bluuebunny/crossref_metadata_2025 huggingface dataset:
Cymbopogon citratus (DC.) Stapf aqueous extract ameliorates loperamide-induced constipation in mice by promoting gastrointestinal motility and regulating the gut microbiota
Authors: Gao Xiaoyu , Hu Yifan , Tao Yafei , Liu Shuangfeng , Chen Haowen , Li Jiayi , Zhao Yan , Sheng Jun , Tian Yang , Fan Yuanhong
Published: October 2022

Slow transit constipation (STC) is the most common type of functional constipation. Drugs with good effects and few side effects are urgently needed form the treatment of STC.Cymbopogon citratus(DC.) Stapf (CC) is an important medicinal and edible spice plant. The wide range of biological activities suggested that CC may have laxative effects, but thus far, it has not been reported. In this study, the loperamide-induced STC mouse model was used to evaluate the laxative effect of the aqueous extract of CC (CCAE), and the laxative mechanism was systematically explored from the perspectives of the enteric nervous system (ENS), neurotransmitter secretion, gastrointestinal motility factors, intestinal inflammation, gut barrier and gut microbiota. The results showed that CCAE not only decreased the serum vasoactive intestinal polypeptide (VIP), induced nitric oxide synthases (iNOS), and acetylcholinesterase (AchE) in STC mice but also increased the expression of gastrointestinal motility factors in colonic interstitial cells of Cajal (ICCs) and smooth muscle cells (SMCs), thereby significantly shortening the defecation time and improving the gastrointestinal transit rate. The significantly affected gastrointestinal motility factors included stem cell factor receptor (c-Kit), stem cell factor (SCF), anoctamin 1 (Ano1), ryanodine receptor 3 (RyR3), smooth muscle myosin light chain kinase (smMLCK) and Connexin 43 (Cx43). Meanwhile, CCAE could repair loperamide-induced intestinal inflammation and intestinal barrier damage by reducing the expression of the pro-inflammatory factorIL-1β and increasing the expression of the anti-inflammatory factorIL-10, chemical barrier (Muc-2) and mechanical barrier (Cldn4,Cldn12,Occludin,ZO-1, andZO-2). Interestingly, CCAE could also partially restore loperamide-induced gut microbial dysbiosis in various aspects, such as microbial diversity, community structure and species composition. Importantly, we established a complex but clear network between gut microbiota and host parameters. Muribaculaceae, Lachnospiraceae and UCG-010 showed the most interesting associations with the laxative phenotypes; several other specific taxa showed significant associations with serum neurotransmitters, gastrointestinal motility factors, intestinal inflammation, and the gut barrier. These findings suggested that CCAE might promote intestinal motility by modulating the ENS-ICCs-SMCs network, intestinal inflammation, intestinal barrier and gut microbiota. CC may be an effective and safe therapeutic choice for STC.
Halometabolites isolated from the marine-derived fungi with potent pharmacological activities
Authors: Chen Yu , Xu Lian-Cheng , Liu Shan , Zhang Zi-Xiang , Cao Guan-Yi
Published: October 2022

Halometabolites, usually produced in marine environment, are an important group of natural halogenated compounds with rich biological functionality and drugability and thus play a crucial role in pharmaceutical and/or agricultural applications. In the exploration of novel halometabolites from marine microorganisms, the growing number of halogenated compounds makes it necessary to fully present these metabolites with diverse structures and considerable bioactivities. This review particularly focuses on the chemodiversity and bioactivities of halometabolites from marine-derived fungi. As a result, a total of 145 naturally halogenated compounds, including 118 chlorinated, 23 brominated, and four iodinated compounds, were isolated from 17 genera of marine-derived fungi. Interestingly, many of halometabolites, especially for the brominated and iodinated compounds, are generated by the substitution of bromide and iodide ions for the chloride ion in cultivation process. In addition, these compounds possess diverse structural types, which are classified into polyketides (62.7%), phenols (16.6%), alkaloids (14.5%), and terpenoids (6.2%). Their cytotoxic, antibacterial, and anti-inflammatory activities indicate the high potential of these halogenated compounds as lead compounds for drug discovery.
In vitro evaluation of the antimicrobial activity of antiseptics against clinical Acinetobacter baumannii strains isolated from combat wounds
Authors: Denysko Tetyana Valeriyivna , Nazarchuk Oleksandr Adamovych , Gruzevskyi Oleksandr , Bahniuk Nataliia Ànatoliivna , Dmytriiev Dmytro Valeriiovych , Chornopyschuk Roman Mykolayovych , Bebyk Vira Volodymyrivna
Published: October 2022

