bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential bioactivities via anticancer, antioxidant, and immunomodulatory properties of cultured mycelial enriched β-D-glucan polysaccharides from a novel fungus Ophiocordyceps sinensis OS8
Authors: Chatnarin Suwannachom , Thirabunyanon Mongkol
Published: April 2023

Background

Ophiocordyceps sinensis is well-known worldwide as a traditional medicine. An alternative natural source of O. sinensis is provided by mycelial cultivation. However, the bioactivities of cultured mycelial-enriched β-D-glucan polysaccharides from a novel fungus O. sinensis OS8 are still unknown.

Methods

We investigated the potential bioactivities via anticancer, antioxidant, and immunomodulatory polysaccharides (OS8P) produced from cultured mycelia of O. sinensis OS8. This strain is a novel fungus isolated from natural O. sinensis, which is further cultured by submerged mycelial cultivation for polysaccharide production.

Results

The yield of mycelial biomass was 23.61 g/l, and it contained 306.1 mg/100 g of adenosine and 3.22 g/100 g of polysaccharides. This OS8P was enriched with β-D-glucan at 56.92% and another form of α-D-glucan at 35.32%. The main components of OS8P were dodecamethyl pentasiloxane, 2,6-bis (methylthiomethyl) pyridine, 2-(4-pyrimidinyl)-1H-Benzimidazole, and 2-Chloro-4-(4-nitroanilino)-6-(O-toluidino)-1,3,5-triazine at the rates of 32.5, 20.0, 17.5, and 16.25%, respectively. The growth of colon cancer cells (HT-29) was significantly inhibited by OS8P, with IC50 value of 202.98 µg/ml, and encouraged apoptosis in HT-29 cells as confirmed by morphological change analysis via AO/PI and DAPI staining, DNA fragmentation, and scanning electron microscopic observations. In addition, significant antioxidant activity was demonstrated by OS8P through DPPH and ABTS assays, with IC50 values of 0.52 and 2.07 mg/ml, respectively. The OS8P also exhibited suitable immunomodulatory activities that significantly enhanced (P< 0.05) the induction of splenocyte proliferation.

Conclusion

The OS8P enriched with β-D-glucan polysaccharides and produced by submerged mycelial culture of a new fungal strain of O. sinensis OS8 strongly inhibited the proliferation of colon cancer cells without any cytotoxicity against normal cells. The potential effect of the OS8P on the cancer cells was due to the stimulation of apoptosis. Also, the OS8P exhibited good antioxidant and immunomodulatory activities. The results indicate that OS8P has promising applications in the functional food industry and/or therapeutic agents for colon cancer.
Bacteroides fragilis strain ZY-312 facilitates colonic mucosa regeneration in colitis via motivating STAT3 signaling pathway induced by IL-22 from ILC3 secretion
Authors: Zhang Wendi , Zhou Qian , Liu Hongbin , Xu Jiahui , Huang Ruo , Shen Binhai , Guo Yandong , Ai Xiuyun , Xu Jun , Zhao Xinmei , Liu Yangyang , Wang Ye , Zhi Fachao
Published: April 2023

Introduction

Probiotics play critical roles in relieving inflammatory bowel disease (IBD). However, the underlying mechanism of Bacteroides fragilis strain ZY-312 (B. fragilis) for colonic mucosa regeneration in IBD remains unclear.

Methods

The weight loss, disease activity index (DAI), colon length, and histopathology-associated index (HAI) were evaluated the therapeutic effects of B. fragilis in a DSS-induced colitis mouse model. Colonic mucosa proliferation and apoptosis level, and mucus density were detected by histological stain. Gut microbiota was sequenced by 16srRNA analysis. The expression of signal transducer and activator of transcription 3 (STAT3) phosphorylation in colonic mucosa was detected in B. fragilis-treated mice in colitis. B. fragilis-regulated immunity factors of motivating downstream STAT3 phosphorylation were screened by ELISA and flow cytometry. Lastly, B. fragilis-mediated colonic mucosa regeneration effects were verified though the knockout of STAT3 (Stat3△IEC) and IL-22 (IL-22-/-) in mice, and inhibitor of STAT3 and IL-22 in co-culture model.

Results

B. fragilis alleviated DSS-induced colitis in mice with less weight loss, DAI, colon length shortening, and HAI. Further the results showed that B. fragilis motivated STAT3 phosphorylation in colonic mucosa with the upregulation of proliferation index Ki-67 and mucus density, the downregulation of apoptosis level, and the modulation of gut microbiota through a Stat3△IEC mice model and STAT3 inhibitor-added model in vitro. Meanhwhile we found that B. fragilis promoted IL-22 production, and increased the percentage of IL-22-secreting type 3 innate lymphocytes (ILC3) in colitis. Consequently, We identified that B. fragilis did not increase the expression of pSTAT3, either proliferation level, mucus density, or alter gut microbiota in IL-22-/- mice.

