After spinal cord injury (SCI), reactive astrocytes can be classified into two distinctive phenotypes according to their different functions: neurotoxic (A1) astrocytes and neuroprotective (A2) astrocytes. Our previous studies proved that photobiomodulation (PBM) can promote motor function recovery and improve tissue repair after SCI, but little is known about the underlying mechanism. Therefore, we aimed to investigate whether PBM contributes to repair after SCI by regulating the activation of astrocytes. Male rats subjected to clip-compression SCI were treated with PBM for two consecutive weeks, and the results showed that recovery of motor function was improved, the lesion cavity size was reduced, and the number of neurons retained was increased. We determined the time course of A1/A2 astrocyte activation after SCI by RNA sequencing (RNA-Seq) and verified that PBM inhibited A1 astrocyte activation and promoted A2 astrocyte activation at 7 days postinjury (dpi) and 14 dpi. Subsequently, potential signaling pathways related to A1/A2 astrocyte activation were identified by GO function analysis and KEGG pathway analysis and then studied in animal experiments and preliminarily analyzed in cultured astrocytes. Next, we observed that the expression of basic fibroblast growth factor (bFGF) and transforming growth factor-β (TGF-β) was upregulated by PBM and that both factors contributed to the transformation of A1/A2 astrocytes in a dose-dependent manner. Finally, we found that PBM reduced the neurotoxicity of A1 astrocytes to dorsal root ganglion (DRG) neurons. In conclusion, PBM can promote better recovery after SCI, which may be related to the transformation of A1/A2 reactive astrocytes.
Rodent Area Prostriata Converges Multimodal Hierarchical Inputs and Projects to the Structures Important for Visuomotor Behaviors
Authors: Chen Chang-Hui , Hu Jin-Meng , Zhang Shun-Yu , Xiang Xiao-Jun , Chen Sheng-Qiang , Ding Song-Lin
Published: November 2021

Area prostriata is a limbic structure critical to fast processing of moving stimuli in far peripheral visual field. Neural substrates underlying this function remain to be discovered. Using both retrograde and anterograde tracing methods, the present study reveals that the prostriata in rat and mouse receives inputs from multimodal hierarchical cortical areas such as primary, secondary, and association visual and auditory cortices and subcortical regions such as the anterior and midline thalamic nuclei and claustrum. Surprisingly, the prostriata also receives strong afferents directly from the rostral part of the dorsal lateral geniculate nucleus. This shortcut pathway probably serves as one of the shortest circuits for fast processing of the peripheral vision and unconscious blindsight since it bypasses the primary visual cortex. The outputs of the prostriata mainly target the presubiculum (including postsubiculum), pulvinar, ventral lateral geniculate nucleus, lateral dorsal thalamic nucleus, and zona incerta as well as the pontine and pretectal nuclei, most of which are heavily involved in subcortical visuomotor functions. Taken together, these results suggest that the prostriata is poised to quickly receive and analyze peripheral visual and other related information and timely initiates and modulates adaptive visuomotor behaviors, particularly in response to unexpected quickly looming threats.
Re-Irradiation With Stereotactic Body Radiotherapy for In-Field Recurrence of Pancreatic Cancer After Prior Stereotactic Body Radiotherapy: Analysis of 24 Consecutive Cases
Authors: Shen Yuxin , Zhu Xiaofei , Cao Fei , Xie Hongliang , Ju Xiaoping , Cao Yangsen , Qing Shuiwang , Jia Zhen , Gu Lei , Fang Fang , Zhang Huojun
Published: November 2021

Purpose/Objectives

Locally recurrent pancreatic cancer is a therapeutic challenge, and aggressive approaches are needed to improve its clinical outcomes. Stereotactic body radiotherapy (SBRT) is a promising treatment for pancreatic cancer with an excellent local control and acceptable toxicity. However, the safety and efficacy of SBRT for in-field recurrence after initial SBRT remain unknown. The aim of the study was to investigate the feasibility of re-irradiation with SBRT for locally recurrent pancreatic cancer after prior definitive SBRT.

Material/Methods

Twenty-four consecutive patients with pancreatic cancer received two courses of SBRT in our center between January 2014 and December 2016. The median prescription dose of the initial and second courses of SBRT was 35.5 Gy/5–7f and 32 Gy/5–8f, respectively. Clinical outcomes including overall survival (OS), disease control, and toxicity were evaluated after treatment.