Healthcare-associated infections (HCAIs) are among the most prominent medical problems worldwide. In the context of increasing antibiotic resistance globally, the use of antiseptics as the main active agent and potentiator of antibiotics for the treatment of purulent-inflammatory complications of traumatic wounds, burns, and surgical wounds can be considered to tackle opportunistic infections and their prevention during war. This study presents a comparative investigation of the antimicrobial efficacy of antiseptics used for surgical antisepsis and antiseptic treatment of skin, mucous membranes, and wounds against multidrug-resistant clinical isolates of Acinetobacter baumannii as a wound pathogen of critical priority (according to the WHO). It was found that strains of A. baumannii, which have natural and acquired resistance to antimicrobial drugs, remain susceptible to modern antiseptics. Antiseptic drugs based on decamethoxine, chlorhexidine, octenidine, polyhexanide, and povidone-iodine 10% and 2% provide effective bactericidal activity against A. baumannii within the working concentrations of these drugs. Chlorhexidine and decamethoxine can inhibit biofilm formation by A. baumannii cells. In terms of bactericidal properties and biofilm formation inhibition, chlorhexidine and decamethoxine are the most effective of all tested antiseptics.
Iron deprivation enhances transcriptional responses to in vitro growth arrest of Mycobacterium tuberculosis
Authors: Alebouyeh Sogol , Cárdenas-Pestana Jorge A. , Vazquez Lucia , Prados-Rosales Rafael , Del Portillo Patricia , Sanz Joaquín , Menéndez Maria Carmen , García Maria J.
Published: October 2022

The establishment ofMycobacterium tuberculosis(Mtb) long-term infectionin vivodepends on several factors, one of which is the availability of key nutrients such as iron (Fe). The relation between Fe deprivation inside and outside the granuloma, and the capacity of Mtb to accumulate lipids and persist in the absence of growth is not well understood. In this context, current knowledge of how Mtb modifies its lipid composition in response to growth arrest, depending on iron availability, is scarce. To shed light on these matters, in this work we compare genome-wide transcriptomic and lipidomic profiles of Mtb at exponential and stationary growth phases using cultures with glycerol as a carbon source, in the presence or absence of iron. As a result, we found that transcriptomic responses to growth arrest, considered as the transition from exponential to stationary phase, are iron dependent for as many as 714 genes (iron-growth interaction contrast, FDR <0.05), and that, in a majority of these genes, iron deprivation enhances the magnitude of the transcriptional responses to growth arrest in either direction. On the one hand, genes whose upregulation upon growth arrest is enhanced by iron deprivation were enriched in functional terms related to homeostasis of ion metals, and responses to several stressful cues considered cardinal features of the intracellular environment. On the other hand, genes showing negative responses to growth arrest that are stronger in iron-poor medium were enriched in energy production processes (TCA cycle, NADH dehydrogenation and cellular respiration), and key controllers of ribosomal activity shut-down, such as the T/A systemmazE6/F6. Despite of these findings, a main component of the cell envelope, lipid phthiocerol dimycocerosate (PDIM), was not detected in the stationary phase regardless of iron availability, suggesting that lipid changes during Mtb adaptation to non-dividing phenotypes appear to be iron-independent. Taken together, our results indicate that environmental iron levels act as a key modulator of the intensity of the transcriptional adaptations that take place in the bacterium upon its transition between dividing and dormant-like phenotypesin vitro.
Anthocyanin biosynthetic pathway switched by metalloregulator PbrR to enable a biosensor for the detection of lead toxicity
Authors: Guo Yan , Huang Zhen-lie , Zhu De-long , Hu Shun-yu , Li Han , Hui Chang-ye
Published: October 2022