Discussion

B. fragilis may indirectly motivate ILC3 to secrete IL-22, followed by IL-22-induced STAT3 phosphorylation, hence promoting colonic mucosa regeneration in colitis. It indicates that B. fragilis has the potential to be a biological agent for IBD therapy.
3D cancer models: One step closer to in vitro human studies
Authors: Manduca Nicoletta , Maccafeo Ester , De Maria Ruggero , Sistigu Antonella , Musella Martina
Published: April 2023

Cancer immunotherapy is the great breakthrough in cancer treatment as it displayed prolonged progression-free survival over conventional therapies, yet, to date, in only a minority of patients. In order to broad cancer immunotherapy clinical applicability some roadblocks need to be overcome, first among all the lack of preclinical models that faithfully depict the local tumor microenvironment (TME), which is known to dramatically affect disease onset, progression and response to therapy. In this review, we provide the reader with a detailed overview of current 3D models developed to mimick the complexity and the dynamics of the TME, with a focus on understanding why the TME is a major target in anticancer therapy. We highlight the advantages and translational potentials of tumor spheroids, organoids and immune Tumor-on-a-Chip models in disease modeling and therapeutic response, while outlining pending challenges and limitations. Thinking forward, we focus on the possibility to integrate the know-hows of micro-engineers, cancer immunologists, pharmaceutical researchers and bioinformaticians to meet the needs of cancer researchers and clinicians interested in using these platforms with high fidelity for patient-tailored disease modeling and drug discovery.
Live-attenuated Japanese encephalitis virus inhibits glioblastoma growth and elicits potent antitumor immunity
Authors: Qi Zhongbing , Zhao Jing , Li Yuhua , Zhang Bin , Hu Shichuan , Chen Yanwei , Ma Jinhu , Shu Yongheng , Wang Yunmeng , Cheng Ping
Published: April 2023

Glioblastomas (GBMs) are highly aggressive brain tumors that have developed resistance to currently available conventional therapies, including surgery, radiation, and systemic chemotherapy. In this study, we investigated the safety of a live attenuated Japanese encephalitis vaccine strain (JEV-LAV) virus as an oncolytic virus for intracerebral injection in mice. We infected different GBM cell lines with JEV-LAV to investigate whether it had growth inhibitory effects on GBM cell lines in vitro. We used two models for evaluating the effect of JEV-LAV on GBM growth in mice. We investigated the antitumor immune mechanism of JEV-LAV through flow cytometry and immunohistochemistry. We explored the possibility of combining JEV-LAV with PD-L1 blocking therapy. This work suggested that JEV-LAV had oncolytic activity against GBM tumor cells in vitro and inhibited their growth in vivo. Mechanistically, JEV-LAV increased CD8+ T cell infiltration into tumor tissues and remodeled the immunosuppressive GBM microenvironment that is non-conducive to immunotherapy. Consequently, the results of combining JEV-LAV with immune checkpoint inhibitors indicated that JEV-LAV therapy improved the response of aPD-L1 blockade therapy against GBM. The safety of intracerebrally injected JEV-LAV in animals further supported the clinical use of JEV-LAV for GBM treatment.
Small-scale oxygen distribution patterns in a coral reef
Authors: Candy Adam S. , Taylor Parkins Shannara K. , Van Duyl Fleur C. , Mueller Benjamin , Arts Milou G. I. , Barnes Will , Carstensen Marie , Scholten Yun J. H. , El-Khaled Yusuf C. , Wild Christian , Wegley Kelly Linda , Nelson Craig E. , Sandin Stuart A. , Vermeij Mark J. A. , Rohwer Forest L. , Picioreanu Cristian , Stocchi Paolo , Haas Andreas F.
Published: April 2023

One mechanism giving fleshy algae a competitive advantage over corals during reef degradation is algal-induced and microbially-mediated hypoxia (typically less than 69.5 µmol oxygen L−1). During hypoxic conditions oxygen availability becomes insufficient to sustain aerobic respiration in most metazoans. Algae are more tolerant of low oxygen conditions and may outcompete corals weakened by hypoxia. A key question on the ecological importance of this mechanism remains unanswered: How extensive are local hypoxic zones in highly turbulent aquatic environments, continuously flushed by currents and wave surge? To better understand the concert of biological, chemical, and physical factors that determine the abundance and distribution of oxygen in this environment, we combined 3D imagery, flow measurements, macro- and micro-organismal abundance estimates, and experimentally determined biogenic oxygen and carbon fluxes as input values for a 3D bio-physical model. The model was first developed and verified for controlled flume experiments containing coral and algal colonies in direct interaction. We then developed a three-dimensional numerical model of an existing coral reef plot off the coast of Curaçao where oxygen concentrations for comparison were collected in a small-scale grid using fiberoptic oxygen optodes. Oxygen distribution patterns given by the model were a good predictor for in situ concentrations and indicate widespread localized differences exceeding 50 µmol L-1 over distances less than a decimeter. This suggests that small-scale hypoxic zones can persist for an extended period of time in the turbulent environment of a wave- and surge- exposed coral reef. This work highlights how the combination of three-dimensional imagery, biogenic fluxes, and fluid dynamic modeling can provide a powerful tool to illustrate and predict the distribution of analytes (e.g., oxygen or other bioactive substances) in a highly complex system.
Characterization and expression profile of transient receptor potential channels in sea cucumber Apostichopus japonicus
Authors: Wang Xuemin , Wang Yixin , Wang Yanlin , Storey Kenneth B. , Chen Muyan
Published: April 2023

Background

In the past few decades, heat waves and seasonal variation linked with global warming are causing frequent fluctuations of water temperature in aquatic environments, resulting in further challenges for marine organisms. As a poikilothermic marine animal and a temperate species, sea cucumber A. japonicus is also very sensitive to temperature variation and shows a limited ability to adapt to environmental temperature changes. However, the molecular mechanisms by which A. japonicus perceives signals from such a diverse environment including the trigger of aestivation still remain unclear. TRP (transient receptor potential) superfamily, as the great potential “sentinel” of the organism in response to the changes of the external environment signals, perceived little attention and will be the future great candidates for sensory function research in echinoderm.