Results

The median interval between two courses of SBRT was 13 months (range: 6–29 months). From the first SBRT, the median OS of 18 patients with limited diseases was 26 months (95% CI: 19.1–32.95 months). The median OS of 12 patients without metastasis was 14 months (95% CI: 10.6–17.4 months) from re-irradiation of SBRT. The overall response rate and disease control rate were 50% and 13%, and 100% and 86.9% after each SBRT, respectively. Carbohydrate antigen 19-9 (CA19-9) levels declined dramatically after re-irradiation within 1 month (p = 0.002) and 3 months (p = 0.028). Twelve (75%) out of 16 patients had pain relief after re-irradiation. None of the patients experienced gastrointestinal toxicity.

Conclusions

Re-irradiation with SBRT can provide favorable outcomes and effective analgesia with mild toxicity after prior SBRT for in-field recurrent pancreatic cancer, which might be feasible for locally relapsed pancreatic cancer.
Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress
Authors: Okuda Keiichiro , Umemura Atsushi , Kataoka Seita , Yano Kota , Takahashi Aya , Okishio Shinya , Taketani Hiroyoshi , Seko Yuya , Nishikawa Taichiro , Yamaguchi Kanji , Moriguchi Michihisa , Nakagawa Hayato , Liu Yu , Mitsumoto Yasuhide , Kanbara Yoshihiro , Shima Toshihide , Okanoue Takeshi , Itoh Yoshito
Published: November 2021

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.
Integrin-β6 Serves as a Potential Prognostic Serum Biomarker for Gastric Cancer
Authors: Li Zequn , Sun Yuqi , Xu Jianfei , Yang Hao , Liu Xiaodong , Tian Yulong , Cao Shougen , Zhou Yanbing
Published: November 2021

Discovering novel biomarkers that easily accessed is a key step towards the personalized medicine approach for gastric cancer patients. Integrin-β6 (ITGB6) is a subtype of integrin that is exclusively expressed on the surface of epithelial cells and is up-regulated in various tumors. In the present study, a retrospective cohort with 135 gastric cancer patients and a prospective cohort with 34 gastric cancer patients were constructed, ITGB6 expression were detected in both the serum specimens and the tissue specimens. Detailed clinicopathological parameters as well as patients’ survival were recorded. A nomogram including ITGB6 expression was also constructed and validated to predict the prognosis of gastric cancer patients. Results showed that serum ITGB6 expression was obviously increased and associated with tumor stage in gastric cancer patients, serum ITGB6 expression was relatively high in patients with liver metastasis. High ITGB6 expression indicated a poor prognosis, and nomogram including serum ITGB6 expression could predict the prognosis of gastric cancer patients effectively. Moreover, serum ITGB6 expression was associated with ITGB6 expression in tumor tissues. Furthermore, combined serum ITGB6 and CEA levels contributed to the risk stratification and prognostic prediction for gastric cancer patients. In addition, the serum expression of ITGB6 decreased significantly after radical surgery, and a new rise in serum ITGB6 expression indicated tumor recurrence or progression. The present study identified a novel serum biomarker for the risk stratification, prognostic prediction and surveillance of gastric cancer patients.
Acupuncture Synergized With Bortezomib Improves Survival of Multiple Myeloma Mice via Decreasing Metabolic Ornithine
Authors: Ke Mengying , Qian Jinjun , Hao Feng , Li Xinying , Wu Hongjie , Luo Xian , Xu Bin , Gu Chunyan , Yang Ye
Published: November 2021

