bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery and Characterization of the Naturally Occurring Inhibitors Against Human Pancreatic Lipase in Ampelopsis grossedentata
Authors: Qin Xiao-Ya , Hou Xu-Dong , Zhu Guang-Hao , Xiong Yuan , Song Yun-Qing , Zhu Liang , Zhao Dong-Fang , Jia Shou-Ning , Hou Jie , Tang Hui , Ge Guang-Bo
Published: February 2022

Pancreatic lipase (PL) inhibitor therapy has been validated as an efficacious way for preventing and treating obesity and overweight. In the past few decades, porcine PL (pPL) is widely used as the enzyme source for screening the PL inhibitors, which generates a wide range of pPL inhibitors. By contrast, the efficacious inhibitors against human PL (hPL) are rarely reported. This study aims to discover the naturally occurring hPL inhibitors from edible herbal medicines (HMs) and to characterize the inhibitory mechanisms of the newly identified hPL inhibitors. Following the screening of the inhibition potentials of more than 100 HMs against hPL, Ampelopsis grossedentata extract (AGE) displayed the most potent hPL inhibition activity. After that, the major constituents in AGE were identified and purified, while their anti-hPL effects were assayed in vitro. The results clearly showed that two abundant constituents in AGE (dihydromyricetin and iso-dihydromyricetin) were moderate hPL inhibitors, while myricetin and quercetin were strong hPL inhibitors [half-maximal inhibitory concentration (IC50) values were around 1.5 μM]. Inhibition kinetic analyses demonstrated that myricetin and quercetin potently inhibited hPL-catalyzed near-infrared fluorogenic substrate of human pancreatic lipase (DDAO-ol) hydrolysis in a non-competitive inhibition manner, with Ki values of 2.04 and 2.33 μM, respectively. Molecular dynamics simulations indicated that myricetin and quercetin could stably bind on an allosteric site of hPL. Collectively, this study reveals the key anti-obesity constituents in AGE and elucidates their inhibitory mechanisms against hPL, which offers convincing evidence to support the anti-obesity and lipid-lowering effects of this edible herb.
Biomarker Testing Patterns and Treatment Outcomes in Patients With Advanced Non-Small Cell Lung Cancer and MET Exon 14 Skipping Mutations: A Descriptive Analysis From the US
Authors: Asad Zadeh Vosta Kolaei Fatemeh , Cai Beilei , Kanakamedala Hemanth , Kim Julia , Doban Vitalii , Zhang Shiyu , Shi Michael
Published: February 2022

Background

MET exon 14 skipping mutation (METex14) is observed in ~3% of non-small cell lung cancer (NSCLC) cases and has been shown to be an independent poor prognostic factor associated with shorter overall disease-specific survival. Broad molecular testing can identify this biomarker in patients with advanced NSCLC (aNSCLC) and allow patients to be matched with the appropriate targeted therapy. This study examines biomarker testing patterns and clinical outcomes of chemotherapy and immuno-oncology (IO) monotherapy in aNSCLC patients with METex14.

Methods

A descriptive retrospective study was conducted using the Flatiron Health–Foundation Medicine Inc. (FMI) clinico-genomic database. Patients with METex14 aNSCLC treated with systemic therapies were included in the biomarker testing analysis. The duration from specimen collection to reported results was assessed for PD-L1– and METex14-tested patients. Clinical outcomes were assessed in patients treated with chemotherapy or IO monotherapy. First-line (1L) and second-line (2L) real-world progression-free survival (rw-PFS) were estimated using Kaplan-Meier analysis.

Results

Of 91 METex14 patients eligible for the biomarker testing analysis, 77% and 60% received PD-L1 and FMI next-generation sequencing (NGS) testing within 3 months post aNSCLC diagnosis. Of those assessed for both PD-L1 and METex14 (n=9), the median duration between specimen collection and reporting was 1 week shorter for PD-L1 than for FMI NGS. Median 1L rw-PFS was 5.7 months (95% CI, 4.6-7.1) and 2.4 months (95% CI, 1.4-3.2) in patients receiving 1L chemotherapy (n=59) and IO monotherapy (n=18), with 3-month 1L rw-PFS rates of 78% and 33%. Median 2L rw-PFS was 3.5 months (95% CI, 1.9-11.1) and 4.7 months (95% CI, 2.8-12.9) in patients receiving 2L chemotherapy (n=16) and IO monotherapy (n=23), with 3-month 2L rw-PFS rates of 54% and 67%.

Conclusions

The median time from biopsy to test results appears 1 week shorter for PD-L1 than for FMI NGS. Chemotherapy and IO monotherapy were the most common regimens utilized but with limited PFS.
Evaluation of the Response of HNSCC Cell Lines to γ-Rays and 12C Ions: Can Radioresistant Tumors Be Identified and Selected for 12C Ion Radiotherapy?
Authors: Ding Lianghao , Sishc Brock J. , Polsdofer Elizabeth , Yordy John S. , Facoetti Angelica , Ciocca Mario , Saha Debabrata , Pompos Arnold , Davis Anthony J. , Story Michael D.
Published: February 2022