Environmental lead pollution mainly caused by previous anthropogenic activities continuously threatens human health. The determination of bioavailable lead is of great significance to predict its ecological risk. Bacterial biosensors using visual pigments as output signals have been demonstrated to have great potential in developing minimal-equipment biosensors for environmental pollutant detection. In this study, the biosynthesis pathway of anthocyanin was heterogeneously reconstructed under the control of the PbrR-based Pb(II) sensory element in Escherichia coli. The resultant metabolic engineered biosensor with colored anthocyanin derivatives as the visual signal selectively responded to concentrations as low as 0.012 μM Pb(II), which is lower than the detection limit of traditional fluorescent protein-based biosensors. A good linear dose–response pattern in a wide Pb(II) concentration range (0.012–3.125 μM) was observed. The color deepening of culture was recognized to the naked eye in Pb(II) concentrations ranging from 0 to 200 μM. Importantly, the response of metabolic engineered biosensors toward Pb(II) was not significantly interfered with by organic and inorganic ingredients in environmental water samples. Our findings show that the metabolic engineering of natural colorants has great potential in developing visual, sensitive, and low-cost bacterial biosensors for the detection and determination of pollutant heavy metals.
Antagonistic potential of Trichoderma as a biocontrol agent against Sclerotinia asari
Authors: Wang Zhiqing , Wang Ziqing , Lu Baohui , Quan Xingzhou , Zhao Guangyuan , Zhang Ze , Liu Wanliang , Tian Yixin
Published: October 2022

In the present study, the inhibitory potential of 14 Trichoderma strains (isolated from Asarum rhizosphere) was investigated against Sclerotinia asari using the plate dilution method. The activity of antioxidant enzymes viz; catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and malondialdehyde (MDA) in S. asari treated with the two Trichoderma strains was also evaluated. Untargeted metabolomic analysis by using LC/MS analysis was carried out to determine differential metabolites in T. hamatum (A26) and T. koningiopsis (B30) groups. Moreover, transcriptome analysis of S. asari during the inhibition of S. asari by B30, and A26 compared with the control (CK) was performed. Results indicated that inhibition rates of T. koningiopsis B30, and T. hamatum A26 were highest compared to other strains. Similarly, non-volatile metabolites extracted from the B30 strain showed a 100% inhibition of S. asari. The activity of CAT, SOD, and POD decreased after treatment with A26 and B30 strains while increasing MDA content of S. asari. Antifungal activity of differential metabolites like abamectin, eplerenone, behenic acid, lauric acid, josamycin, erythromycin, and minocycline exhibited the highest inhibition of S. asari. Transcriptome analysis showed that differentially expressed genes were involved in many metabolic pathways which subsequently contributed toward antifungal activity of Trichoderma. These findings suggested that both Trichoderma strains (B30 and A26) could be effectively used as biocontrol agents against Sclerotinia disease of Asarum.
Transforming growth factor-β in tumour development
Authors: Trelford Charles B. , Dagnino Lina , Di Guglielmo Gianni M.
Published: October 2022

Transforming growth factor-β (TGFβ) is a ubiquitous cytokine essential for embryonic development and postnatal tissue homeostasis. TGFβ signalling regulates several biological processes including cell growth, proliferation, apoptosis, immune function, and tissue repair following injury. Aberrant TGFβ signalling has been implicated in tumour progression and metastasis. Tumour cells, in conjunction with their microenvironment, may augment tumourigenesis using TGFβ to induce epithelial-mesenchymal transition, angiogenesis, lymphangiogenesis, immune suppression, and autophagy. Therapies that target TGFβ synthesis, TGFβ-TGFβ receptor complexes or TGFβ receptor kinase activity have proven successful in tissue culture and in animal models, yet, due to limited understanding of TGFβ biology, the outcomes of clinical trials are poor. Here, we review TGFβ signalling pathways, the biology of TGFβ during tumourigenesis, and how protein quality control pathways contribute to the tumour-promoting outcomes of TGFβ signalling.
Prospective pilot study of tirofiban in progressive stroke after intravenous thrombolysis
Authors: Zhang Yan , Wang Jianliang , Ma Zhaoxi , Mu Guihua , Liang Da , Li Yifan , Qian Xiaoyan , Zhang Luyuan , Shen Fang , Zhang Lei , Yu Jie , Liu Yang
Published: October 2022

Background

Intravenous thrombolysis (IVT) is a standard procedure for the treatment of patients with acute ischemic stroke (AIS). Improving the therapeutic efficacy of IVT is an important task for neurologists. The aim of this study was to evaluate the efficacy and safety of early low-dose tirofiban treatment in AIS patients with early neurological deterioration (END) after IVT.