Multiple myeloma (MM) is a hematological malignancy worldwide in urgent need for novel therapeutic strategies. Since Velcade (bortezomib) was approved for the treatment of relapsed/refractory MM in 2003, we have seen considerable improvement in extending MM patient survival. However, most patients are fraught with high recurrence rate and incurability. Acupuncture is known for alleviating patient symptoms and improving the quality of life, but it is not well investigated in MM, especially in combination with bortezomib. In this study, we employed LC-MS and UHPLC-MS together with bioinformatics methods to test serum samples from 5TMM3VT MM murine model mice with four different treatments [control (C) group, bortezomib (V) treatment group, acupuncture (A) group, and combined (VA) group]. MM mice in group VA had longer survival time than mice in group A or group V. Joint pathway analysis indicated the underlying arginine and proline metabolism pathway among the 32 significantly decreased metabolites in group VA. CCK-8 assay and in vivo experiments validated that ornithine, the metabolite of arginine, promoted MM cell proliferation. In addition, gene expression omnibus (GEO) database analysis suggested that MM patients with higher ornithine decarboxylase 1 (ODC1) expression were evidently associated with poor overall survival. In summary, this study demonstrates the synergistic effects of acupuncture and bortezomib on extending the survival of MM model mice and provides potential therapeutic targets in the treatment of MM.
Development and Validation of a Nomogram for Preoperative Prediction of Localization of Neonatal Gastrointestinal Perforation
Authors: Huang Yao , Wu Yuhua , Jin Dongmei , Tang Qing , Yuan Peng , Lu Qi
Published: November 2021

Background: Information regarding the localization of gastrointestinal perforation is crucial for the following surgical procedure. This study was to determine the key indicators and develop a prediction model for the localization in neonates with gastrointestinal perforation.

Methods: A nomogram to predict the location of neonatal gastrointestinal perforation was developed using a cohort of patients who underwent surgery between July 2009 and May 2021. Baseline variables were analyzed using logistics regression and nomogram developed using significant predictors. The predictive performance of the nomogram was assessed by the concordance index (C-index), calibration curve, and area under the receiver operating characteristic (ROC) curve (AUC). The nomogram was further validated in an integrated external cohort.

Results: We investigated the data of 201 patients, of which 65 (32.3%) were confirmed with upper gastrointestinal perforation by surgery. Multivariate logistic regression analysis identified the following as independent predictors: preterm [OR: 5.014 (1.492–18.922)], time of onset [OR: 0.705 (0.582–0.829)], preoperative hemoglobin [OR:1.017 (1.001–1.033)], bloody stool: No [OR: 4.860 (1.270–23.588)], shock [OR: 5.790 (1.683–22.455)] and sepsis: No [OR 3.044 (1.124–8.581)]. Furthermore, the nomogram was effective in predicting the perforation site, with an AUC of 0.876 [95% confidence interval (CI): 0.830–0.923]. Internal validation showed that the average AUC was 0.861. Additionally, the model achieved satisfactory discrimination (AUC, 0.900; 95% CI, 0.826–0.974) and calibration (Hosmer-Lemeshow test, P = 0.4802) in external validation.

Conclusions: The nomogram based on the six factors revealed good discrimination and calibration, suggesting good clinical utility. The nomogram could help surgeons predict the location of gastrointestinal perforation before surgery to make a surgical plan.
Therapeutic Effects of Melatonin on Ocular Diseases: Knowledge Map and Perspective
Authors: Yu Haozhe , Wang Qicong , Wu Wenyu , Zeng Weizhen , Feng Yun
Published: November 2021

Melatonin plays a critical role in the pathophysiological process including circadian rhythm, apoptosis, and oxidative stress. It can be synthesized in ocular tissues, and its receptors are also found in the eye, triggering more investigations concentrated on the role of melatonin in the eye. In the past decades, the protective and therapeutic potentials of melatonin for ocular diseases have been widely revealed in animal models. Herein, we construct a knowledge map of melatonin in treating ocular diseases through bibliometric analysis and review its current understanding and clinical evidence. The overall field could be divided into twelve topics through keywords co-occurrence analysis, in which the glaucoma, myopia, and retinal diseases were of greatest research interests according to the keywords burst detection. The existing clinical trials of melatonin in ocular diseases mainly focused on the glaucoma, and more research should be promoted, especially for various diseases and drug administration. We also discuss its bioavailability and further research topics including developing melatonin sensors for personalized medication, acting as stem cell therapy assistant drug, and consuming food-derived melatonin for facilitating its clinical transformation.
Cost-Effectiveness of Domestic PD-1 Inhibitor Camrelizumab Combined With Chemotherapy in the First-Line Treatment of Advanced Nonsquamous Non–Small-Cell Lung Cancer in China
Authors: Qiao Liu , Zhou Zhen , Zeng Xiaohui , Tan Chongqing
Published: November 2021

Objective: Camrelizumab is the first domestic PD-1inhibitor approved to be combined with chemotherapy as a first-line therapy for advanced nonsquamous non–small-cell lung cancer (NSCLC) in China. The purpose of this study was to determine whether using camrelizumab in the first-line setting is cost-effective in China when compared with traditional chemotherapy or the imported PD-1inhibitor pembrolizumab.