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Thirty percent of patients will experience locoregional recurrence for which median survival is less than 1 year. Factors contributing to treatment failure include inherent resistance to X-rays and chemotherapy, hypoxia, epithelial to mesenchymal transition, and immune suppression. The unique properties of 12C radiotherapy including enhanced cell killing, a decreased oxygen enhancement ratio, generation of complex DNA damage, and the potential to overcome immune suppression make its application well suited to the treatment of HNSCC. We examined the 12C radioresponse of five HNSCC cell lines, whose surviving fraction at 3.5 Gy ranged from average to resistant when compared with a larger panel of 38 cell lines to determine if 12C irradiation can overcome X-ray radioresistance and to identify biomarkers predictive of 12C radioresponse. Cells were irradiated with 12C using a SOBP with an average LET of 80 keV/μm (CNAO: Pavia, Italy). RBE values varied depending upon endpoint used. A 37 gene signature was able to place cells in their respective radiosensitivity cohort with an accuracy of 86%. Radioresistant cells were characterized by an enrichment of genes associated with radioresistance and survival mechanisms including but not limited to G2/M Checkpoint MTORC1, HIF1α, and PI3K/AKT/MTOR signaling. These data were used in conjunction with an in silico-based modeling approach to evaluate tumor control probability after 12C irradiation that compared clinically used treatment schedules with fixed RBE values vs. the RBEs determined for each cell line. Based on the above analysis, we present the framework of a strategy to utilize biological markers to predict which HNSCC patients would benefit the most from 12C radiotherapy.
Evaluation of Multisource Adaptive MRI Fusion for Gross Tumor Volume Delineation of Hepatocellular Carcinoma
Authors: Cheung Andy Lai-Yin , Zhang Lei , Liu Chenyang , Li Tian , Cheung Anson Ho-Yin , Leung Chun , Leung Angus Kwong-Chuen , Lam Sai-Kit , Lee Victor Ho-Fun , Cai Jing
Published: February 2022

Purpose

Tumor delineation plays a critical role in radiotherapy for hepatocellular carcinoma (HCC) patients. The incorporation of MRI might improve the ability to correctly identify tumor boundaries and delineation consistency. In this study, we evaluated a novel Multisource Adaptive MRI Fusion (MAMF) method in HCC patients for tumor delineation.

Methods

Ten patients with HCC were included in this study retrospectively. Contrast-enhanced T1-weighted MRI at portal-venous phase (T1WPP), contrast-enhanced T1-weighted MRI at 19-min delayed phase (T1WDP), T2-weighted (T2W), and diffusion-weighted MRI (DWI) were acquired on a 3T MRI scanner and imported to in-house-developed MAMF software to generate synthetic MR fusion images. The original multi-contrast MR image sets were registered to planning CT by deformable image registration (DIR) using MIM. Four observers independently delineated gross tumor volumes (GTVs) on the planning CT, four original MR image sets, and the fused MRI for all patients. Tumor contrast-to-noise ratio (CNR) and Dice similarity coefficient (DSC) of the GTVs between each observer and a reference observer were measured on the six image sets. Inter-observer and inter-patient mean, SD, and coefficient of variation (CV) of the DSC were evaluated.

Results

Fused MRI showed the highest tumor CNR compared to planning CT and original MR sets in the ten patients. The mean ± SD tumor CNR was 0.72 ± 0.73, 3.66 ± 2.96, 4.13 ± 3.98, 4.10 ± 3.17, 5.25 ± 2.44, and 9.82 ± 4.19 for CT, T1WPP, T2W, DWI, T1WDP, and fused MRI, respectively. Fused MRI has the minimum inter-observer and inter-patient variations as compared to original MR sets and planning CT sets. GTV delineation inter-observer mean DSC across the ten patients was 0.81 ± 0.09, 0.85 ± 0.08, 0.88 ± 0.04, 0.89 ± 0.08, 0.90 ± 0.04, and 0.95 ± 0.02 for planning CT, T1WPP, T2W, DWI, T1WDP, and fused MRI, respectively. The patient mean inter-observer CV of DSC was 3.3%, 3.2%, 1.7%, 2.6%, 1.5%, and 0.9% for planning CT, T1WPP, T2W, DWI, T1WDP, and fused MRI, respectively.

Conclusion

The results demonstrated that the fused MRI generated using the MAMF method can enhance tumor CNR and improve inter-observer consistency of GTV delineation in HCC as compared to planning CT and four commonly used MR image sets (T1WPP, T1WDP, T2W, and DWI). The MAMF method holds great promise in MRI applications in HCC radiotherapy treatment planning.
HAUS5 Is A Potential Prognostic Biomarker With Functional Significance in Breast Cancer
Authors: Huang Zhijian , Yang Jiasheng , Qiu Wenjing , Huang Jing , Chen Zhirong , Han Yuanyuan , Ye Changsheng
Published: February 2022

Background

Breast cancer (BRCA) has become the most frequently appearing, lethal, and aggressive cancer with increasing morbidity and mortality. Previously, it was discovered that the HAUS5 protein is involved in centrosome integrity, spindle assembly, and the completion of the cytoplasmic division process during mitosis. By encouraging chromosome misdivision and aneuploidy, HAUS5 has the potential to cause cancer. The significance of HAUS5 in BRCA and the relationship between its expression and clinical outcomes or immune infiltration remains unclear.

Methods

Pan-cancer was analyzed by TIMER2 web and the expression differential of HAUS5 was discovered. The prognostic value of HAUS5 for BRCA was evaluated with KM plotter and confirmed with Gene Expression Omnibus (GEO) dataset. Following that, we looked at the relationship between the high and low expression groups of HAUS5 and breast cancer clinical indications. Signaling pathways linked to HAUS5 expression were discovered using Gene Set Enrichment Analysis (GSEA). The relative immune cell infiltrations of each sample were assessed using the CIBERSORT algorithm and ESTIMATE method. We evaluated the Tumor Mutation Burden (TMB) value between the two sets of samples with high and low HAUS5 expression, as well as the differences in gene mutations between the two groups. The proliferation changes of BRCA cells after knockdown of HAUS5 were evaluated by fluorescence cell counting and colony formation assay.