Methods

BLAST program was applied to identify the AjTRPs based on A. japonicus transcriptome database. Gene structure analysis of AjTRPs and phylogenetic analysis of TRPs were performed. The expression profiles of AjTRPs in different tissues and in response to different heat stress treatments (chronic/ acute) were measured using qRT-PCR.

Results

A total of 54 TRPs were identified in A. japonicus. Gene structure analysis showed that the exon numbers and the domains of AjTRPs varied greatly. Phylogenetic analysis indicated that AjTPRs were mainly grouped into six subfamilies: TRPA, TRPM, TRPC, TRPV, TRPML, and TRPP. Copy numbers of each TRP member in marine invertebrates including A. japonicus were more than those in vertebrates, however some TRP channel members were lost in invertebrates. Expression profile detection suggested that the representative 15 AjTRP genes belonging to 6 subfamilies were expressed in all tissues examined.

Conclusion

Our findings indicate that the plastic evolutionary history of TRP channel genes and suggest that TRPM2-1, TRPM2-2, TRPM3, and TRPC3-1 are potential thermo-TRP proteins involved in thermal regulation in A. japonicus. This work facilitates the knowledge of TRP-mediated sensory systems in echinoderms, provides new insights into the mechanisms of aestivation and global warming adaptation in marine invertebrates.
Transport properties of moisture and ionic chelators in concrete
Authors: Lu Rongwei , Guan Xinchun
Published: April 2023

The transport properties of moisture and ionic chelators in the concrete affect not only the durability of the concrete, but also the effectiveness of the repair material in repairing cracks in the concrete. The transport of water and ionic chelators in the concrete was investigated by capillary absorption tests and ICP-OES (Inductively Coupled Plasma Optical Emission Spectrometer). It was found that the smaller the radius of the capillary pore within the concrete, the longer it takes to saturate it with water.The different pore sizes of capillaries take different times to reach saturation, which is one of the reasons for the “square root shift phenomenon” of capillary water absorption in concrete. The higher the initial concentration, the easier it is for the ion chelators to be transported inside the concrete within a certain transport depth range. However, after a certain range of transport depth, the initial concentration does not have a significant effect on the transport of the ion chelators. This is not the same as the transport pattern of nonchelated ions. Comparing the transport processes of chelated and non-chelated ions within the concrete, it was found that chelated ions form aggregation zones when transported within the concrete. The analysis suggests that the repair of pores and cracks within the concrete by the chelating agent promotes the creation of aggregation zones. Other factors such as the presence of chelated ions, the transport medium, changes in porosity, and wet and dry cycles can all influence the formation of chelated ion aggregates.
Phylogeography of Francisella tularensis subspecies holarctica and epidemiology of tularemia in Switzerland
Authors: Schütz Sara Doina , Liechti Nicole , Altpeter Ekkehardt , Labutin Anton , Wütrich Tsering , Schmidt Kristina Maria , Buettcher Michael , Moser Michel , Bruggmann Rémy , Wittwer Matthias
Published: April 2023

Tularemia, an endemic disease that mainly affects wild animals and humans, is caused by Francisella tularensis subsp. holarctica (Fth) in Switzerland. The Swiss Fth population consist of multiple different subclades which are distributed throughout the country. The aim of this study is to characterize the genetic diversity of Fth in Switzerland and to describe the phylogeographic relationship of isolates by single nucleotide polymorphism (SNP) analysis. This analysis is combined with human surveillance data from reported cases over the last 10 years and in vitro and in silico antibiotic resistance tests to provide insight into the epidemiology of tularemia in Switzerland. We sequenced the whole genomes of 52 Fth strains of human or tick origin collected in Switzerland between 2009 and 2022 and analyzed together with all publicly available sequencing data of Swiss and European Fth. Next, we performed a preliminary classification with the established canonical single nucleotide polymorphism nomenclature. Furthermore, we tested 20 isolates from all main Swiss clades for antimicrobial susceptibility against a panel of antimicrobial agents. All 52 sequenced isolates from Switzerland belong to major clade B.6, specifically subclades B.45 and B.46, previously described in Western Europe. We were able to accurately reconstruct the population structure according to the global phylogenetic framework. No resistance to clinically recommended antibiotics could be identified in vitro or in silico in the western B.6 strains.
Efficacy and safety of selegiline for the treatment of Parkinson's disease: A systematic review and meta-analysis
Authors: Wang Ke , Liu Ze-Hui , Li Xin-Ya , Li Yan-Fei , Li Jia-Rui , Hui Jiao-Jiao , Li Jing-Xuan , Zhou Jun-Wen , Yi Zhan-Miao
Published: April 2023

Background

Drug efficacy generally varies with different durations. There is no systematic review analyzing the effect of selegiline for Parkinson's disease (PD) on different treatment duration. This study aims to analyze how the efficacy and safety of selegiline changes for PD over time.

Methods

PubMed, the Cochrane Library, Embase, China National Knowledge Infrastructure and Wanfang Database were systematically retrieved for randomized controlled trials (RCTs) and observational studies of selegiline for PD. The search period was from inception to January 18th, 2022. The efficacy outcomes were measured by the mean change from baseline in the total and sub Unified Parkinson's Disease Rating Scale (UPDRS), Hamilton Depression Rating Scale (HAMD) and Webster Rating Scale (WRS) scores. The safety outcomes were measured by the proportion of participants having any adverse events overall and that in different system organ classes.

