bluuebunny/crossref_metadata_2025 huggingface dataset:
Breakdown of the central synapses in C9orf72-linked ALS/FTD
Authors: Ghaffari Layla T. , Trotti Davide , Haeusler Aaron R. , Jensen Brigid K.
Published: September 2022

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease that leads to the death of motor and cortical neurons. The clinical manifestations of ALS are heterogenous, and efficacious treatments to significantly slow the progression of the disease are lacking. Cortical hyper-excitability is observed pre-symptomatically across disease-causative genetic variants, as well as in the early stages of sporadic ALS, and typically precedes motor neuron involvement and overt neurodegeneration. The causes of cortical hyper-excitability are not yet fully understood but is mainly agreed to be an early event. The identification of the nucleotide repeat expansion (GGGGCC)nin theC9ORF72gene has provided evidence that ALS and another neurodegenerative disease, frontotemporal dementia (FTD), are part of a disease spectrum with common genetic origins. ALS and FTD are diseases in which synaptic dysfunction is reported throughout disease onset and stages of progression. It has become apparent that ALS/FTD-causative genes, such asC9ORF72, may have roles in maintaining the normal physiology of the synapse, as mutations in these genes often manifest in synaptic dysfunction. Here we review the dysfunctions of the central nervous system synapses associated with the nucleotide repeat expansion inC9ORF72observed in patients, organismal, and cellular models of ALS and FTD.
Similarities and differences in the nutritional composition of nuts and seeds in Serbia
Authors: Dodevska Margarita , Kukic Markovic Jelena , Sofrenic Ivana , Tesevic Vele , Jankovic Milica , Djordjevic Brizita , Ivanovic Nevena Dj.
Published: September 2022

Nuts and seeds are an indispensable part of the plant-based diet, which is becoming increasingly popular due to the evidence of their health benefits and contribution to sustainability and planetary health. Since the health effects of consuming nuts and seeds directly depend on their nutritional composition and consumed amount, it is essential to know the exact chemical composition of each nut and seed so that appropriate dietary interventions can be adequately planned. The present study aimed to examine the chemical composition of nuts and seeds obtained from the Serbian market and to highlight the similarities and differences in their nutritional composition. In twenty-four samples of nuts and seeds, the content of total lipids, including fatty acid profile, total proteins, including amino acid profile, total carbohydrates (sugars and fibers), phytosterols, and minerals were determined. Content of selected nutrients in grams (g) or milligrams (mg) of nuts and seeds was expressed in one portion (28 g) and as a percentage of contribution of Reference Intakes (% RI) and Dietary Reference Value (% DRV) for macronutrients and minerals, respectively. Some of the seed representatives appeared to be rich sources of essential omega-3 fatty acid, α-linolenic acid (ALA) (flax seed vs. walnut, 6.50 vs. 0.56 g per portion, respectively), dietary fibers (chia seed vs. raw almond, 10.6 vs. 3.4 g per portion, respectively), calcium (black sesame seed vs. almond roasted, 32.4% NRV vs. 8.1% NRV per portion, respectively), magnesium (hemp seed vs. Brazil nut, 38.3% NRV vs. 27.8% NRV per portion, respectively), and zinc (hemp seed vs. pine nut, 21.4% NRV vs. 17.6% NRV per portion, respectively). Our results highlighted the crucial role of seeds in the diet, especially as a better source of nutrients compared to nuts. Furthermore, it was seen that nuts and seeds are different and complementary in their composition. Thus, in order to meet the needs for certain nutrients for which nuts and seeds are used as dietary sources (essential fatty acids, minerals, dietary fibers), it would be beneficial to combine both nuts and seeds as a part of a healthy dietary pattern.
Lagenaria siceraria fruit: A review of its phytochemistry, pharmacology, and promising traditional uses
Authors: Saeed Muhammad , Khan Muhammad Sajjad , Amir Kinza , Bi Jannat Bi , Asif Muhammad , Madni Asadullah , Kamboh Asghar Ali , Manzoor Zahid , Younas Umair , Chao Sun
Published: September 2022

Since ancient times, the Cucurbitaceae family is used as a therapeutic option in human medicine. This family has around 130 genera and 800 species. Researchers have studied the various plants of this family including Lagenaria siceraria due to their medicinal potential. Various properties are beneficial for human health, that have been attributed to L. siceraria like antioxidant, hypolipidemic, diuretic, laxative, hepatoprotective, analgesic, antihypertensive, cardioprotective, central nervous system stimulant, anthelmintic, free radical scavenging, immunosuppressive, and adaptogenic. The fruit of this plant is commonly used as a vegetable that has a low-calorie value. The species possess a diverse set of biological compounds like flavonoids, sterols, saponins, and terpenoids. Vitamins, choline, flavonoids, minerals, proteins, terpenoids, and other phytochemicals are also found in the edible parts of this plant. Besides 17 different amino acids, many minerals are reported to be present in the seeds of L. siceraria. According to the USDA nutritional database per 100 g of L. siceraria contains 14 Kcal energy, 3.39 g carbohydrates, 0.62 g protein, 0.2 g fat, and 0.5 g fiber. L. siceraria performs a wide range of pharmacological and physiological actions. The literature reviewed from various sources including PubMed, Science Direct, Google scholar, etc. shows the remarkable potential to treat various human and animal illnesses due to its' potent bioactive chemicals. The key objective of this thorough analysis is to present a summary of the data about the beneficial and harmful effects of L. siceraria intake on human health, as well as in veterinary fields.
Mitochondrial metabolic determinants of multiple myeloma growth, survival, and therapy efficacy
Authors: Nair Remya , Gupta Pulkit , Shanmugam Mala
Published: September 2022