Result

HAUS5 is strongly expressed in most malignancies, and distinct associations exist between HAUS5 and prognosis in BRCA patients. Upregulated HAUS5 was associated with poor clinicopathological characteristics such as tumor T stage, ER, PR, and HER2 status. mitotic prometaphase, primary immunodeficiency, DNA replication, cell cycle related signaling pathways were all enriched in the presence of elevated HAUS5 expression, according to GSEA analysis. The BRCA microenvironment’s core gene, HAUS5, was shown to be related with invading immune cell subtypes and tumor cell stemness. TMB in the HAUS5-low expression group was significantly higher than that in the high expression group. The mutation frequency of 15 genes was substantially different in the high expression group compared to the low expression group. BRCA cells’ capacity to proliferate was decreased when HAUS5 was knocked down.

Conclusion

These findings show that HAUS5 is a positive regulator of BRCA progression that contributes to BRCA cells proliferation. As a result, HAUS5 might be a novel prognostic indicator and therapeutic target for BRCA patients.
Molecular Endoscopy for the Diagnosis and Therapeutic Monitoring of Colorectal Cancer
Authors: Waldner Maximilian J. , Neurath Markus F.
Published: February 2022

Colorectal cancer (CRC) is one of the leading causes of cancer related death in the western world. Its successful treatment requires early detection and removal of precursor lesions as well as individualized treatment of advanced disease. During recent years, molecular imaging techniques have shown promising results to improve current clinical practice. For instance, molecular endoscopy resulted in higher detection rates of precursors in comparison to conventional endoscopy in preclinical and clinical studies. Molecular confocal endomicroscopy allowed a further classification of suspect lesions as well as the prediction and monitoring of the therapeutic response. In this review, we summarize recent achievements for molecular imaging of CRC in preclinical studies, initial clinical trials and the remaining challenges for future translation into clinical practice.
Effects of Enteral Nutrition on Patients With Oesophageal Carcinoma Treated With Concurrent Chemoradiotherapy: A Prospective, Multicentre, Randomised, Controlled Study
Authors: Lyu Jiahua , Shi Anhui , Li Tao , Li Jie , Zhao Ren , Zhu Shuchai , Wang Jianhua , Xing Ligang , Yang Daoke , Xie Conghua , Shen Liangfang , Zhang Hailin , Zhu Guangying , Wang Jing , Pan Wenyan , Li Fang , Lang Jinyi , Shi Hanping
Published: February 2022

Background

The oesophageal carcinoma patients show high incidence of malnutrition, which negatively affects their therapy outcome. Moreover, benefits of enteral nutrition remain to be studied in details in these patients. Therefore, we set to assess the effects of enteral nutrition on the nutritional status, treatment toxicities and survival in the oesophageal carcinoma patients treated with concurrent chemoradiotherapy (CCRT).

Materials and Methods

Eligible patients were randomly assigned to either the experimental or control group. The patients in the experimental group were treated with a whole-course enteral nutrition management, while the control group were provided a unsystematic nutrition without setting intake goals for energy and protein. The primary endpoint was a change in body weight, while the secondary endpoints included nutrition-related haematological indicators, toxicities, completion rate of treatment and survival.

Results

A total of 222 patients were randomised to either the experimental (n=148) or control (n=74) group. Patients in the experimental group showed significantly less decrease in body weight, serum albumin and haemoglobin levels, a lower incidence rates of grade ≥3 myelosuppression and infection, and a higher completion rate of CCRT than those in the control group. While analyses of the 2 and 3 year overall survival (OS) and progression-free survival (PFS) did not reveal differences between these groups, we observed a significantly higher OS at 1 year (83.6% vs. 70.0%). In the subgroup analysis, patients with patient-generated subjective global assessment (PG-SGA)=C were likely to have better OS and PFS with enteral nutrition.

Conclusions

In EC patients treated with CCRT, enteral nutrition conferred positive effects on the nutritional status, treatment toxicities and prognosis, which mandate its inclusion in clinical practice.

Clinical Trial Registration

This prospective trial has been registered with www.clinicaltrials.gov as NCT02399306.
Clip or Tattooing: A Comparative Study for Preoperative Colon Cancer Endoscopic Localization
Authors: Zhang Shengyu , Wang Qiang , Feng Yunlu , Zhang Guannan , Chen Yang , Zheng Weiyang , Wu Xi , Yang Aiming
Published: February 2022

Background and Aim

Preoperative endoscopic markers have been extensively used for the localization of colonic neoplastic lesions in laparoscopic surgery. We conducted this respective cohort study to compare the localization accuracy of two commonly used endoscopic marker strategies (endoscopic clip plus abdominal plain film and endoscopic tattooing).

Methods

Patients who received preoperative colonoscopy localization for colonic neoplasia and underwent an elective laparoscopic operation afterward between 2013 and 2020 were included in this retrospective study. The localization accuracy of the two endoscopic strategies was compared, and the predictors of successful endoscopic localization were identified by multivariate regression.

Results

In total, 195 patients [average age 62.4 ± 9.2 years, 123 male (63.1%)] undergoing preoperative colonoscopy localization and subsequent laparoscopic colectomy for colonic neoplasms were included. Endoscopic localization was finally proven to be successful in 150 (76.9%) patients in the surgery. Compared to the tattooing group, patients who had successful localization for colonic lesions were fewer in the clip group (64 of 101 cases, 63.4% vs. 86 of 94 cases, 91.5%, p < 0.001). The multivariate regression analysis showed that the endoscopic tattooing strategy, endoscopic clip strategy, and lesion location were all predictors for successful localization (all with p < 0.001).