Methods

In this prospective and randomized pilot study, 73 AIS patients with END were recruited from a local hospital in China. Of these, 14 patients were treated with regular antiplatelet agents (aspirin plus clopidogrel) and 59 patients were treated with tirofiban within 24 h of IVT, followed by regular antiplatelet therapy. Neurological deficits and functional recovery were assessed with NIHSS and modified Rankin Scale (mRS) at 7 and 90 days. During the 90-day follow-up period, both hemorrhagic (e.g., intracerebral hemorrhage) and non-hemorrhagic (e.g., pneumonia) events were recorded.

Results

Treatment with tirofiban compared with regular antiplatelet therapy: (1) improved functional recovery of AIS patients to mRS (≤2) at both 7 and 90 days (odds ratios [ORs], 1.37 and 1.64; 95% confidence interval [CI], 1.16–1.61 and 1.26–2.12; P = 0.008 and < 0.001, respectively), and (2) reduced NIHSS scores from 11.14 ± 2.38 to 5.95 ± 3.48 at day 7 (P < 0.001) and from 8.14 ± 2.74 to 4.08 ± 3.50 at day 90 (P < 0.001). Tirofiban treatment did not increase the risk of hemorrhagic complications. Multivariate regression analysis showed that tirofiban treatment independently predicted a favorable functional outcome (P ≤ 0.001).

Conclusion

Early treatment with low-dose tirofiban in AIS patients with neurologic deterioration after IVT potentially improved functional recovery and attenuated neurologic deficits as early as 7 days and did not increase the risk of various hemorrhagic complications. However, the therapeutic efficacy of tirofiban treatment in END patients needs to be determined by future randomized clinical trials with a large study population.

Clinical trial registration

http://www.chictr.org.cn/, Identifier ChiCTR2200058513.
Lead location as a determinant of motor benefit in subthalamic nucleus deep brain stimulation for Parkinson’s disease
Authors: Vitek Jerrold L. , Patriat Rémi , Ingham Lisa , Reich Martin M. , Volkmann Jens , Harel Noam
Published: October 2022

Background

Subthalamic nucleus (STN) deep brain stimulation (DBS) is regarded as an effective treatment for patients with advanced Parkinson’s disease (PD). Clinical benefit, however, varies significantly across patients. Lead location has been hypothesized to play a critical role in determining motor outcome and may account for much of the observed variability reported among patients.

Objective

To retrospectively evaluate the relationship of lead location to motor outcomes in patients who had been implanted previously at another center by employing a novel visualization technology that more precisely determines the location of the DBS lead and its contacts with respect to each patient’s individually defined STN.

Methods

Anatomical models were generated using novel imaging in 40 PD patients who had undergone bilateral STN DBS (80 electrodes) at another center. Patient-specific models of each STN were evaluated to determine DBS electrode contact locations with respect to anterior to posterior and medial to lateral regions of the individualized STNs and compared to the change in the contralateral hemi-body Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III) motor score.

Results

The greatest improvement in hemi-body motor function was found when active contacts were located within the posterolateral portion of the STN (71.5%). Motor benefit was 52 and 36% for central and anterior segments, respectively. Active contacts within the posterolateral portion also demonstrated the greatest reduction in levodopa dosage (77%).

Conclusion

The degree of motor benefit was dependent on the location of the stimulating contact within the STN. Although other factors may play a role, we provide further evidence in support of the hypothesis that lead location is a critical factor in determining clinical outcomes in STN DBS.
Patch-clamp analysis of nicotinic synapses whose strength straddles the firing threshold of rat sympathetic neurons
Authors: Kullmann Paul H. M. , Horn John P.
Published: October 2022