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the clonal proliferation of antibody producing plasma cells. Despite the use of next generation proteasome inhibitors (PI), immunomodulatory agents (IMiDs) and immunotherapy, the development of therapy refractory disease is common, with approximately 20% of MM patients succumbing to aggressive treatment-refractory disease within 2 years of diagnosis. A large emphasis is placed on understanding inter/intra-tumoral genetic, epigenetic and transcriptomic changes contributing to relapsed/refractory disease, however, the contribution of cellular metabolism and intrinsic/extrinsic metabolites to therapy sensitivity and resistance mechanisms is less well understood. Cancer cells depend on specific metabolites for bioenergetics, duplication of biomass and redox homeostasis for growth, proliferation, and survival. Cancer therapy, importantly, largely relies on targeting cellular growth, proliferation, and survival. Thus, understanding the metabolic changes intersecting with a drug’s mechanism of action can inform us of methods to elicit deeper responses and prevent acquired resistance. Knowledge of the Warburg effect and elevated aerobic glycolysis in cancer cells, including MM, has allowed us to capitalize on this phenomenon for diagnostics and prognostics. The demonstration that mitochondria play critical roles in cancer development, progression, and therapy sensitivity despite the inherent preference of cancer cells to engage aerobic glycolysis has re-invigorated deeper inquiry into how mitochondrial metabolism regulates tumor biology and therapy efficacy. Mitochondria are the sole source for coupled respiration mediated ATP synthesis and a key source for the anabolic synthesis of amino acids and reducing equivalents. Beyond their core metabolic activities, mitochondria facilitate apoptotic cell death, impact the activation of the cytosolic integrated response to stress, and through nuclear and cytosolic retrograde crosstalk maintain cell fitness and survival. Here, we hope to shed light on key mitochondrial functions that shape MM development and therapy sensitivity.
A pro-oxidant combination of resveratrol and copper down-regulates hallmarks of cancer and immune checkpoints in patients with advanced oral cancer: Results of an exploratory study (RESCU 004)
Authors: Pilankar Aishwarya , Singhavi Hitesh , Raghuram Gorantla V. , Siddiqui Sophiya , Khare Naveen Kumar , Jadhav Vishalkumar , Tandel Harshali , Pal Kavita , Bhattacharjee Atanu , Chaturvedi Pankaj , Mittra Indraneel
Published: September 2022

Background

Our earlier studies have shown that cell-free chromatin particles (cfChPs) that are released from dying cancer cells are readily internalised by bystander cells leading to activation of two hallmarks of cancer viz. genome instability and inflammation. These hallmarks could be down-regulated by deactivating cfChPs via medium of oxygen radicals generated upon admixing small quantities of the nutraceuticals resveratrol (R) and copper (Cu). In this exploratory study, we investigated whether oral administration of R and Cu (R-Cu) would down-regulate the hallmarks of cancer and immune checkpoints in advanced squamous cell carcinoma of oral cavity (OSCC).

Patients and methods

The study comprised of 25 patients divided into 5 equal groups. Five patients acted as controls; the remaining 20 were given R-Cu in four escalating doses. The lowest dose of R-Cu was 5.6mg and 560ng respectively, and the highest dose was 500mg and 5mg respectively. An initial biopsy was taken from patients at first presentation, and a second biopsy was taken 2 weeks later on the operating table. R-Cu was administered orally twice daily in the intervening period. Confocal microscopy was performed on tumour sections after fluorescent immuno-staining with anti-DNA and anti-histone antibodies to detect presence of cfChPs in the tumour micro-environment (TME). Immunofluorescence analysis was performed for 23 biomarkers representing the 10 Hallmarks of cancer, including 5 immune checkpoints, defined by Hanahan and Weinberg.

Results

Confocal microscopy detected copious presence of cfChPs in TME of OSCC, which were eradicated/deactivated following two-week treatment with R-Cu. Eradication of cfChPs from TME was associated with marked down-regulation of 21/23 biomarkers, including the five immune checkpoints. The lower two doses of R-Cu were more effective than the higher doses. No adverse effects attributable to R-Cu were observed.

Conclusion

These results suggest that cfChPs released into TME from dying cancer cells are global instigators for cancer hallmarks and immune checkpoints in surviving cancer cells. The ability of R-Cu to deactivate cfChPs raises the prospect of a novel and non-toxic form of cancer treatment which sans killing of cancer cells, and instead induces healing by down-regulating cancer hallmarks and immune check-points.

Clinical Trial Registration

http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=19801&EncHid=&userName=CTRI/2018/03/012459.
Propensity score-matched comparison of robotic- and video-assisted thoracoscopic surgery, and open lobectomy for non-small cell lung cancer patients aged 75 years or older
Authors: Pan Hanbo , Gu Zenan , Tian Yu , Jiang Long , Zhu Hongda , Ning Junwei , Huang Jia , Luo Qingquan
Published: September 2022

Introduction

Although robot-assisted thoracoscopic surgery (RATS) has been widely applied in treating non-small cell lung cancer (NSCLC), its advantages remain unclear for very old patients. The present study compared the perioperative outcomes and survival profiles among RATS, video-assisted thoracoscopic surgery (VATS), and open lobectomy (OL), aiming to access the superiority of RATS for NSCLC patients aged ≥75 years.