Material and Methods: A Markov model was built to simulate 3-week patient transitions over a 30-year horizon from the perspective of the Chinese healthcare system. Health states included stable disease, first progression, second progression, and death. A direct comparison between first-line camrelizumab in combination with pemetrexed and carboplatin (CPC) and pemetrexed plus carboplatin (PC) was performed by calculating transition probabilities from the CameL trial. An indirect comparison between first-line CPC and pembrolizumab in combination with pemetrexed and platinum (PPP) was performed by calculating transition probabilities using a network meta-analysis. Costs in the Chinese setting were collected from the local public database and literatures. Sensitivity analyses explored the uncertainty around model parameters.

Results: In the primary analysis, first-line CPC gained an additional 0.41 quality-adjusted life-years (QALYs) with an incremental cost of $3,486 compared with PC, resulting in an incremental cost-effectiveness ratio (ICER) of $8,378 per QALY gained. In the secondary analysis, first-line PPP yielded an additional 0.10 QALYs at an incremental cost of $6,710, resulting in an ICER of $65,563 per QALY gained.

Conclusion: For Chinese patients with advanced nonsquamous NSCLC without targetable genetic aberrations, our primary analysis results supported first-line CPC as a cost-effective treatment compared with traditional PC chemotherapy. The findings of our secondary analysis suggested that first-line PPP would not be a cost-effective option compared with first-line CPC. This analysis provided strong evidence for promoting the widespread use of first-line CPC in China and, to some extent, stimulated the enthusiasm for the development of domestic cancer drugs.
The Adroitness of Andrographolide as a Natural Weapon Against Colorectal Cancer
Authors: Paul Silpita , Roy Dia , Pati Subhadip , Sa Gaurisankar
Published: November 2021

The conventional carcinoma treatment generally encompasses the employment of radiotherapy, chemotherapy, surgery or use of cytotoxic drugs. However, recent advances in pharmacological research have divulged the importance of traditional treatments in cancer. The aim of the present review is to provide an overview of the importance of one such medicinal herb of Chinese and Indian origin: Andrographis paniculate on colorectal cancer with special emphasis on its principal bioactive component andrographolide (AGP) and its underlying mechanisms of action. AGP has long been known to possess medicinal properties. Studies led by numerous groups of researchers shed light on its molecular mechanism of action. AGP has been shown to act in a multi-faceted manner in context of colorectal cancer by targeting matrix metalloproteinase-9, Toll-like receptor or NFκB signaling pathways. In this review, we highlighted the recent studies that show that AGP can act as an effective immunomodulator by harnessing effective anti-tumor immune response. Recent studies strongly recommend further research on this compound and its analogues, especially under in-vivo condition to assess its actual potential as a prospective and efficient candidate against colorectal cancer. The current review deals with the roles of this phytomedicine in context of colorectal cancer and briefly describes its perspectives to emerge as an essential anti-cancer drug candidate. Finally, we also point out the drawbacks and difficulties in administration of AGP and indicate the use of nano-formulations of this phytomedicine for better therapeutic efficacy.
Duhaldea pterocaula (Franch.) Anderb. Attenuates Nociception and Inflammation via GABAA Receptors
Authors: Huang Chunli , Dong Changsheng , Zhu Yanan , Yu Yang , Jin Huizi , Zhang Yan
Published: November 2021