Conclusion

Compared with endoscopic clip plus abdominal plain film, endoscopic tattooing had higher localization accuracy and less intraoperative colonoscopy counseling; the endoscopic clip strategy, tattooing strategy, and colonic lesion location were all predictors of successful endoscopic localization.
Advances in Hodgkin Lymphoma: Including the Patient’s Voice
Authors: Smith Christine Moore , Friedman Debra L.
Published: February 2022

Since the initial treatment with radiation therapy in the 1950s, the treatment of Hodgkin lymphoma has continued to evolve, balancing cure and toxicity. This approach has resulted in low rates of relapse and death and fewer short and late toxicities from the treatments used in pursuit of cure. To achieve this balance, the field has continued to progress into an exciting era where the advent of more targeted therapies such as brentuximab vedotin, immunotherapies such as PD-1 inhibitors, and chimeric antigen receptor T-cells (CAR-T) targeted at CD30 are changing the landscape. As in the past, cooperative group and international collaborations are key to continuing to drive the science forward. Increased focus on patient-reported outcomes can further contribute to the goal of improved outcomes by examining the impact on the individual patient in the acute phase of therapy and on long-term implications for survivors. The goals of this review are to summarize recent and current clinical trials including reduction or elimination of radiation, immunotherapies and biologically-targeted agents, and discuss the use of patient-reported outcomes to help discern directions for new therapeutic regimens and more individualized evaluation of the balance of cure and toxicity.
Neonatal Impedance Cardiography in Asphyxiated Piglets—A Feasibility Study
Authors: Berisha Gazmend , Solberg Rønnaug , Klingenberg Claus , Solevåg Anne Lee
Published: February 2022

Objectives

Impedance cardiography (ICG) is a non-invasive method for continuous cardiac output measurement and has the potential to improve monitoring and treatment of sick neonates. PhysioFlow® is a signal-morphology ICG-system showing promising results in adults with low and high cardiac output, but no data from neonates or neonatal models exist. The aim of this study was to investigate PhysioFlow® feasibility in asphyxiated newborn piglets.

Methods

Fifteen piglets, under continuous arterial heart rate (HR) and blood pressure (BP) monitoring, were asphyxiated until asystole. Cardiopulmonary resuscitation was performed and the piglets monitored after return of spontaneous circulation (ROSC). Arterial lactate was measured at baseline, every 5 min throughout asphyxiation, at asystole, and at 10 min and later every 30 min after ROSC. PhysioFlow® measured cardiac stroke volume (SV) and HR, and calculated cardiac index (CI) (L/m2/min). Registrations with a signal quality < 75% were excluded, and registrations recorded for 30 min from start of asphyxia analyzed. Pearson correlations were calculated for CI; and HR, mean BP and blood lactate.

Results

The piglets were asphyxiated for median (interquartile range) 30 (20–35) min and had a lactate at asystole of 15.0 (9.1–17.0) mmol/L. Out of a total of 20.991 registrations in all animals combined, there were 10.148 (48.3%) registrations with a signal quality ≥ 75%. Signal quality ≥ 75% varied in individual piglets from 7 to 82% of registrations. We analyzed 1.254 registrations recorded 30 min from initiation of asphyxia, i.e., in piglets with brief asphyxia times, this included cardiopulmonary resuscitation and post-ROSC observation. There was a positive correlation between CI and SVI (r = 0.90, p < 0.001), and between CI and HR (r = 0.446, p < 0.001). There was no correlation between CI, or mean BP or lactate (p = 0.98 and 0.51, respectively).

Conclusion

About half of ICG-registrations in asphyxiated piglets were of good quality. However, signal quality was highly variable between piglets. In total, there was a higher proportion of reliable ICG-registrations than reported from clinical delivery room studies using electrical velocimetry. Our data are physiologically plausible and supports further research evaluating PhysioFlow® for cardiac output monitoring in perinatal asphyxia. In particular, factors influencing inter-individual variations in signal quality should be explored.
Parental and School Influences on Character Attributes Among Chinese Adolescents
Authors: Zhu Xiaoqin , Shek Daniel T. L. , Yu Lu
Published: February 2022

Objectives

While there are many theoretical propositions on parental and school impacts on character formation among adolescents, limited empirical evidence is available. To fill the research gaps, this study examined how parental factors (e.g., behavioral control, support, parent–child relationship, and psychological control) and school factors (teacher–student relationship and student–student relationship) affect adolescents' character attributes in the areas of “treating others well,” “self-discipline and law-abidance,” and “traditional Chinese virtues,” from both child and parent perspectives.

Methods

We used survey data collected from 2,472 Chinese adolescents (Mean age = 14.76 ± 1.82 years; 1,271 girls) and 412 Chinese parents (Mean age = 45.68 ± 6.53 years; 313 mothers) in Hong Kong.

Results

Structural equation modeling revealed significant positive effects of positive parental factors and relational factors in school on children's character attributes. However, psychological control as the indicator of negative parenting did not serve as a negative predictor of adolescents' character attributes.

Conclusion

These findings shed light on the unique contribution of different parental and school factors to character development among Chinese adolescents. The findings also imply the importance of promoting ecological assets in family and school through parent and teacher training in effective character education, which is essential for children and adolescents' healthy development.
Associations Between Mental Health Problems in Adolescence and Educational Attainment in Early Adulthood: Results of the German Longitudinal BELLA Study
Authors: Meißner Carina , Meyrose Ann-Katrin , Kaman Anne , Michalkiewicz Martha , Ravens-Sieberer Ulrike
Published: February 2022