Methods

Pathological IA-IIIB NSCLC patients aged ≥75 years who underwent RATS, VATS, or OL between June 2015 and June 2021 in Shanghai Chest Hospital were included. Propensity score matching (PSM, 1:1:1 RATS versus VATS versus OL) was based on 10 key prognostic factors. The primary endpoints were perioperative outcomes, and the secondary endpoints were disease-free (DFS), overall (OS), and cancer-specific survival (CS).

Results

A total of 504 cases (126 RATS, 200 VATS, and 178 OL) were enrolled, and PSM led to 97 cases in each group. The results showed that RATS led to: 1) the best surgical-related outcomes including the shortest operation duration (p <0.001) and the least blood loss (p <0.001); 2) the fastest postoperative recoveries including the shortest ICU stay (p = 0.004), chest tube drainage duration (p <0.001), and postoperative stay (p <0.001), and the most overall costs (p <0.001); 3) the lowest incidence of postoperative complications (p = 0.002), especially pneumonia (p <0.001). There was no difference in the resection margins, reoperation rates, intraoperative blood transfusion, and volume of chest tube drainage among the three groups. Moreover, RATS assessed more N1 (p = 0.009) and total (p = 0.007) lymph nodes (LNs) than VATS, while the three surgical approaches dissected similar numbers of N1, N2, and total LN stations and led to a comparable incidence of postoperative nodal upstaging. Finally, the three groups possessed comparable DFS, OS, and CS rates. Further subgroup analysis found no difference in DFS or OS among the three groups, and multivariable analysis showed that the surgical approach was not independently correlated with survival profiles.

Conclusion

RATS possessed the superiority in achieving better perioperative outcomes over VATS and OL in very old NSCLC patients, though the three surgical approaches achieved comparable survival outcomes.
Long response duration to pembrolizumab in metastatic, castration-resistant prostate cancer with microsatellite instability-high and neuroendocrine differentiation: A case report
Authors: Yoshida Tsukasa , Yaegashi Hiroshi , Toriumi Ren , Kadomoto Suguru , Iwamoto Hiroaki , Izumi Kouji , Kadono Yoshifumi , Ikeda Hiroko , Mizokami Atsushi
Published: September 2022

Background

The detection of microsatellite instability in urologic cancers is rare, especially in metastatic, castration-resistant prostate cancer with neuroendocrine differentiation.

Case presentation

This is a case of a 66-year-old Asian male patient with prostate adenocarcinoma who had metastases at initial presentation. Despite combined androgen deprivation therapy, his prostate-specific antigen (PSA) progressively increased, and prostate re-biopsy revealed small cell carcinoma. He was treated with platinum-based systemic chemotherapy, and his tumor markers, including PSA, remained negative; however, his local symptoms worsened. Subsequently, microsatellite instability-high was detected, and pembrolizumab was administered resulting in complete remission with the resolution of symptoms and continued therapeutic effect for more than 14 months.

Conclusion

Microsatellite instability testing should be considered, despite its low detection rate, because the response to pembrolizumab in metastatic, castration-resistant prostate cancer with detectable microsatellite instability is associated with a prolonged duration of response.
Real-world survival of colon cancer after radical surgery: A single-institutional retrospective analysis
Authors: Pang Xiangyi , Xu Benjie , Lian Jie , Wang Ren , Wang Xin , Shao Jiayue , Tang Shuli , Lu Haibo
Published: September 2022

The survival rate for colon cancer after radical surgery has been the focus of extensive debate. To assess the postoperative survival and prognostic factors for overall survival (OS), we collected clinicopathological information for 2,655 patients. The survival time and potential risk factors for OS were analyzed by using Kaplan–Meier curves, Cox proportional hazards models, best subset regression (BSR), and least absolute shrinkage and selection operator (LASSO). The 5-year survival rates of stage I–IV colon cancer were 96.6%, 88.7%, 69.9%, and 34.3%, respectively. Adjuvant chemotherapy improved the survival rate (90.4% vs. 82.4%, with versus without adjuvant chemotherapy, respectively) in stage II patients with high-risk factors. Elevated preoperative carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were significantly associated with worse OS compared with patients without these elevations. Less than 12 versus more than 12 harvested lymph nodes (LNs) affected prognosis (84.6% vs. 89.7%, respectively). Regarding the lymph node ratio (LNR), the 5-year OS rate was 89.2%, 71.5%, 55.8%, and 34.5% in patients with LNR values of 0, 0.3, 0.3–0.7, and >0.7, respectively. We constructed a nomogram comprising the independent factors associated with survival to better predict prognosis. On the basis of these findings, we propose that stage II colon cancer patients without high-risk factors and with both elevated preoperative CEA and CA199 should receive adjuvant therapy. Furthermore, the LNR could complement TNM staging in patients with <12 harvested LNs. Our nomogram might be useful as a new prognosis prediction system for colon cancer patients.
Performance of the IOTA ADNEX model combined with HE4 for identifying early-stage ovarian cancer
Authors: Yang Suying , Tang Jing , Rong Yue , Wang Min , Long Jun , Chen Cheng , Wang Cong
Published: September 2022

Objective

This work was designed to investigate the performance of the International Ovarian Tumor Analysis (IOTA) ADNEX (Assessment of Different NEoplasias in the adneXa) model combined with human epithelial protein 4 (HE4) for early ovarian cancer (OC) detection.