Duhaldea pterocaula (Franch.) Anderb, also known as Inula pterocaula Franch (I. pterocaula), is a folk medicine of the Yi nationality in China. The Inula plants display various biological activities, including anti-nociceptive and anti-inflammatory properties. I. pterocaula has been traditionally used for the treatment of bronchitis, vasculitis, and dizziness. However, very few studies have been reported on the pharmacology of I. pterocaula. The present study aims to characterize the anti-nociceptive and anti-inflammatory properties of I. pterocaula and explore the underlying mechanism. I. pterocaula was extracted by 95% ethanol and further portioned with petroleum ether, ethyl acetate (EA) and n-butanol, sequentially, to obtain corresponding factions with different polarities. The EA fraction (IPEA) was found to be one of the most effective fractions. It demonstrated potent analgesic effects in both acute and inflammatory pain mouse models, and caused no anti-nociceptive tolerance. Furthermore, IPEA improved the tolerance of mice to morphine. IPEA also showed potent anti-inflammatory effects on LPS-induced septic mice. BIC, a GABAAR antagonist, reversed the effects of IPEA in pain and inflammation models. Collectively, GABAARs play a key role in the pharmacological effects of IPEA. I. pterocaula may be useful as a complementary or alternative therapeutic agent for the treatment of pain and inflammation.
Monoclonal Antibodies Targeting IL-5 or IL-5Rα in Eosinophilic Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis
Authors: Zhang Chuchu , Wang Yalei , Zhang Meng , Su Xiaojie , Lei Ting , Yu Haichuan , Liu Jian
Published: November 2021

Background: Although the predominant airway inflammation in chronic obstructive pulmonary disease (COPD) is neutrophilic, approximately 20–40% of COPD patients present with eosinophilic airway inflammation. Compared with non-eosinophilic COPD patients, eosinophilic COPD patients are characterized by a greater number of total exacerbations and higher hospitalization rates. Furthermore, anti-interleukin-5 (IL-5) therapy, consisting of monoclonal antibodies (mAbs) targeting IL-5 or IL-5 receptor α (IL-5Rα), has been proven to be effective in severe eosinophilic asthma. This meta-analysis aimed to determine the efficacy and safety of anti-IL-5 therapy in eosinophilic COPD.

Methods: We searched the PubMed, Web of Science, Embase, and Cochrane Library databases from inception to August 2020 (updated in June 2021) to identify studies comparing anti-IL-5 therapy (including mepolizumab, benralizumab, and reslizumab) with placebo in eosinophilic COPD patients.

Results: Anti-IL-5 therapy was associated with a decrease in acute exacerbation rate (RR 0.89; 95% CI 0.84 to 0.95, I2 = 0%) and the severe adverse events (RR 0.90; 95% CI 0.84 to 0.97, I2 = 0%). However, no significant improvement was observed in pre-bronchodilator forced expiratory volume in 1 s (FEV1) (WMD 0.01; 95% CI −0.01 to 0.03, I2 = 25.9%), SGRQ score (WMD −1.17; 95% CI −2.05 to −0.29, I2 = 0%), and hospital admission rate (RR 0.91; 95% CI 0.78 to 1.07, I2 = 20.8%).

Conclusion: Anti-IL-5 therapy significantly reduced the annual acute exacerbation rate and severe adverse events in eosinophilic COPD patients. However, it did not improve lung function, quality of life, and hospitalization rate.
Therapeutic Drug Monitoring and Pharmacogenetic Testing in Northern China
Authors: Zhang Chunyan , Lei Jing , Liu Yi , Wang Yu , Huang Lin , Feng Yufei
Published: November 2021

Background: Therapeutic drug monitoring (TDM) and pharmacogenetic (PGx) testing are widely used as approaches to improve individualized (personalized) pharmacotherapy. Little is known about TDM and PGx testing services in China. This study is aimed to describe the TDM and PGx testing services in northern China, and to lay the foundation for improving these services.

Methods: We developed an electronic survey using online software and disseminated it to 32 public hospitals in northern China from May to July 2019. The data were analyzed using the Statistical Package for Social Sciences (SPSS) program (Ver.27.0).

Results: We collected 29 of the 32 questionnaires (90.6% response rate) from public hospitals in seven provinces of northern China. Twenty-two public hospitals (76%) utilized TDM; immune suppressants, antiepileptic drugs and anti-infective drugs were the main drugs monitored. The hospitals that did not provide TDM service were traditional Chinese medicine hospitals and hospitals with a smaller number of hospital beds. Seventeen public hospitals (58.6%) had PGx testing programs. The hospitals that did not offer PGx testing service had a smaller number of hospital beds and had fewer daily outpatients.