Neurons in paravertebral sympathetic ganglia are innervated by converging nicotinic synapses of varying strength. Based upon intracellular recordings of excitatory postsynaptic potentials (EPSPs) with sharp microelectrodes these synapses were classified in the past as either primary (strong) or secondary (weak) by their ability to trigger postsynaptic action potentials. Here we present an analysis of 22 synapses whose strength straddled threshold, thereby distinguishing them from the original classification scheme for primary and secondary synapses. Recordings at 36°C were made from intact superior cervical ganglia isolated from 13 male and 3 female Sprague-Dawley rats and from 4 male spontaneously hypertensive (SHR) rats. Ganglia were pretreated with collagenase to permit patch recording. By dissecting a 1 cm length of the presynaptic cervical sympathetic nerve as part of the preparation and through use of graded presynaptic stimulation it was possible to fractionate synaptic inputs by their distinct latencies and magnitudes, and by the presynaptic stimulus threshold for each component. Comparison of cell-attached extracellular recordings with intracellular recordings of synaptic potentials and synaptic currents indicated that straddling EPSPs are not an artifact of shunting damage caused by intracellular recording. The results also showed that in cells where a single presynaptic shock elicits multiple action potentials, the response is driven by multiple synapses and not by repetitive postsynaptic firing. The conductance of straddling synapses also provides a direct estimate of the threshold synaptic conductance (9.8 nS ± 7.6 nS, n = 22, mean ± SD). The results are discussed in terms of their implications for ganglionic integration and an existing model of synaptic amplification.
Corresponding anatomical of the macaque superior parietal lobule areas 5 (PE) subdivision reveal similar connectivity patterns with humans
Authors: Wang Qianshan , Wang Yue , Xu Wenyi , Chen Xiaofeng , Li Xueqi , Li Qi , Li Haifang
Published: October 2022

Using the animal brain as a cross-species tool for human brain research based on imaging features can provide more potential to reveal comprehensive human brain analysis. Previous studies have shown that human Brodmann area 5 (BA5) and macaque PE are homologous regions. They are both involved in processes depth and direction information during the touch process in the arm movement. However, recent studies show that both BA5 and PE are not homogeneous. According to the cytoarchitecture, BA5 is subdivided into three different subregions, and PE can be subdivided into PEl, PEla, and PEm. The species homologous relationship among the subregions is not clear between BA5 and PE. At the same time, the subdivision of PE based on the anatomical connection of white matter fiber bundles needs more verification. This research subdivided the PE of macaques based on the anatomical connection of white matter fiber bundles. Two PE subregions are defined based on probabilistic fiber tracking, one on the anterior side and the other on the dorsal side. Finally, the research draws connectivity fingerprints with predefined homologous target areas for the BA5 and PE subregions to reveal the characteristics of structure and functions and gives the homologous correspondence identified.
Effects of iron deficiency and iron supplementation at the host-microbiota interface: Could a piglet model unravel complexities of the underlying mechanisms?
Authors: Abbas Munawar , Hayirli Zeynep , Drakesmith Hal , Andrews Simon C. , Lewis Marie C.
Published: October 2022

Iron deficiency is the most prevalent human micronutrient deficiency, disrupting the physiological development of millions of infants and children. Oral iron supplementation is used to address iron-deficiency anemia and reduce associated stunting but can promote infection risk since restriction of iron availability serves as an innate immune mechanism against invading pathogens. Raised iron availability is associated with an increase in enteric pathogens, especially Enterobacteriaceae species, accompanied by reductions in beneficial bacteria such as Bifidobacteria and lactobacilli and may skew the pattern of gut microbiota development. Since the gut microbiota is the primary driver of immune development, deviations from normal patterns of bacterial succession in early life can have long-term implications for immune functionality. There is a paucity of knowledge regarding how both iron deficiency and luminal iron availability affect gut microbiota development, or the subsequent impact on immunity, which are likely to be contributors to the increased risk of infection. Piglets are naturally iron deficient. This is largely due to their low iron endowments at birth (primarily due to large litter sizes), and their rapid growth combined with the low iron levels in sow milk. Thus, piglets consistently become iron deficient within days of birth which rapidly progresses to anemia in the absence of iron supplementation. Moreover, like humans, pigs are omnivorous and share many characteristics of human gut physiology, microbiota and immunity. In addition, their precocial nature permits early maternal separation, individual housing, and tight control of nutritional intake. Here, we highlight the advantages of piglets as valuable and highly relevant models for human infants in promoting understanding of how early iron status impacts physiological development. We also indicate how piglets offer potential to unravel the complexities of microbiota-immune responses during iron deficiency and in response to iron supplementation, and the link between these and increased risk of infectious disease.
Spectral CT for preoperative prediction of lymphovascular invasion in resectable gastric cancer: With external prospective validation
Authors: Li Jing , Wang Yi , Wang Rui , Gao Jian-bo , Qu Jin-rong
Published: October 2022

Objectives

To develop and externally validate a spectral CT based nomogram for the preoperative prediction of LVI in patients with resectable GC.