Methods

A total of 376 women who were hospitalized and operated on in Women and Children’s Hospital of Chongqing Medical University were selected. Ultrasonographic images, cancer antigen-125 (CA 125) levels, and HE4 levels were obtained. All cases were analyzed and the histopathological diagnosis serves as the reference standard. Based on the IOTA ADNEX model post-processing software, the risk prediction value was calculated. We analyzed receiver operating characteristic curves to determine whether the IOTA ADNEX model alone or combined with HE4 provided better diagnostic accuracy.

Results

The area under the curve (AUC) of the ADNEX model alone or combined with HE4 in predicting benign and malignant ovarian tumors was 0.914 (95% CI, 0.881–0.941) and 0.916 (95% CI, 0.883–0.942), respectively. With the cutoff risk of 10%, the ADNEX model had a sensitivity of 0.93 (95% CI, 0.87–0.97) and a specificity of 0.73 (95% CI, 0.67–0.78), while combined with HE4, it had a sensitivity of 0.90 (95% CI, 0.84–0.95) and a specificity of 0.81 (95% CI, 0.76–0.86). The IOTA ADNEX model combined with HE4 was better at improving the accuracy of the differential diagnosis between different OCs than the IOTA ADNEX model alone. A significant difference was found in separating borderline masses from Stage II–IV OC (p = 0.0257).

Conclusions

A combination of the IOTA ADNEX model and HE4 can improve the specificity of diagnosis of ovarian benign and malignant tumors and increase the sensitivity and effectiveness of the differential diagnosis of Stage II–IV OC and borderline tumors.
Prolonged neoadjuvant chemotherapy without radiation versus total neoadjuvant therapy for locally advanced rectal cancer: A propensity score matched study
Authors: Zhao Xuan , Han Peiyi , Zhang Luyang , Ma Junjun , Dong Feng , Zang Lu , He Zirui , Zheng Minhua
Published: September 2022

Background

Although neoadjvuant chemoradiotherapy (CRT) improves the local control rate of locally advanced rectal cancer (LARC), it fails to significantly improve disease-free survival (DFS) and overall survival (OS). We explored the efficacy of prolonged neoadjuvant chemotherapy (pNCT) without radiation and compared this schema with total neoadjuvant therapy (TNT).

Material and methods

Patients diagnosed with LARC and received TNT (4 cycles of induction CapeOX/FOLFOX followed with CRT) or pNCT (6~8 cycles of CapeOX/FOLFOX) between June 2016 and October 2021 were retrospective analyzed. All patients underwent total mesorectal excision (TME). A 1:1 propensity score match was performed to adjust baseline potential confounders. The tumor response, toxicity, recurrence-free survival (RFS) and OS were observed.

Results

A total of 184 patients with 92 patients in each group were finally enrolled. The median follow-up time was 35 months. TNT showed better pathological complete response (pCR) rate (25.0% vs 16.3%) and objective regression rate (73.9% vs 59.8%) than pNCT. TNT and pNCT produce similar 3-year RFS and OS rates in patients with mid-to-upper rectal cancer. TNT was associated with improved tumor responsiveness in all patients and improved 3-year RFS rates in those with low rectal cancer.

Conclusion

pNCT is an option for patients with mid-to-upper rectal cancer, but radiation is still necessary for low rectal cancer. To determine optimal schema for neoadjuvant therapy and patient selection, additional randomized controlled studies are needed.
Understanding the basis of major depressive disorder in oncological patients: Biological links, clinical management, challenges, and lifestyle medicine
Authors: Fraile-Martinez Oscar , Alvarez-Mon Miguel A. , Garcia-Montero Cielo , Pekarek Leonel , Guijarro Luis G. , Lahera Guillermo , Saez Miguel A. , Monserrat Jorge , Motogo Domitila , Quintero Javier , Alvarez-Mon Melchor , Ortega Miguel A.
Published: September 2022

In recent years, the incidence of different types of cancer and patient survival have been rising, as well as their prevalence. The increase in survival in recent years exposes the patients to a set of stressful factors such as more rigorous follow-up and more aggressive therapeutic regimens that, added to the diagnosis of the disease itself, cause an increase in the incidence of depressive disorders. These alterations have important consequences for the patients, reducing their average survival and quality of life, and for these reasons, special emphasis has been placed on developing numerous screening tests and early recognition of depressive symptoms. Despite that cancer and major depressive disorder are complex and heterogeneous entities, they also share many critical pathophysiological mechanisms, aiding to explain this complex relationship from a biological perspective. Moreover, a growing body of evidence is supporting the relevant role of lifestyle habits in the prevention and management of both depression and cancer. Therefore, the present study aims to perform a thorough review of the intricate relationship between depression and cancer, with a special focus on its biological links, clinical management, challenges, and the central role of lifestyle medicine as adjunctive and preventive approaches to improve the quality of life of these patients.
First-line treatment of camrelizumab combined with chemotherapy in advanced gastroenteropancreatic neuroendocrine carcinoma: Study protocol for a prospective, multicenter, phase II study
Authors: Li Xiaofen , Ma Qing , Chang Chen , Li Hao , Cao Dan
Published: September 2022

Background

Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a group of rare but highly aggressive malignancies. The standard chemotherapy regimens composed of etoposide and cisplatin/carboplatin (EP/EC) are of limited efficacy. This prospective, multicenter, phase II study is conducted to explore the effectiveness and safety of first-line anti-PD-1 antibody (camrelizumab) combined with chemotherapy in advanced GEP-NEC patients.