Results

Among the 3,786 studies obtained, 27 RCTs and 11 observational studies met the inclusion criteria. Twenty-three studies reported an outcome which was also reported in at least one other study, and were included in meta-analyses. Compared with placebo, selegiline was found with a stronger reduction of total UPDRS score with increasing treatment duration [mean difference and 95% CIs in 1 month: −3.56 (−6.67, −0.45); 3 months: −3.32 (−3.75, −2.89); 6 months: −7.46 (−12.60, −2.32); 12 months: −5.07 (−6.74, −3.41); 48 months: −8.78 (−13.75, −3.80); 60 months: −11.06 (−16.19, −5.94)]. A similar trend was also found from the point estimates in UPDRS I, II, III, HAMD and WRS score. The results of observational studies on efficacy were not entirely consistent. As for safety, compared with placebo, selegiline had higher risk of incurring any adverse events [rate: 54.7% vs. 62.1%; odd ratio and 95% CIs: 1.58 (1.02, 2.44)], with the excess adverse events mainly manifested as neuropsychiatric disorders [26.7% vs. 31.6%; 1.36 (1.06, 1.75)] and no significant change over time. The statistically difference in overall adverse event between selegiline and active controls was not found.

Conclusion

Selegiline was effective in improving total UPDRS score with increasing treatment duration, and had a higher risk of incurring adverse events, especially the adverse events in the neuropsychiatric system.

Systematic review registration

https://www.crd.york.ac.uk/prospero/, identifier: PROSPERO CRD42021233145.
Novel duplication of the cell adhesion molecule L1-like gene in an individual with cognitive impairment, tall stature, and obesity: A case report
Authors: Onate-Quiroz Kenny V. , Nwosu Benjamin Udoka , Salemi Parissa
Published: April 2023

The gene that codes for the close homolog of L1 (CHL1 gene) is located in the 3p26.3 cytogenetic band in the distal portion of the 3p chromosome. This gene is highly expressed in the central nervous system and plays an important role in brain formation and plasticity. Complete or partial CHL 1 gene-deficient mice have demonstrated neurocognitive deficits. In humans, mutations of the CHL 1 gene are infrequent with most mutations described in the literature as deletions. This case report describes an individual with a duplication in the CHL 1 and a presentation consistent with a syndromic form of neurocognitive impairment. To the best of our knowledge, this mutation has not been previously described in the literature.
Rapid injection of lumbar dorsal root ganglia under direct vision: Relevant anatomy, protocol, and behaviors
Authors: Yuan Xiaoman , Han Siyi , Zhao Fengtian , Manyande Anne , Gao Feng , Wang Jie , Zhang Wen , Tian Xuebi
Published: April 2023

Introduction

Dorsal root ganglia (DRG) are anatomically well-defined structures that contain all primary sensory neurons and are distension nodules of the dorsal root in the spinal cord near the medial surface of each foramen. Therefore, DRG is considered to be a desirable target for injection to manage chronic pain. But it presents a limitation in probing deep into it without in vivo injection technology.

Methods

Here, we described a technique for administering intraganglionic injections of lumbar DRG under direct vision. We use partial osteotomy rather than laminectomy, which removes more bone, to preserve spinal structures while gaining adequate DRG access. To monitor the intraoperative progress of the DRG injection, a non-toxic dye was utilized. The effectiveness of the injection on the diffusion of AAV (adeno-associated virus) within the ganglion was assessed by histopathology at postoperative day 21.

Results

Behavioral tests showed that neither motor nor sensory abilities were affected by saline or AAV injections. Meanwhile, the decreased pain threshold of SNI (spared nerve injury) was considerably restored by pharmacological inhibition of DRG neurons.

Discussion

Our research achieved a new minimally invasive and intuitive intra-ganglionic injection in mice. In addition, the present protocol may serve as a valuable resource for planning preclinical studies of DRG injection.
Case report: A longitudinal study of an unusual rapidly progressive dementia case
Authors: Liu Xiaoyan , Fan Ziqi , Chen Xuanyu , Zhang Yanyan , He Fangping , Ma Xiaohua , Ke Qing
Published: April 2023

It is daunting to determine the etiology of rapidly progressive dementia (RPD), which includes metabolic, neoplastic, infectious, autoimmune, neurodegenerative and other conditions. Herein, we illustrate an unusual case of a patient primarily exhibiting RPD, overlapping sleep dysfunction, psychosis and abnormal movement, which was finally defined as anti-IgLON5 disease, a novel and rare autoimmune encephalopathy. Furthermore, we longitudinally described his cognitive and psychological performance in detail, and determined that early initiation of immunotherapy in this patient did not result in a good outcome. These data highlight anti-IgLON5 disease as a possible differential diagnosis in patients with RPD.
A review of technological innovations leading to modern endovascular brain aneurysm treatment
Authors: Lauzier David C. , Huguenard Anna L. , Srienc Anja I. , Cler Samuel J. , Osbun Joshua W. , Chatterjee Arindam R. , Vellimana Ananth K. , Kansagra Akash P. , Derdeyn Colin P. , Cross Dewitte T. , Moran Christopher J.
Published: April 2023