Mental health problems (MHP) in adolescence are a major public health concern of the 21st century. Global prevalence estimates range between 10 and 20%. Most MHP manifest by adolescence and persistence rates are high, often accumulating further impairment in early adulthood and beyond. We analyzed data of N = 433 participants from the German longitudinal BELLA study to examine whether MHP in adolescence negatively affect educational attainment in early adulthood. Externalizing and internalizing MHP among adolescents aged 11–17 years were assessed at baseline using the Strengths and Difficulties Questionnaire. Educational attainment was assessed at the 6-year follow-up based on level of education, failure to attain the expected level of education, and dropout from vocational or academic training. Findings from logistic regression analyses suggest that more pronounced externalizing MHP in adolescence predict a lower level of education in early adulthood. We did not find a corresponding effect for internalizing MHP. Adolescents with higher-educated parents were less likely to attain a lower level of education themselves and less likely to fail in attaining their expected level of education. Our findings support that educational attainment presents a central channel for intergenerational reproduction of education and forms an important pathway for upward, but also downward social mobility. The current study emphasizes school as a central setting to implement measures to prevent onset and persistence of MHP and to foster equal opportunities in education.
New Vistas in microRNA Regulatory Interactome in Neuropathic Pain
Authors: Gada Yash , Pandey Amitkumar , Jadhav Nikita , Ajgaonkar Saiprasad , Mehta Dilip , Nair Sujit
Published: February 2022

Neuropathic pain is a chronic pain condition seen in patients with diabetic neuropathy, cancer chemotherapy-induced neuropathy, idiopathic neuropathy as well as other diseases affecting the nervous system. Only a small percentage of people with neuropathic pain benefit from current medications. The complexity of the disease, poor identification/lack of diagnostic and prognostic markers limit current strategies for the management of neuropathic pain. Multiple genes and pathways involved in human diseases can be regulated by microRNA (miRNA) which are small non-coding RNA. Several miRNAs are found to be dysregulated in neuropathic pain. These miRNAs regulate expression of various genes associated with neuroinflammation and pain, thus, regulating neuropathic pain. Some of these key players include adenylate cyclase (Ac9), toll-like receptor 8 (Tlr8), suppressor of cytokine signaling 3 (Socs3), signal transducer and activator of transcription 3 (Stat3) and RAS p21 protein activator 1 (Rasa1). With advancements in high-throughput technology and better computational power available for research in present-day pharmacology, biomarker discovery has entered a very exciting phase. We dissect the architecture of miRNA biological networks encompassing both human and rodent microRNAs involved in the development of neuropathic pain. We delineate various microRNAs, and their targets, that may likely serve as potential biomarkers for diagnosis, prognosis, and therapeutic intervention in neuropathic pain. miRNAs mediate their effects in neuropathic pain by signal transduction through IRAK/TRAF6, TLR4/NF-κB, TXIP/NLRP3 inflammasome, MAP Kinase, TGFβ and TLR5 signaling pathways. Taken together, the elucidation of the landscape of signature miRNA regulatory networks in neuropathic pain will facilitate the discovery of novel miRNA/target biomarkers for more effective management of neuropathic pain.
Pingchan Granule for Motor Symptoms and Non-Motor Symptoms of Parkinson’s Disease: A Randomized, Double-Blind, Placebo-Controlled Study
Authors: Gu Si-Chun , Ye Qing , Wang Chang-De , Zhao Shao-Rong , Zhou Jie , Gao Chen , Zhang Yu , Liu Zhen-Guo , Yuan Can-Xing
Published: February 2022

Background: Pingchan granule (PCG) is a traditional Chinese medicine for treating Parkinson’s disease (PD).

Objective: This study aimed at evaluating the efficacy and safety of PCG for motor and non-motor symptoms of PD.

Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, 292 participants with mild-to-moderate PD were included and followed for 36 weeks (24 week treatment, 12-week follow-up after intervention), randomly assigned at a 1:1 ratio to receive PCG or placebo. The primary outcomes included the severity of motor symptoms assessed by the Unified Parkinson’s disease Rating Scale (UPDRS) part 3 (UPDRS-III) score and the rate of disease progression assessed by the total UPDRS score. Secondary outcomes included non-motor symptoms assessed using the Scale for Outcomes in Parkinson’s Disease-Autonomic (SCOPA-AUT), Parkinson’s disease Sleep Scale (PDSS), 24-item Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), UPDRS part 2 (UPDRS-II), and 39-item Parkinson’s Disease Questionnaire (PDQ-39) scores. Assessments were done at baseline (T0), 12 weeks (T1), 24 weeks (T2), and 36 weeks (T3).

Results: Generalized estimating equation analyses revealed that the PCG group had significantly better improvement in UPDRS-III score at T1, T2, and T3 [time-by-group interaction, T1: β, −0.92 (95% CI, −1.59–−0.25; p = 0.01); T2: β, −2.08 (95% CI, −2.90–−1.27; p < 0.001); T3: β, −4.54 (95% CI, −5.37–−3.71; p < 0.001))]. The PCG group showed a greater decrease (rate of disease change) in the total UPDRS score between T0 and T2 [−2.23 (95% CI, −2.72–−1.73; p < 0.001) points per week vs. −0.21 (95% CI, −0.80–0.39; p = 0.50) points per week in the placebo group, p < 0.001]. Ameliorations of SCOPA-AUT, PDSS, HAM-D, HAM-A, UPDRS-II, and PDQ-39 scores were also observed.

Conclusion: PCG had a long-lasting and extensive symptomatic efficacy for both motor and non-motor symptoms of PD with good tolerance.