Methods

Patients with unresectable or metastatic GEP-NEC will receive camrelizumab combined with standard first-line chemotherapy every 3 weeks (camrelizumab 200 mg, administered intravenously on day 1; etoposide 100 mg/m2, administered intravenously on days 1–3; cisplatin 75 mg/m2, administered intravenously on day 1 or carboplatin area under the curve 5 mg/ml per min, administered intravenously on day 1). All patients were naïve to systemic therapy in the advanced setting. The primary endpoint is a 6-month progression-free survival (PFS) rate. The secondary endpoints are objective response rate, PFS, overall survival and adverse reactions.

Discussion

This is the first study to investigate the therapeutic potential of camrelizumab plus chemotherapy for advanced GEP-NEC. It is expected that this trial will propose a new and effective treatment strategy for GEP-NEC in the first-line setting.

Clinical Trial Registration

This trial is registered at the Chinese Clinical Trial Registry http://www.chictr.org.cn, identifier ChiCTR2100047314.

Date of Registration

June 12, 2021.
Testicular tumors in the “elderly” population
Authors: Secondino Simona , Rosti Giovanni , Tralongo Antonino C. , Nolè Franco , Alaimo Domiziana , Carminati Ornella , Naspro Richard Lawrence John , Pedrazzoli Paolo
Published: September 2022

Germ cell tumors arise in childhood but peak at around 30 years of age. They are the most common cancers in males under the age of 35. Over 95% arise in the testes while a minority originate in extragonadal sites such as the anterior mediastinum, or mainly in childhood the pineal gland or the sacrococcygeal area. These tumors show an extraordinary sensitivity to chemotherapy (and for seminoma, also to radiation) and cure rates are relatively high even in second or subsequent relapses. Very few data are present in the literature regarding patients diagnosed after 50 years and no specific trials have been conducted in this setting. Nearly all patients reported in the literature had testicular cancers, with occasional reports of extragonadal tumors. Despite the fact that > 50 years may be considered an “elderly” population, these patients are treated with the same cisplatin containing combinations as their younger counterparts with consequent higher toxicity. In this review we will present epidemiological and clinical data from this rare population of patients with testicular cancer.
Association of serum Interleukin-8 level with lymph node metastasis and tumor recurrence in gastric cancer
Authors: Li Xiang , Xie Guiping , Zhai Jing , He Yani , Wang Tongya , Wang Yaohui , Shen Lizong
Published: September 2022

The level of pretherapeutic serum interleukin-8 (sIL-8) has been demonstrated to correlate with chemoresistance in gastric cancer. However, its clinicopathological significance of sIL-8 in gastric cancer remains unknown. Herein, a total of 335 patients diagnosed with gastric adenocarcinoma were enrolled. The clinicopathological features were collected, and the sIL-8 levels were measured using enzyme-linked immunosorbent assay. The sIL-8 levels ranged from 1.48 pg/ml to 1025.22 pg/ml with > 15.41 pg/ml defined as high according to the receiver operating characteristic analysis. sIL-8 levels were strongly associated with Lauren classification and tumor recurrence. High sIL-8 correlated with lymph node metastasis (LNM) in the intestinal- and diffuse-type tumors and acted as an independent risk factor for LNM in both types. Patients with high sIL-8 levels had worse relapse-free survival than those with low sIL-8 levels. High sIL-8 level was associated with tumor relapse in the intestinal- and diffuse-type tumors, and was also an independent risk factor in the intestinal- and mixed-type tumors. Further analysis revealed that sIL-8 levels were positively associated with LNM and tumor relapse in patients with negative carcinoembryonic antigen (CEA), but not in those with elevated serum CEA levels. In conclusion, this retrospective study demonstrated that the pretherapeutic sIL-8 level has predictive value for LNM and tumor recurrence, and may serve as a potential tumor marker in gastric cancer.
Exercise improves choroid plexus epithelial cells metabolism to prevent glial cell-associated neurodegeneration
Authors: Chen Yisheng , Luo Zhiwen , Sun Yaying , Li Fangqi , Han Zhihua , Qi Beijie , Lin Jinrong , Lin Wei-Wei , Yao Mengxuan , Kang Xueran , Huang Jiebin , Sun Chenyu , Ying Chenting , Guo Chenyang , Xu Yuzhen , Chen Jiwu , Chen Shiyi
Published: September 2022