Tools and techniques utilized in endovascular brain aneurysm treatment have undergone rapid evolution in recent decades. These technique and device-level innovations have allowed for treatment of highly complex intracranial aneurysms and improved patient outcomes. We review the major innovations within neurointervention that have led to the current state of brain aneurysm treatment.
Comparative in-silico analysis of microbial dysbiosis discern potential metabolic link in neurodegenerative diseases
Authors: Chauhan Vipin , Chauhan Nitin K. , Dutta Somit , Pathak Dhruv , Nongthomba Upendra
Published: April 2023

A healthy gut flora contains a diverse and stable commensal group of microorganisms, whereas, in disease conditions, there is a shift toward pathogenic microbes, termed microbial dysbiosis. Many studies associate microbial dysbiosis with neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Although, an overall comparative analysis of microbes and their metabolic involvement in these diseases is still lacking. In this study, we have performed a comparative analysis of microbial composition changes occurring in these four diseases. Our research showed a high resemblance of microbial dysbiosis signatures between AD, PD, and MS. However, ALS appeared dissimilar. The most common population of microbes to show an increase belonged to the phyla, Bacteroidetes, Actinobacteria, Proteobacteria, and Firmicutes. Although, Bacteroidetes and Firmicutes were the only phyla that showed a decrease in their population. The functional analysis of these dysbiotic microbes showed several potential metabolic links which can be involved in the altered microbiome-gut-brain axis in neurodegenerative diseases. For instance, the microbes with elevated populations lack pathways for synthesizing SCFA acetate and butyrate. Also, these microbes have a high capacity for producing L-glutamate, an excitatory neurotransmitter and precursor of GABA. Contrastingly, Tryptophan and histamine have a lower representation in the annotated genome of elevated microbes. Finally, the neuroprotective compound spermidine was less represented in elevated microbes' genomes. Our study provides a comprehensive catalog of potential dysbiotic microbes and their metabolic involvement in neurodegenerative disorders, including AD, PD, MS, and ALS.
Effects of noninvasive brain stimulation on dual-task performance in different populations: A systematic review
Authors: Lin Xiaoying , Zhang Yanming , Chen Xi , Wen Lifen , Duan Lian , Yang Lei
Published: April 2023

Background

Increasing research has investigated the use of noninvasive brain stimulation (NIBS) on augmenting dual-task (DT) performance.

Objective

To investigate the effects of NIBS on DT performance in different populations.

Methods

Extensive electronic database search (from inception to November 20, 2022) was conducted in PubMed, Medline, Cochrane Library, Web of Science and CINAHL to identify randomized controlled trials (RCTs) that investigated the effects of NIBS on DT performance. Main outcomes were balance/mobility and cognitive function under both single-task (ST) and DT conditions.

Results

Fifteen RCTs were included, involving two types of intervention techniques: transcranial direct current stimulation (tDCS) (twelve RCTs) and repetitive transcranial magnetic stimulation (rTMS) (three RCTs); and four different population groups: healthy young adults, older adults, Parkinson’s disease (PD), and stroke. For tDCS, under DT condition, significant improvement in speed was only observed in one PD and one stroke RCT, and stride time variability in one older adults RCT. Reduction in DTC in some gait parameters was demonstrated in one RCT. Only one RCT showed significant reduction in postural sway speed and area during standing under DT condition in young adults. For rTMS, significant improvements in fastest walking speed and time taken to Timed-up-and-go test under both ST and DT conditions were observed at follow-up in one PD RCT only. No significant effect on cognitive function in any RCT was observed.

Conclusion

Both tDCS and rTMS showed promising effects in improving DT walking and balance performance in different populations, however, due to the large heterogeneity of included studies and insufficient data, any firm conclusion cannot be drawn at present.
Effects of alcohol and PARP inhibition on RNA ribosomal engagement in cortical excitatory neurons
Authors: Krishnan Harish R. , Vallerini Gian Paolo , Gavin Hannah E. , Guizzetti Marina , Rizavi Hooriyah S. , Gavin David P. , Sharma Rajiv P.
Published: April 2023

We report on the effects of ethanol (EtOH) and Poly (ADP-ribose) polymerase (PARP) inhibition on RNA ribosomal engagement, as a proxy for protein translation, in prefrontal cortical (PFC) pyramidal neurons. We hypothesized that EtOH induces a shift in RNA ribosomal-engagement (RE) in PFC pyramidal neurons, and that many of these changes can be reversed using a PARP inhibitor. We utilized the translating ribosome affinity purification (TRAP) technique to isolate cell type-specific RNA. Transgenic mice with EGFP-tagged Rpl10a ribosomal protein expressed only in CaMKIIα-expressing pyramidal cells were administered EtOH or normal saline (CTL) i.p. twice a day, for four consecutive days. On the fourth day, a sub-group of mice that received EtOH in the previous three days received a combination of EtOH and the PARP inhibitor ABT-888 (EtOH + ABT-888). PFC tissue was processed to isolate both, CaMKIIα pyramidal cell-type specific ribosomal-engaged RNA (TRAP-RNA), as well as genomically expressed total-RNA from whole tissue, which were submitted for RNA-seq. We observed EtOH effects on RE transcripts in pyramidal cells and furthermore treatment with a PARP inhibitor “reversed” these effects. The PARP inhibitor ABT-888 reversed 82% of the EtOH-induced changes in RE (TRAP-RNA), and similarly 83% in the total-RNA transcripts. We identified Insulin Receptor Signaling as highly enriched in the ethanol-regulated and PARP-reverted RE pool and validated five participating genes from this pathway. To our knowledge, this is the first description of the effects of EtOH on excitatory neuron RE transcripts from total-RNA and provides insights into PARP-mediated regulation of EtOH effects.
Sarcopenia is an independent risk factor for all-cause mortality rate in patients with diabetic foot ulcers
Authors: Yang Qin , Ni Xia , Zhang Yingxiao , Zhu Baozhen , Zeng Qinglian , Yang Chan , Shi Jiale , Zhang Chunlin , Cai Jiahui , Hu Jinbo , Li Qifu , Jiang Yingsong , Cheng Qingfeng , Cheng Chao
Published: April 2023