Conclusion: TDM is available in the vast majority of public hospitals in northern China, although mainly in tertiary hospitals. PGx testing, a newer approach, is less widely available. We recommend that more hospitals be encouraged to provide TDM and PGx testing services and more efforts be directed toward quality control, delivery of results and counseling of patients based on those results.
Quantification of Chlorogenic Acid and Vanillin from Coffee Peel Extract and its Effect on α-Amylase Activity, Immunoregulation, Mitochondrial Oxidative Stress, and Tumor Suppressor Gene Expression Levels in H2O2-Induced Human Mesenchymal Stem Cells
Authors: Khalil Alyahya Heba , Subash-Babu Pandurangan , Mohammad Salamatullah Ahmad , Hayat Khizar , Albader Nawal , Alkaltham Mohammed Saeed , Ahmed Mohammed Asif , Arzoo Shaista , Bourhia Mohammed
Published: November 2021

Background: Polyphenols and flavonoid-rich foods help in arresting reactive oxygen species development and protecting DNA from oxidative damage. Coffee peel (CP) preparations are consumed as beverages, and their total polyphenol or flavonoid content and their effect on oxidative stress–induced human mesenchymal stem cells (hMSCs) are poorly understood.

Method: We prepared hot water extracts of CP (CPE) and quantified the amount of total polyphenol and flavonoid using HPLC analysis. In addition, CPE have been studied for their α-amylase inhibitory effect and beneficial effects in oxidative stress–induced hMSCs.

Results: The obtained results show that the availability of chlorogenic acid, vanillin, and salicylic acid levels in CPE is more favorable for enhancing cell growth, nuclear integrity, and mitochondrial efficiency which is confirmed by propidium iodide staining and JC-1 staining. CPE treatment to hMSCs for 48 h reduced oxidative stress by decreasing mRNA expression levels of LPO and NOX-4 and in increasing antioxidant CYP1A, GSH, GSK-3β, and GPX mRNA expressions. Decreased pro-inflammatory (TNF-α, NF-κβ, IL-1β, TLR-4) and increased tumor suppressor genes (except Bcl-2) such as Cdkn2A, p53 expressions have been observed.

Conclusions: The availability of CGA in CPs effectively reduced mitochondrial oxidative stress, reduced pro-inflammatory cytokines, and increased tumor suppressor genes.
Real-World Data of Tigecycline-Associated Drug-Induced Liver Injury Among Patients in China: A 3-year Retrospective Study as Assessed by the Updated RUCAM
Authors: Shi Xiaoping , Zuo Chengchun , Yu Lingling , Lao Donghui , Li Xiaoyu , Xu Qing , Lv Qianzhou
Published: November 2021

Background: Tigecycline, a glycylcycline antibiotic, is increasingly used clinically for the treatment of severe infections caused by multidrug-resistant bacteria, but it is also associated with hepatotoxicity. However, the incidence and risk factors of tigecycline-associated drug-induced liver injury (DILI) are unclear. We conducted this study to investigate the incidence, characteristics and risk factors of tigecycline-associated DILI in the real-world clinic setting.

Patients and Methods: A retrospective analysis was conducted in inpatients who received tigecycline treatment from January 2018 to January 2020. Based on the biochemical criteria of DILI and the causality assessment by Roussel Uclaf Causality Assessment Method (RUCAM) using cases with a probable or highly probable causality grading, two clinical pharmacists and one clinician worked together to screen patients for tigecycline-associated DILI. Then patients with DILI were randomly matched by gender in a ratio of 1:2 to the remaining patients in the tigecycline cohort without biochemical abnormalities to identify risk factors.

Results: A total of 973 patients from 1,250 initial participants were included. The incidence of tigecycline-associated DILI was 5.7% (55/973). Among 55 DILI patients, 10 cases presented with the hepatocellular pattern, 4 cases belonged to the mixed pattern, and 41 presented with the cholestatic pattern. Most cases reached the severity of grade 1 and 2. The rate of recovery in hepatocellular pattern, mixed pattern, and cholestatic pattern was 70.0, 50.0, and 41.5%, respectively. The proportion of the DILI cases treated with high dose (100 mg) and prolonged duration (>14 days) was significantly higher than standard dose and routine duration (100.0% vs. 18.1%, p < 0.05). Logistic regression analysis showed that high maintenance dose (OR = 1.028, p = 0.002), prolonged duration (OR = 1.208, p = 0.000), and number of hepatotoxic drugs (OR = 2.232, p = 0.000) were independent factors of tigecycline-associated DILI.