Recent studies have shown that physical activities can prevent aging-related neurodegeneration. Exercise improves the metabolic landscape of the body. However, the role of these differential metabolites in preventing neurovascular unit degeneration (NVU) is still unclear. Here, we performed single-cell analysis of brain tissue from young and old mice. Normalized mutual information (NMI) was used to measure heterogeneity between each pair of cells using the non-negative Matrix Factorization (NMF) method. Astrocytes and choroid plexus epithelial cells (CPC), two types of CNS glial cells, differed significantly in heterogeneity depending on their aging status and intercellular interactions. The MetaboAnalyst 5.0 database and the scMetabolism package were used to analyze and calculate the differential metabolic pathways associated with aging in the CPC. These mRNAs and corresponding proteins were involved in the metabolites (R)-3-Hydroxybutyric acid, 2-Hydroxyglutarate, 2-Ketobutyric acid, 3-Hydroxyanthranilic acid, Fumaric acid, L-Leucine, and Oxidized glutathione pathways in CPC. Our results showed that CPC age heterogeneity-associated proteins (ECHS1, GSTT1, HSD17B10, LDHA, and LDHB) might be directly targeted by the metabolite of oxidized glutathione (GSSG). Further molecular dynamics and free-energy simulations confirmed the insight into GSSG’s targeting function and free-energy barrier on these CPC age heterogeneity-associated proteins. By inhibiting these proteins in CPC, GSSG inhibits brain energy metabolism, whereas exercise improves the metabolic pathway activity of CPC in NVU by regulating GSSG homeostasis. In order to develop drugs targeting neurodegenerative diseases, further studies are needed to understand how physical exercise enhances NVU function and metabolism by modulating CPC-glial cell interactions.
Pien-Tze-Huang alleviates CCl4-induced liver fibrosis through the inhibition of HSC autophagy and the TGF-β1/Smad2 pathway
Authors: Zhang Yuqin , Hua Liping , Lin Chunfeng , Yuan Mingzhou , Xu Wei , Raj D. Anand , Venkidasamy Baskar , Cespedes-Acuna Carlos L. , Nile Shivraj Hariram , Yan Guohong , Zheng Haiyin
Published: September 2022

Ethnopharmacological relevance: Pien-Tze-Huang (PZH)—a traditional Chinese medicine (TCM) compound—has been employed to treat various liver inflammation and tumors for over 10 decades. Interestingly, most of the pharmacological effects had been validated and explored toward liver ailment along with pro-inflammatory conditions and cancer at the cellular and molecular level to date.

Aim of the study: The present study aimed to investigate the therapeutic effect of PZH on autophagy and TGF-β1 signaling pathways in rats with liver fibrosis and hepatic stellate cell line (HSC).

Materials and methods: Male SD rats with carbon tetrachloride (CCl4)-induced liver fibrosis were used as the animal model. Next, PZH treatment was given for 8 weeks. Afterward, the therapeutic effects of PZH were analyzed through a hepatic tissue structure by hematoxylin-eosin (H&E), Van Gieson (VG) staining, and transmission electron microscopy (TEM), activity of ALT and AST by enzyme-associated immunosorbent assay as well. Subsequently, mRNA and protein expression were examined by quantitative polymerase chain reaction (qPCR), Western blotting, and immunohistochemistry (IHC). Then, the cell vitality of PZH-treated HSC and the expression of key molecules prevailing to autophagy were studied in vitro. Meanwhile, SM16 (a novel small molecular inhibitor which inhibits TGFβ-induced Smad2 phosphorylation) was employed to confirm PZH’s effects on the proliferation and autophagy of HSC.

Results: PZH pharmacologically exerted anti-hepatic fibrosis effects as demonstrated by protecting hepatocytes and improving hepatic function. The results revealed the reduced production of extracellular collagen by adjusting the balance of matrix metalloproteinase (MMP) 2, MMP9, and tissue inhibitor of matrix metalloproteinase 1 (TIMP1) in PZH-treated CCl4-induced liver fibrosis. Interestingly, PZH inhibited the activation of HSC by down-regulating TGF-β1 and phosphorylating Smad2. Furthermore, PZH down-regulated yeast Atg6 (Beclin-1) and microtubule-associated protein light chain 3 (LC3) toward suppressing HSC autophagy, and PZH exhibited similar effects to that of SM16.

Conclusion: To conclude, PZH alleviated CCl4-induced liver fibrosis to reduce the production of extracellular collagen and inhibiting the activation of HSC. In addition, their pharmacological mechanisms related to autophagy and TGF-β1/Smad2 signaling pathways were revealed for the first time.
The pharmacology, pharmacokinetics, and toxicity of spinosin: A mini review
Authors: Kuang Xiaolan , She Ganshu , Ma Ting , Cai Wanna , Zhao Jingjing , Liu Bo , Xu Fangfang
Published: September 2022

Spinosin, a natural flavone-C-glycoside that is mainly isolated from the seeds of Ziziphus jujuba Mill. var. spinosa. It exerts the effects to ameliorate the neurological disorders, such as hypnosis effects, improvement of cognitive function, sedation effects, and anxiolytic effects, as well as anti-melanogenic effect, cardioprotective effects, and anti-cancer activity. However, the insufficient basic research, unclear mechanisms, and poor bioavailability may limit the prospects of spinosin in clinical utilization. In this review, we comprehensively summarized the latest information on the pharmacology, pharmacokinetics, toxicity, and NMR characteristic of spinosin, to evaluate its potential therapeutic for clinical application, hoping to provide some rational perspective for the innovative agent development and usage of spinosin in future.
Ca2+-stimulated adenylyl cyclases as therapeutic targets for psychiatric and neurodevelopmental disorders
Authors: Chen Jiao , Ding Qi , An Lulu , Wang Hongbing
Published: September 2022