Objective

This study aimed to determine whether sarcopenia affects the all-cause mortality rate of patients with diabetic foot ulcers (DFUs).

Research design and methods

The clinic-based observational study included 217 patients treated at the Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University during a 4-year period. All subjects underwent dual-energy X-ray absorptiometry to determine their body composition during hospitalization. Diagnosis of sarcopenia was based on the Baumgartner diagnostic criteria. Patients were followed up regularly by phone calls until April 1, 2019, and their survival status was recorded.Univariate and multivariate Cox risk ratio regression models were used to analyze factors influencing the all-cause mortality rate of patients with DFUs.

Results

Of the 217 patients, 158 people survived (82.7%), 33 died (17.3%), and 26 were lost to follow-up. The median follow-up time was 23 (Range 11–34) months. The majority of patients were male (68.6%), with a mean age of 67.29 ± 11.14 years. The 5-year survival rate was 68.3% and 45.9% for all study patients (n = 217) and sarcopenia patients (n = 81), respectively. Multivariate Cox risk regression model showed that age (HR 1.042[95%CI:1.006, 1.078], P = 0.021), sarcopenia (HR 5.051[95%CI:1.968, 12.961], P = 0.001), and serum creatinine (HR 1.007[95%CI: 1.003, 1.010], P < 0.001) were independent risk factors for all-cause mortality rate of patients with DFUs. Kaplan-Meier survival curve indicated that the survival rate of patients with sarcopenia was significantly lower than non-sarcopenia patients (P < 0.001).

Conclusions

Sarcopenia is an independent risk factor for all-cause mortality of patients with DFUs and hence an important prognostic factor for patients with DFUs. Active prevention and improvement of sarcopenia can potentially improve the survival outcomes of this patient population.
Global status of research on cutaneous squamous cell carcinoma and its programmed cell death: Bibliometric and visual analysis from 2012 to middle 2022
Authors: Zhang Yalin , Guo Zhigang , Wang Huimin , Li Bo
Published: April 2023

Objective

This study was aimed to analyze the research status and development trend of cutaneous squamous cell carcinoma (CSCC), focusing on the field of programmed cell death of CSCC, and providing suggestions for the research of CSCC.

Methods

The publications related to CSCC and CSCC programmed cell death were searched in the Web of Science Core Collection (WOSCC) database, and timespan was set from 2012 to middle 2022. Research trends, authors, major country collaborations, research institutions, representative journals, publishers, and keywords were analyzed with CiteSpace and VOSviewer.

Results

After screening, a total of 3656 publications on CSCC and 156 publications on CSCC cell programmed death were obtained. The number of published articles increased gradually with the years. The United States ranked first in terms of the number of published papers. Research in this field had focused on dermatology. Most of the institutions in both regions were from European and American countries. Harvard University was the most prolific institution. Wiley was the most prolific publisher. The popular keywords for programmed cell death in CSCC were cutaneous squamous cell carcinoma, diagnosis, pd 1, head, nivolumab and risk. Keywords in CSCC field were divided into 7 clusters: cutaneous squamous cell carcinoma, sentinel lymph node biopsy, skin cancer, B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) inhibitor and human Papillomaviruses, and P63 expression. Squamous cell carcinoma, cancer, head and expression were the most popular keywords. The popular keywords for programmed cell death in CSCC were cutaneous squamous cell carcinoma, diagnosis, pd 1, head, nivolumab and risk.

Conclusion

This study analyzed the research status of cutaneous squamous cell carcinoma and programmed cell death from 2012 to middle 2022. Understanding research status and hotspots can help scholars, countries and policymakers to better understand the background and research frontier of CSCC, and guide further research directions.
Strategies to overcome myeloid cell induced immune suppression in the tumor microenvironment
Authors: Cao Jennifer , Chow Lyndah , Dow Steven
Published: April 2023

Cancer progression and metastasis due to tumor immune evasion and drug resistance is strongly associated with immune suppressive cellular responses, particularly in the case of metastatic tumors. The myeloid cell component plays a key role within the tumor microenvironment (TME) and disrupts both adaptive and innate immune cell responses leading to loss of tumor control. Therefore, strategies to eliminate or modulate the myeloid cell compartment of the TME are increasingly attractive to non-specifically increase anti-tumoral immunity and enhance existing immunotherapies. This review covers current strategies targeting myeloid suppressor cells in the TME to enhance anti-tumoral immunity, including strategies that target chemokine receptors to deplete selected immune suppressive myeloid cells and relieve the inhibition imposed on the effector arms of adaptive immunity. Remodeling the TME can in turn improve the activity of other immunotherapies such as checkpoint blockade and adoptive T cell therapies in immunologically “cold” tumors. When possible, in this review, we have provided evidence and outcomes from recent or current clinical trials evaluating the effectiveness of the specific strategies used to target myeloid cells in the TME. The review seeks to provide a broad overview of how myeloid cell targeting can become a key foundational approach to an overall strategy for improving tumor responses to immunotherapy.
In vitro models of breast cancer bone metastasis: analyzing drug resistance through the lens of the microenvironment
Authors: Lamouline Anaïs , Bersini Simone , Moretti Matteo
Published: April 2023