Trial registration: Chinese Clinical Trial Register, ChiCTR-INR-17011949.
Investigation of Antidiabetic Effect of Pistacia atlantica Leaves by Activity-Guided Fractionation and Phytochemical Content Analysis by LC-QTOF-MS
Authors: Pekacar Sultan , Deliorman Orhan Didem
Published: February 2022

In this study, the antidiabetic, antiobesity, antioxidant, and antihyperlipidemic effects potential of Pistacia atlantica Desf. leaves were evaluated by in vitro methods. The effects of the leaves of the plant on pancreatic lipase, pancreatic cholesterol esterase, and PTP1B enzymes were investigated for the first time and it was observed that leaf methanol extract (IC50: 123.67 ± 0.40 μg/ml) and n-hexane sub-extract (IC50: 61.03 ± 0.11 μg/ml) had much stronger effects on pancreatic cholesterol esterase enzyme than simvastatin (IC50: 142.30 ± 5.67 μg/ml). The methanolic extract of P. atlantica leaves exerted strong inhibitory effect on the enzymes (α-amylase and α-glucosidase) effective on carbohydrate digestion. It was thought that the methanol extract could provide significant benefits against oxidative stress in diabetes mellitus since it showed antioxidant activities (DPPH radical scavenging activity and reducing power) as strong as reference compounds (ascorbic acid and quercetin). Qualitative and quantitative analyzes of rutin (0.328 ± 0.000 g/100 g dry extract), methyl gallate (5.245 ± 0.014 g/100 g dry extract), quercetin-3-O-glucoside (0.231 ± 0.000 g/100 g dry extract), and gallic acid (0.528 ± 0.127 g/100 g dry extract) in methanol extract were performed by RP-HPLC. The phytochemical content of the active sub-fraction obtained from the leaf methanol extract by activity-guided fractionation and column chromatography studies was characterized by LC-QTOF-MS. The presence of trigalloylglucose, digalloylglucose, and methyl gallate in the G6 coded sub-fraction obtained by chromatographic techniques from the ethyl acetate sub-extract, which has the highest inhibitory effect on α-amylase and α-glucosidase enzymes, was determined by LC-QTOF-MS. In addition to the G5 coded subfraction, a strong α-glucosidase enzyme inhibitory activity was also observed in the G6 coded sub-fraction, and methyl gallate, methyl digallate, 2″-O-galloyl-quercetin-3-O-hexoside, and myricetin-3-O-hexoside were identified in this sub-fraction. This study displayed that the methanol extract of P. atlantica leaves could be a potential source for bioactive compounds with antidiabetic effects by showing inhibitory effects on enzymes involved in carbohydrate digestion.
Jiegeng Decoction Potentiates the Anticancer Efficacy of Paclitaxel in vivo and in vitro
Authors: Chen Haifang , Li Guofeng , Liu Ye , Lang Yifan , Yang Wuliang , Zhang Wugang , Liang Xinli
Published: February 2022

Paclitaxel (PTX) has been the first-line treatment for lung cancer; however, its clinical use is limited due to multidrug resistance (MDR) and adverse effects. Thus, there is an urgent need to explore agents that can enhance the anticancer efficacy of PTX by reducing drug resistance and adverse reactions. Jiegeng decoction (JG) was used as the meridian guide drug and adjuvant drug in treatment of lung cancer. However, the mechanism of adjuvant effect was unclear. The aim of this study was to determine whether JG could potentiate the anticancer effect of PTX. Tissue distribution of PTX was detected using HPLC-MS/MS. The anti-lung cancer effect of the combination of PTX and JG in Lewis lung cancer C57BL/6J mice was evaluated based on the body weight and tumor-inhibition rate. PTX concentration in tumors was determined using HPLC-MS and in vivo imaging. Biochemical indices were detected using biochemical analyzer and ELISA. The anticancer mechanism of the PTX-JG combination in A549/PTX cells was elucidated based on cell proliferation, annexin V-FITC apoptosis assay, and western blotting. Tissue distribution analysis showed that the distribution of PTX increased in the lungs, liver, and heart upon administering the combination of PTX and JG. JG remarkably enhanced the anticancer effect of PTX by increasing the red blood cell and platelet counts; increasing hemoglobin, interleukin (IL)-2, and tumor necrosis factor-α levels; increasing CD4+T cells and the CD4+/CD8+ ratio; and decreasing IL-10 levels. JG administration led to the increased distribution of PTX at the tumor lesion sites and also potentiated the anticancer effect of PTX by inhibiting tumor cell proliferation and promoting apoptosis. Moreover, JG reversed PTX resistance by inhibiting the expression of lung resistance-related proteins, multiresistance protein 1, P-glycoprotein, and breast cancer-resistant protein. Furthermore, the combination of JG and PTX decreased alanine aminotransferase and aspartate aminotransferase levels and did not affect creatine kinase-MB levels. Therefore, our discovery suggests that JG increased the anticancer effect of PTX by downregulating the MDR-related protein and demonstrated a synergistic enhancement of immunity. Thus, the combination of PTX with JG shows potential in the management of lung cancer owing to its synergistic and detoxifying effects.
Targeting Angiogenesis in Breast Cancer: Current Evidence and Future Perspectives of Novel Anti-Angiogenic Approaches
Authors: Ayoub Nehad M. , Jaradat Sara K. , Al-Shami Kamal M. , Alkhalifa Amer E.
Published: February 2022