As the main secondary messengers, cyclic AMP (cAMP) and Ca2+ trigger intracellular signal transduction cascade and, in turn, regulate many aspects of cellular function in developing and mature neurons. The group I adenylyl cyclase (ADCY, also known as AC) isoforms, including ADCY1, 3, and 8 (also known as AC1, AC3, and AC8), are stimulated by Ca2+ and thus functionally positioned to integrate cAMP and Ca2+ signaling. Emerging lines of evidence have suggested the association of the Ca2+-stimulated ADCYs with bipolar disorder, schizophrenia, major depressive disorder, post-traumatic stress disorder, and autism. In this review, we discuss the molecular and cellular features as well as the physiological functions of ADCY1, 3, and 8. We further discuss the recent therapeutic development to target the Ca2+-stimulated ADCYs for potential treatments of psychiatric and neurodevelopmental disorders.
Traditional Chinese Medicine: A promising strategy to regulate inflammation, intestinal disorders and impaired immune function due to sepsis
Authors: Wang Xu-Hua , Xu Ding-Qiao , Chen Yan-Yan , Yue Shi-Jun , Fu Rui-Jia , Huang Lu , Tang Yu-Ping
Published: September 2022

Sepsis is described as a dysregulation of the immune response to infection, which leads to life-threatening organ dysfunction. The interaction between intestinal microbiota and sepsis can’t be ignored. Furthermore, the intestinal microbiota may regulate the progress of sepsis and attenuate organ damage. Thus, maintaining or restoring microbiota may be a new way to treat sepsis. Traditional Chinese medicine (TCM) assumes a significant part in the treatment of sepsis through multi-component, multi-pathway, and multi-targeting abilities. Moreover, TCM can prevent the progress of sepsis and improve the prognosis of patients with sepsis by improving the imbalance of intestinal microbiota, improving immunity and reducing the damage to the intestinal barrier. This paper expounds the interaction between intestinal microbiota and sepsis, then reviews the current research on the treatment of sepsis with TCM, to provide a theoretical basis for its clinical application.
Structural modeling of the hERG potassium channel and associated drug interactions
Authors: Maly Jan , Emigh Aiyana M. , DeMarco Kevin R. , Furutani Kazuharu , Sack Jon T. , Clancy Colleen E. , Vorobyov Igor , Yarov-Yarovoy Vladimir
Published: September 2022

The voltage-gated potassium channel, KV11.1, encoded by the human Ether-à-go-go-Related Gene (hERG), is expressed in cardiac myocytes, where it is crucial for the membrane repolarization of the action potential. Gating of the hERG channel is characterized by rapid, voltage-dependent, C-type inactivation, which blocks ion conduction and is suggested to involve constriction of the selectivity filter. Mutations S620T and S641A/T within the selectivity filter region of hERG have been shown to alter the voltage dependence of channel inactivation. Because hERG channel blockade is implicated in drug-induced arrhythmias associated with both the open and inactivated states, we used Rosetta to simulate the effects of hERG S620T and S641A/T mutations to elucidate conformational changes associated with hERG channel inactivation and differences in drug binding between the two states. Rosetta modeling of the S641A fast-inactivating mutation revealed a lateral shift of the F627 side chain in the selectivity filter into the central channel axis along the ion conduction pathway and the formation of four lateral fenestrations in the pore. Rosetta modeling of the non-inactivating mutations S620T and S641T suggested a potential molecular mechanism preventing F627 side chain from shifting into the ion conduction pathway during the proposed inactivation process. Furthermore, we used Rosetta docking to explore the binding mechanism of highly selective and potent hERG blockers - dofetilide, terfenadine, and E4031. Our structural modeling correlates well with much, but not all, existing experimental evidence involving interactions of hERG blockers with key residues in hERG pore and reveals potential molecular mechanisms of ligand interactions with hERG in an inactivated state.
Alkaloid ligands enable function of homomeric human α10 nicotinic acetylcholine receptors
Authors: Hone Arik J. , McIntosh J. Michael
Published: September 2022

In the nervous system, nicotinic acetylcholine receptors (nAChRs) rapidly transduce a chemical signal into one that is electrical via ligand-gated ion flux through the central channel of the receptor. However, some nAChR subunits are expressed by non-excitable cells where signal transduction apparently occurs through non-ionic mechanisms. One such nAChR subunit, α10, is present in a discreet subset of immune cells and has been implicated in pathologies including cancer, neuropathic pain, and chronic inflammation. Longstanding convention holds that human α10 subunits require co-assembly with α9 subunits for function. Here we assessed whether cholinergic ligands can enable or uncover ionic functions from homomeric α10 nAChRs. Xenopus laevis oocytes expressing human α10 subunits were exposed to a panel of ligands and examined for receptor activation using voltage-clamp electrophysiology. Functional expression of human α10 nAChRs was achieved by exposing the oocytes to the alkaloids strychnine, brucine, or methyllycaconitine. Furthermore, acute exposure to the alkaloid ligands significantly enhanced ionic responses. Acetylcholine-gated currents mediated by α10 nAChRs were potently inhibited by the snake toxins α-bungarotoxin and α-cobratoxin but not by α-conotoxins that target α9 and α9α10 nAChRs. Our findings indicate that human α10 homomers are expressed in oocytes and exposure to certain ligands can enable ionic functions. To our knowledge, this is the first demonstration that human α10 subunits can assemble as functional homomeric nAChRs. These findings have potential implications for receptor regulatory-mechanisms and will enable structural, functional, and further pharmacological characterization of human α10 nAChRs.
Iron dyshomeostasis and ferroptosis in Alzheimer’s disease: Molecular mechanisms of cell death and novel therapeutic drugs and targets for AD
Authors: Zhang Yuan , Wang Man , Chang Wenguang
Published: September 2022