Even though breast cancers usually have a good outcome compared to other tumors, the cancer can progress and create metastases in different parts of the organism, the bone being a predilection locus. These metastases are usually the cause of death, as they are mostly resistant to treatments. This resistance can be caused by intrinsic properties of the tumor, such as its heterogeneity, but it can also be due to the protective role of the microenvironment. By activating signaling pathways protecting cancer cells when exposed to chemotherapy, contributing to their ability to reach dormancy, or even reducing the amount of drug able to reach the metastases, among other mechanisms, the specificities of the bone tissue are being investigated as important players of drug resistance. To this date, most mechanisms of this resistance are yet to be discovered, and many researchers are implementing in vitro models to study the interaction between the tumor cells and their microenvironment. Here, we will review what is known about breast cancer drug resistance in bone metastasis due to the microenvironment and we will use those observations to highlight which features in vitro models should include to properly recapitulate these biological aspects in vitro. We will also detail which elements advanced in vitro models should implement in order to better recapitulate in vivo physiopathology and drug resistance.
Prognostic role of plasma vitamin D and its association with disease characteristics in germ cell tumours
Authors: Lesko Peter , Vlkova Barbora , Kalavska Katarina , De Angelis Valentina , Novotna Vera , Obertova Jana , Orszaghova Zuzana , Palacka Patrik , Rejlekova Katarina , Sycova-Mila Zuzana , Kollarik Boris , Aziri Ramadan , Pindak Daniel , Mardiak Jozef , Chovanec Michal , Celec Peter , Mego Michal
Published: April 2023

Background

Testicular cancer is the most common malignancy among young men. Vitamin D has pluripotent effects on cancer pathogenesis and plays a role in the metastatic cascade. The aim of this study is to analyze plasma vitamin D in association with clinico-pathological findings and prognosis in patients with germ-cell tumors (GCTs).

Methods

This study included 120 newly diagnosed and/or relapsed GCT patients treated from April 2013 to July 2020, for whom plasma was available in the biobank. Blood samples were drawn the 1st chemotherapy cycle as well as before the 2nd cycle. Plasma vitamin D was measured using ELISA and correlated with disease characteristics and the outcome. For survival analysis, the cohort was dichotomized into “low” and “high” based on median vitamin D.

Results

There was no significant difference in vitamin D plasma levels between healthy donors and GCT patients (p = 0.71). Vitamin D level was not associated with disease characteristics except for brain metastases, where patients with brain metastases had a vitamin D level that was 32% lower compared to patients without brain metastases, p = 0.03. Vitamin D was also associated with response to chemotherapy, with an approximately 32% lower value in patients with an unfavorable response compared to a favorable response, p = 0.02. Moreover, low plasma levels of vitamin D were significantly associated with disease recurrence and inferior progression-free survival (PFS), but not with overall survival (OS) (HR = 3.02, 95% CI 1.36–6.71, p = 0.01 for PFS and HR = 2.06, 95% CI 0.84–5.06, p = 0.14 for OS, respectively).

Conclusion

Our study suggests the prognostic value of pretreatment vitamin D concentrations in GCT patients. Low plasma vitamin D was associated with an unfavorable response to therapy and disease recurrence. However, it remains to be determined whether the biology of the disease confirms a causative role for low vitamin D and whether its supplementation affects the outcome.
GPR35 antagonist CID-2745687 attenuates anchorage-independent cell growth by inhibiting YAP/TAZ activity in colorectal cancer cells
Authors: Otkur Wuxiyar , Liu Xiaolong , Chen Huan , Li Siyi , Ling Ting , Lin Hanchen , Yang Renyu , Xia Tian , Qi Huan , Piao Hai-Long
Published: April 2023

Background and purpose: GPR35, a member of the orphan G-protein-coupled receptor, was recently implicated in colorectal cancer (CRC). However, whether targeting GPR35 by antagonists can inhibit its pro-cancer role has yet to be answered.

Experimental approach: We applied antagonist CID-2745687 (CID) in established GPR35 overexpressing and knock-down CRC cell lines to understand its anti-cell proliferation property and the underlying mechanism.

Key results: Although GPR35 did not promote cell proliferation in 2D conditions, it promoted anchorage-independent growth in soft-agar, which was reduced by GPR35 knock-down and CID treatment. Furthermore, YAP/TAZ target genes were expressed relatively higher in GPR35 overexpressed cells and lower in GPR35 knock-down cells. YAP/TAZ activity is required for anchorage-independent growth of CRC cells. By detecting YAP/TAZ target genes, performing TEAD4 luciferase reporter assay, and examining YAP phosphorylation and TAZ protein expression level, we found YAP/TAZ activity is positively correlated to GPR35 expression level, which CID disrupted in GPR35 overexpressed cells, but not in GPR35 knock-down cells. Intriguingly, GPR35 agonists did not promote YAP/TAZ activity but ameliorated CID’s inhibitory effect; GPR35-promoted YAP/TAZ activity was only partly attenuated by ROCK1/2 inhibitor.