Angiogenesis is a vital process for the growth and dissemination of solid cancers. Numerous molecular pathways are known to drive angiogenic switch in cancer cells promoting the growth of new blood vessels and increased incidence of distant metastasis. Several angiogenesis inhibitors are clinically available for the treatment of different types of advanced solid cancers. These inhibitors mostly belong to monoclonal antibodies or small-molecule tyrosine kinase inhibitors targeting the classical vascular endothelial growth factor (VEGF) and its receptors. Nevertheless, breast cancer is one example of solid tumors that had constantly failed to respond to angiogenesis inhibitors in terms of improved survival outcomes of patients. Accordingly, it is of paramount importance to assess the molecular mechanisms driving angiogenic signaling in breast cancer to explore suitable drug targets that can be further investigated in preclinical and clinical settings. This review summarizes the current evidence for the effect of clinically available anti-angiogenic drugs in breast cancer treatment. Further, major mechanisms associated with intrinsic or acquired resistance to anti-VEGF therapy are discussed. The review also describes evidence from preclinical and clinical studies on targeting novel non-VEGF angiogenic pathways in breast cancer and several approaches to the normalization of tumor vasculature by targeting pericytes, utilization of microRNAs and extracellular tumor-associate vesicles, using immunotherapeutic drugs, and nanotechnology.
Relationship Between the Structure and Immune Activity of Components From the Active Polysaccharides APS-II of Astragali Radix by Enzymolysis of Endo α-1,4-Glucanase
Authors: Li Ke , Li Xue-qin , Li Guang-xin , Cui Lian-jie , Qin Xue-mei , Li Zhen-yu , Du Yu-guang , Liu Yue-tao , Li Ai-ping , Zhao Xing-yun , Fan Xin-hui
Published: February 2022

Astragali Radix polysaccharides (APSs) have a wide range of biological activities. Our preliminary experiment showed that APS-Ⅱ (10 kDa) was the main immunologically active component of APSs. However, the characteristic structure related to activity of APS-Ⅱ needs further verification and clarification. In this study, APS-II was degraded by endo α-1,4-glucosidase. The degraded products with different degrees of polymerization [1–3 (P1), 3–6 (P2), 7–14 (P3), and 10–18 (P4)] were obtained using a polyacrylamide gel chromatography column. The structural features of the different products were characterized by HPGPC, monosaccharide composition, Fourier transform infrared spectrum, GC–MS, nuclear magnetic resonance, and UPLC-ESI-QTOF-MS analysis. Specific immune and non-specific immune cell tests were used to identify the most immunogenic fractions of the products. The backbone of P4 was speculated to be α-D-1,4-linked glucans and rich in C2 (25.34%) and C6 (34.54%) branches. Immune screening experiments indicated that the activity of P4 was better than that of APS-II and the other three components. In this research, the relationship between the structure of APS-Ⅱ and the immune activity from the degradation level of polysaccharides was studied, laying a foundation for the quality control and product development of APSs.
Mechanism of Action of Small-Molecule Agents in Ongoing Clinical Trials for SARS-CoV-2: A Review
Authors: Zhao Lei , Li Song , Zhong Wu
Published: February 2022

Since the first reports from December 2019, COVID-19 caused an overwhelming global pandemic that has affected 223 countries, seriously endangering public health and creating an urgent need for effective drugs to treat SARS-CoV-2 infection. Currently, there is a lack of safe, effective, and specific therapeutic drugs for COVID-19, with mainly supportive and symptomatic treatments being administered to patients. The preferred option for responding to an outbreak of acute infectious disease is through drug repurposing, saving valuable time that would otherwise be lost in preclinical and clinical research, hastening clinical introduction, and lowering treatment costs. Alternatively, researchers seek to design and discover novel small-molecule candidate drugs targeting the key proteins in the life cycle of SARS-CoV-2 through an in-depth study of the infection mechanism, thus obtaining a number of candidate compounds with favorable antiviral effects in preclinical and clinical settings. There is an urgent need to further elucidate the efficacy and mechanism of action of potential anti-SARS-CoV-2 small-molecule drugs. Herein, we review the candidate small-molecule anti-SARS-CoV-2 drugs in ongoing clinical trials, with a major focus on their mechanisms of action in an attempt to provide useful insight for further research and development of small-molecule compounds against SARS-CoV-2 infection.
Signal Transduction Mechanisms Quantitatively Observed One Molecule at a Time
Authors: Li Pei , Chen Ting , Chen Liang , Tan Yan-Wen
Published: February 2022

Improved single-molecule methods can largely increase our understanding of underlying molecular mechanism during cellular signal transduction. In contrast to conventional bulk methods, monitoring molecules one at a time can circumvent averaging effects and acquire unique information. With single-molecule techniques, quantitative characterizations can be achieved at microscopic level, especially for biochemical systems with strong heterogeneity. Here we review four fundamental single-molecule techniques including total internal reflection fluorescence imaging, single-molecule fluorescence recovery after photobleaching, single-molecule Förster resonance energy transfer, and fluorescence correlation/cross-correlation spectroscopy. These techniques are frequently employed in quantitatively investigating the molecular translocation, protein-protein interactions, aggregations, and conformational dynamics involved in the signal transduction both in vitro and in vivo. We also summarized the basic principles and implementations of these single-molecule techniques, as well as the conjunct applications extending the single-molecule measurements to multiple dimensions.
Organization and Dynamics of the Red Blood Cell Band 3 Anion Exchanger SLC4A1: Insights From Molecular Dynamics Simulations
Authors: Kalli Antreas C. , Reithmeier Reinhart A. F.
Published: February 2022

Molecular dynamics (MD) simulations have provided new insights into the organization and dynamics of the red blood cell Band 3 anion exchanger (AE1, SLC4A1). Band 3, like many solute carriers, works by an alternating access mode of transport where the protein rapidly (104/s) changes its conformation between outward and inward-facing states via a transient occluded anion-bound intermediate. While structural studies of membrane proteins usually reveal valuable structural information, these studies provide a static view often in the presence of detergents. Membrane transporters are embedded in a lipid bilayer and associated lipids play a role in their folding and function. In this review, we highlight MD simulations of Band 3 in realistic lipid bilayers that revealed specific lipid and protein interactions and were used to re-create a model of the Wright (Wr) blood group antigen complex of Band 3 and Glycophorin A. Current MD studies of Band 3 and related transporters are focused on describing the trajectory of substrate binding and translocation in real time. A structure of the intact Band 3 protein has yet to be achieved experimentally, but cryo-electron microscopy in combination with MD simulations holds promise to capture the conformational changes associated with anion transport in exquisite molecular detail.
Weighing in on Adipogenesis
Authors: Nunn Elizabeth R. , Shinde Abhijit B. , Zaganjor Elma
Published: February 2022