Conclusion: Tigecycline was associated with liver injury, with a slightly higher incidence (5.7%) than the frequency of “frequent” (5%) defined by the Medical Dictionary for Regulatory Activities. Patients with a high maintenance dose and prolonged tigecycline regimen, as well as concomitant use of multiple hepatotoxic drugs should be paid more attention.
Transcription Factor Control of Lymphatic Quiescence and Maturation of Lymphatic Neovessels in Development and Physiology
Authors: Tabrizi Zarah B. , Ahmed Nada S. , Horder Joseph L. , Storr Sarah J. , Benest Andrew V.
Published: November 2021

The lymphatic system is a vascular system comprising modified lymphatic endothelial cells, lymph nodes and other lymphoid organs. The system has diverse, but critical functions in both physiology and pathology, and forms an interface between the blood vascular and immune system. It is increasingly evident that remodelling of the lymphatic system occurs alongside remodelling of the blood microvascular system, which is now considered a hallmark of most pathological conditions as well as being critical for normal development. Much attention has focussed on how the blood endothelium undergoes phenotypic switching in development and disease, resulting in over two decades of research to probe the mechanisms underlying the resulting heterogeneity. The lymphatic system has received less attention, and consequently there are fewer descriptions of functional and molecular heterogeneity, but differential transcription factor activity is likely an important control mechanism. Here we introduce and discuss significant transcription factors of relevance to coordinating cellular responses during lymphatic remodelling as the lymphatic endothelium dynamically changes from quiescence to actively remodelling.
The Effects of Exercise on White and Brown Adipose Tissue Cellularity, Metabolic Activity and Remodeling
Authors: Garritson Jacob D. , Boudina Sihem
Published: November 2021

Emerging evidence suggests a significant functional role of adipose tissue in maintaining whole-body metabolic health. It is well established that obesity leads to compositional and morphological changes in adipose tissue that can contribute to the development of cardiometabolic disorders. Thus, the function and size of adipocytes as well as perfusion and inflammation can significantly impact health outcomes independent of body mass index. Lifestyle interventions such as exercise can improve metabolic homeostasis and reduce the risk for developing cardiometabolic disorders. Adipose tissue displays remarkable plasticity in response to external stimuli such as dietary intervention and exercise. Here we review systemic and local effects of exercise that modulate white and brown adipose tissue cellularity, metabolic function and remodeling in humans and animals.
Local Victory: Assessing Interspecific Competition in Seagrass From a Trait-Based Perspective
Authors: Moreira-Saporiti Agustín , Bejarano Sonia , Viana Inés G. , Belshe Elizabeth Fay , Mtolera Matern S. P. , Teichberg Mirta
Published: November 2021

Tropical seagrass meadows are formed by an array of seagrass species that share the same space. Species sharing the same plot are competing for resources, namely light and inorganic nutrients, which results in the capacity of some species to preempt space from others. However, the drivers behind seagrass species competition are not completely understood. In this work, we studied the competitive interactions among tropical seagrass species of Unguja Island (Zanzibar, Tanzania) using a trait-based approach. We quantified the abundance of eight seagrass species under different trophic states, and selected nine traits related to light and inorganic nutrient preemption to characterize the functional strategy of the species (leaf maximum length and width, leaves per shoot, leaf mass area, vertical rhizome length, shoots per meter of ramet, rhizome diameter, roots per meter of ramet, and root maximum length). From the seagrass abundance we calculated the probability of space preemption between pairs of seagrass species and for each individual seagrass species under the different trophic states. Species had different probabilities of space preemption, with the climax species Thalassodendron ciliatum, Enhalus acoroides, Thalassia hemprichii, and the opportunistic Cymodocea serrulata having the highest probability of preemption, while the pioneer and opportunistic species Halophila ovalis, Syringodium isoetifolium, Halodule uninervis, and Cymodocea rotundata had the lowest. Traits determining the functional strategy showed that there was a size gradient across species. For two co-occurring seagrass species, probability of preemption was the highest for the larger species, it increased as the size difference between species increased and was unaffected by the trophic state. Competitive interactions among seagrass species were asymmetrical, i.e., negative effects were not reciprocal, and the driver behind space preemption was determined by plant size. Seagrass space preemption is a consequence of resource competition, and the probability of a species to exert preemption can be calculated using a trait-based approach.