Conclusion and implications: GPR35 promoted YAP/TAZ activity partly through Rho-GTPase with its agonist-independent constitutive activity, and CID exhibited its inhibitory effect. GPR35 antagonists are promising anti-cancer agents that target hyperactivation and overexpression of YAP/TAZ in CRC.
Cannabinoid receptor agonist attenuates angiotensin II–induced enlargement and mitochondrial dysfunction in rat atrial cardiomyocytes
Authors: Altieri Danielle I. , Etzion Yoram , Anderson Hope D.
Published: April 2023

Pathological remodeling of atrial tissue renders the atria more prone to arrhythmia upon arrival of electrical triggers. Activation of the renin-angiotensin system is an important factor that contributes to atrial remodeling, which may result in atrial hypertrophy and prolongation of P-wave duration. In addition, atrial cardiomyocytes are electrically coupled via gap junctions, and electrical remodeling of connexins may result in dysfunction of coordinated wave propagation within the atria. Currently, there is a lack of effective therapeutic strategies that target atrial remodeling. We previously proposed that cannabinoid receptors (CBR) may have cardioprotective qualities. CB13 is a dual cannabinoid receptor agonist that activates AMPK signaling in ventricular cardiomyocytes. We reported that CB13 attenuates tachypacing-induced shortening of atrial refractoriness and inhibition of AMPK signaling in the rat atria. Here, we evaluated the effects of CB13 on neonatal atrial rat cardiomyocytes (NRAM) stimulated by angiotensin II (AngII) in terms of atrial myocyte enlargement and mitochondrial function. CB13 inhibited AngII-induced enhancement of atrial myocyte surface area in an AMPK-dependent manner. CB13 also inhibited mitochondrial membrane potential deterioration in the same context. However, AngII and CB13 did not affect mitochondrial permeability transition pore opening. We further demonstrate that CB13 increased Cx43 compared to AngII-treated neonatal rat atrial myocytes. Overall, our results support the notion that CBR activation promotes atrial AMPK activation, and prevents myocyte enlargement (an indicator that suggests pathological hypertrophy), mitochondrial depolarization and Cx43 destabilization. Therefore, peripheral CBR activation should be further tested as a novel treatment strategy in the context of atrial remodeling.
Evaluating the safety and efficacy of the leukotriene receptor antagonist montelukast as adjuvant therapy in obese patients with type 2 diabetes mellitus: A double-blind, randomized, placebo-controlled trial
Authors: El-Khateeb Eman , El-Berri Eman I. , Mosalam Esraa M. , Nooh Mohamed Z. , Abdelsattar Shimaa , Alghamdi Amira M. , Alrubia Sarah , Abdallah Mahmoud S.
Published: April 2023

Background: Type 2 diabetes mellitus (T2DM) is common with obesity. Metformin is a first-line therapy for this condition. However, it has only a minor impact on weight loss in some patients.

Aim: This study aimed to evaluate the effectiveness, tolerability, and safety of combining montelukast therapy with metformin in obese diabetic patients.

Methods: One hundred obese diabetic adult patients were recruited and randomized into two equal groups. Group 1 received placebo plus metformin 2 g/d, and Group 2 received 2 g/d metformin plus 10 mg/d montelukast. Demographic, anthropometric measurements (e.g., body weight, body mass index [BMI], and visceral adiposity index), lipid profile, diabetes control measures (fasting blood glucose, glycated hemoglobin [HbA1c], and homeostatic model assessment for insulin resistance [HOMA-IR]), adiponectin, and inflammatory markers (e.g., TNF-α, IL-6, and leukotriene B4) were assessed and reported for each group at baseline and after 12 weeks of treatment.

Results: Both interventions significantly reduced all the measured parameters, except for adiponectin and HDL-C, levels of which increased compared to baseline data (p < 0.001). The montelukast group significantly improved in all parameters compared to the placebo group (ANCOVA test p < 0.001). The percentage changes in BMI, HbA1c, HOMA-IR, and inflammatory markers were 5%, 9%, 41%, and 5%–30%, respectively, in the placebo group compared to 8%, 16%, 58%, and 50%–70%, respectively, in the montelukast group.

Conclusion: Montelukast adjuvant therapy was superior to metformin-only therapy in diabetes control and weight loss, most likely due to its increased insulin sensitivity and anti-inflammatory properties. The combination was tolerable and safe throughout the study duration.

Clinical Trial Registration: [Clinicaltrial.gov], identifier [NCT04075110].
Geomorphodynamics, evolution, and ecology of vertical roots
Authors: Heidelman Martin , Vural Dervis Can
Published: April 2023

The roots of some coastal and wetland trees grow peculiar vertical protrusions, the function of which remains unclear. Here, using computational simulations based on first-principles fluid and sedimentation dynamics, we argue that the protrusions work together to create an elevated patch of sediment downstream of the tree, thereby creating its own fertile flood-protected breeding grounds for the seedlings. In our simulations, we vary the vertical root diameter, root spacing and total root area and show that there is an optimal vertical root spacing that depends on root thickness. Next, we quantify and discuss the cooperative effects between adjacent vertical root patches. Lastly, by varying vertical root spacing of a patch of trees, we estimate a maximal vegetation density for which vertical-root production has a beneficial geomorphological response. Our hypothesis suggests that vertical roots, such as the ‘knee roots’ of baldcypress trees, have an important role in shaping riparian geomorphology and community structure.