Obesity is a growing health concern worldwide because of its contribution to metabolic syndrome, type II diabetes, insulin resistance (IR), and numerous cancers. In obesity, white adipose tissue (WAT) expands through two mechanisms: increase in adipocyte cell number by precursor cell differentiation through the process of adipogenesis (hyperplasia) and increase in existing mature adipocyte cell size (hypertrophy). While hypertrophy is associated with the negative effects of obesity on metabolic health, such as inflammation and lipotoxicity, adipogenesis prevents obesity-mediated metabolic decline. Moreover, in metabolically healthy obesity adipogenesis is increased. Thus, it is vital to understand the mechanistic basis for adipose expansion to inform novel therapeutic approaches to mitigate the dysfunction of this tissue and associated diseases. In this mini-review, we summarize recent studies on the regulation of adipogenesis and provide a perspective on targeting adipogenesis as a potential therapeutic avenue for metabolic disorders.
Transcription and Post-translational Regulation of Autophagy in Insects
Authors: Li Rongsong , Xiao Yang , Li Kang , Tian Ling
Published: February 2022

Autophagy attracts great attention, and numerous progresses have been obtained in the last two decades. Autophagy is implicated in mammalian neurodegenerative diseases, tumorigenesis, as well as development in insects. The regulatory mechanism of autophagy is well documented in yeast and mammals, whereas it is not fully illustrated in insects. Drosophila melanogaster and Bombyx mori are the two well-studied insects for autophagy, and several insect-mammalian evolutionarily conserved or insect-specific mechanisms in regulating autophagy are reported. In this review, we summarize the most recent studies of autophagy regulated at both transcriptional and post-translational levels by insect hormone in cooperation with other signals, such as nutrient, which will provide a reference and deep thinking for studies on autophagy in insects.
New Insights Into Energy Substrate Utilization and Metabolic Remodeling in Cardiac Physiological Adaption
Authors: Shi Xiaomeng , Qiu Hongyu
Published: February 2022

Cardiac function highly relies on sufficient energy supply. Perturbations in myocardial energy metabolism play a causative role in cardiac pathogenesis. Accumulating evidence has suggested that modifications of cardiac metabolism are also an essential part of the adaptive responses to various physiological conditions in the heart to meet specific energy needs. The review highlighted some new studies on basic myocardial energy substrate metabolism and updated recent findings regarding cardiac metabolic remodeling and their associated mechanisms under physiological conditions, including exercise and cardiac development. Studying basic metabolic profiles in the heart in these conditions can contribute to understanding the significance of metabolic regulation in the heart during physiological adaption and gaining further insights into the maladaptive metabolic changes associated with cardiac pathogenesis, thus opening up new avenues to exploring novel therapeutic strategies in cardiac diseases.
Modulation in Biofertilization and Biofortification of Wheat Crop by Inoculation of Zinc-Solubilizing Rhizobacteria
Authors: Yadav Ramesh Chandra , Sharma Sushil K. , Varma Ajit , Rajawat Mahendra Vikram Singh , Khan Mohammad Shavez , Sharma Pawan K. , Malviya Deepti , Singh Udai B. , Rai Jai P. , Saxena Anil K.
Published: February 2022

Zinc is an important micronutrient needed for the optimum growth and development of plants. Contrary to chemical zinc fertilizers, the use of zinc-solubilizing bacteria is an environmentally friendly option for zinc enrichment in edible parts of crops. This study was conducted with the objective of selecting potential zinc-solubilizing rhizobacteria from the rhizosphere of chickpea grown in soils of eastern Uttar Pradesh and further assessing their impact on the magnitude of zinc assimilation in wheat crops. Among 15 isolates, CRS-9, CRS-17, CRS-30, and CRS-38 produced net soluble zinc in broth to the tune of 6.1, 5.9, 5.63, and 5.6 μg ml–1, respectively, in zinc phosphate with the corresponding pH of 4.48, 5.31, 5.2, and 4.76. However, the bacterial strains CRS-17, CRS-30, CRS-38, and CRS-9 showed maximum zinc phosphate solubilization efficiency of 427.79, 317.39, 253.57, and 237.04%, respectively. The four bacterial isolates were identified as Bacillus glycinifermentans CRS-9, Microbacterium oxydans CRS-17, Paenarthrobacter nicotinovorans CRS-30, and Bacillus tequilensis CRS-38 on the basis of morphological and biochemical studies and 16S rRNA gene sequencing. Bacterial inoculants significantly colonized the roots of wheat plants and formed a biofilm in the root matrix. These strains significantly increased seed germination (%) and vigor indices in wheat grown under glasshouse conditions. After 30 days of sowing of wheat under microcosm conditions, eight zinc transporter (TaZIP) genes were expressed maximally in roots, with concomitant accumulation of higher zinc content in the bacterially treated plant compared to the absolute control. Out of the four strains tested, two bacteria, B. tequilensis CRS-38 and P. nicotinovorans CRS-30, improved seed germination (%), vigor indices (2–2.5 folds), plant biomass, grain yield (2.39 g plant–1), and biofortificated grains (54.25 μg g–1Zn) of wheat. To the best of our knowledge, this may be the first report on the presence of zinc solubilization trait in B. glycinifermentans CRS-9, M. oxydans CRS-17, and P. nicotinovorans CRS-30.