Alzheimer’s disease (AD) is a degenerative disease of the central nervous system that is the most common type of senile dementia. Ferroptosis is a new type of iron-dependent programmed cell death identified in recent years that is different from other cell death forms. Ferroptosis is induced by excessive accumulation of lipid peroxides and reactive oxygen species (ROS) in cells. In recent years, it has been found that ferroptosis plays an important role in the pathological process of AD. Iron dyshomeostasis contribute to senile plaques (SP) deposition and neurofibrillary tangles (NFTs). Iron metabolism imbalance in brain and the dysfunction of endogenous antioxidant systems including system Xc- and glutathione peroxidase (GPX) are closely related to the etiopathogenesis of AD. Dysfunction of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy induced ferroptosis can accelerates the pathological process of AD. In addition, NRF2, through regulating the expression of a considerable number of genes related to ferroptosis, including genes related to iron and glutathione metabolism, plays an important role in the development of AD. Here, we review the potential interaction between AD and ferroptosis and the major pathways regulating ferroptosis in AD. We also review the active natural and synthetic compounds such as iron chelators, lipid peroxidation inhibitors and antioxidants available to treat AD by alleviating iron dyshomeostasis and preventing ferroptosis in mice and cell models to provide valuable information for the future treatment and prevention of AD.
Essential oil from the roots of Paeonia lactiflora pall. has protective effect against corticosterone-induced depression in mice via modulation of PI3K/Akt signaling pathway
Authors: Sun Jia-Yi , Liu Yi-Tong , Jiang Sheng-Nan , Guo Peng-Mei , Wu Xin-Yu , Yu Jia
Published: September 2022

For thousands of years, the roots of Paeonia lactiflora Pall (PLP) has been considered by traditional Chinese medicine as a drug that can improve mental or emotional disorders, including depression, anxiety and affective disorders. Unfortunately, the research on the mechanism of action and active ingredients of this beneficial drug is not comprehensive. This study focused on the activity of essential oil from PLP (EOP), systematically studied the antidepressant effect of EOP for the first time, and discussed the potential mechanism of its antidepressant effect. In this study, we used a mouse model of corticosterone (CORT)-induced depression, and found that EOP had a significant antidepressant effect on the symptoms of CORT-induced depression in mice, and significantly down-regulated the levels of CRH, ACTH and cortisol in the brain tissues of mice. In addition, we found that EOP treatment alleviated CORT-induced hippocampal neuron injury in mice In vitro experiments. It was also found that EOP could inhibit CORT-induced apoptosis and improve the proliferation ability and cell viability of PC12 cells. Further, with the help of network analysis, it was revealed that PI3K-Akt might be one of the main signaling pathways of EOP against CORT-induced hippocampal neuron apoptosis. In this study, we also found that EOP up-regulated the phosphorylation of PI3K and Akt in CORT-induced mouse hippocampal neurons and PC12 cells, and promoted the nuclear transcription of Nrf2 in CORT-induced PC12 cells. In conclusion, with the integrated approach, we demonstrated that EOP exerted anti-apoptotic effects on hippocampal neurons through PI3K/Akt/Nrf2 signaling pathway.
Satellite-borne atomic clock based on diffuse laser-cooled atoms
Authors: Meng Yan-Ling , Jiang Xiao-Jun , Wu Jing , Ye Mei-Feng , Cheng Hua-Dong , Li Lin , Liu Liang
Published: September 2022

The technique of laser cooling of atoms gives an opportunity to improve the performance of atomic clocks by using laser-cooled atoms. The most successful cold atom clock, called the atomic fountain, is now widely used as the primary frequency standard in many labs. The cold atom clock for satellite applications, however, has not been reported so far due to special requirements of space applications. Here, we report the development of an engineering model of a satellite-borne cold atom clock, which satisfied all requirements of in-orbit operation. The core of the clock’s principle is the laser cooling of atoms by diffuse laser lights inside the microwave cavity. The structure of the physics package is presented, and its main parameters are also given. The principle and design of the optical bench are described. The initial test results are presented, and the possible improvements are also discussed.
Influence of launch beam distribution on power flow and angular division multiplexing in seven-core silica optical fibers
Authors: Savović Svetislav , Dai Wenjing , Djordjevich Alexandar , Aidinis Konstantinos , Li Zheng , Min Rui
Published: September 2022

We analyze the effect of launch beam distribution on space-division multiplexing (SDM) performance in multimode multicore silica optical fibers (MM MC SOF) with seven cores. The time-independent power flow equation (TI PFE) is used to explore the effect of the width of the distribution of the Gaussian launch beam on power flow in each of the seven cores. We show that the optical fiber length at which the equilibrium mode distribution (EMD) and steady-state distribution (SSD) are obtained is greatly influenced by the width of the Gaussian launch beam distribution. We further show that when the width of the Gaussian launch beam distribution widens, the optical fiber length at which angular division multiplexing (ADM) in each of the seven cores can be realized with minimal crosstalk between neighboring angular optical channels decreases. We demonstrate that, for increasing the capacity of an optical fiber transmission system, an SDM system with two- and three-channel ADM and multicore optical fiber multiplexing can be implemented with the proposed seven-core MM MC SOF at optical fiber lengths up to ≈1 km (2 ADM channels × 7 cores) and ≈200 m (3 ADM channels × 7 cores), respectively. Such characterization of MM MC SOFs under various launch conditions is important for building a multicore optical fiber SDM transmission system.