Methods

The two centered study contained a retrospective primary dataset of 224 pathologically confirmed gastric adenocarcinomas (161 males, 63 females; mean age: 60.57 ± 10.81 years, range: 20-86 years) and an external prospective validation dataset from the second hospital (77 males and 35 females; mean age, 61.05 ± 10.51 years, range, 31 to 86 years). Triple-phase enhanced CT scans with gemstone spectral imaging mode were performed within one week before surgery. The clinicopathological characteristics were collected, the iodine concentration (IC) of the primary tumours at arterial phase (AP), venous phase (VP), and delayed phase (DP) were measured and then normalized to aorta (nICs). Univariable analysis was used to compare the differences of clinicopathological and IC values between LVI positive and negative groups. Independent predictors for LVI were screened by multivariable logistic regression analysis in primary dataset and used to develop a nomogram, and its performance was evaluated by using ROC analysis and tested in validation dataset. Its clinical use was evaluated by decision curve analysis (DCA).

Results

Tumor thickness, Borrmann classification, CT reported lymph node (LN) status and nICDP were independent predictors for LVI, and the nomogram based on these indicators was significantly associated with LVI (P<0.001). It yielded an AUC of 0.825 (95% confidence interval [95% CI], 0.769-0.872) and 0.802 (95% CI, 0.716-0.871) in primary and validation datasets (all P<0.05), with promising clinical utility by DCA.

Conclusion

This study presented a dual energy CT quantification based nomogram, which enables preferable preoperative individualized prediction of LVI in patients with GC.
A novel prognostic model based on three integrin subunit genes-related signature for bladder cancer
Authors: Tu Hongtao , Liu Haolin , Zhang Longfei , Tan Zhiyong , Wang Hai , Jiang Yongming , Xia Zhongyou , Guo Liwei , Xia Xiaodong , Gu Peng , Liu Xiaodong
Published: October 2022

Background

Presently, a comprehensive analysis of integrin subunit genes (ITGs) in bladder cancer (BLCA) is absent. This study endeavored to thoroughly analyze the utility of ITGs in BLCA through computer algorithm-based bioinformatics.

Methods

BLCA-related materials were sourced from reputable databases, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). R software-based bioinformatics analyses included limma-differential expression analysis, survival-Cox analysis, glmnet-Least absolute shrinkage and selection operator (LASSO), clusterProfiler-functional annotation, and gsva-estimate-immune landscape analysis. The expression difference of key genes was verified by quantitative real-time polymerase chain reaction (qRT-PCR).

Results

Among the 11 ITGs that were abnormally expressed in BLCA, ITGA7, ITGA5, and ITGB6 were categorized as the optimal variables for structuring the risk model. The high-risk subcategories were typified by brief survival, abysmal prognosis, prominent immune and stromal markers, and depressed tumor purity. The risk model was also an isolated indicator of the impact of clinical outcomes in BLCA patients. Moreover, the risk model, specifically the high-risk subcategory with inferior prognosis, became heavily interlinked with the immune-inflammatory response and smooth muscle contraction and relaxation.

Conclusion

This study determined three ITGs with prognostic values (ITGA7, ITGA5, and ITGB6), composed a novel (ITG-associated) prognostic gene signature, and preliminarily probed the latent molecular mechanisms of the model.
GAPDH in neuroblastoma: Functions in metabolism and survival
Authors: Cornett Kevin , Puderbaugh Anna , Back Olivia , Craven Rolf
Published: October 2022

Neuroblastoma is a pediatric cancer of neural crest cells. It develops most frequently in nerve cells around the adrenal gland, although other locations are possible. Neuroblastomas rely on glycolysis as a source of energy and metabolites, and the enzymes that catalyze glycolysis are potential therapeutic targets for neuroblastoma. Furthermore, glycolysis provides a protective function against DNA damage, and there is evidence that glycolysis inhibitors may improve outcomes from other cancer treatments. This mini-review will focus on glyceraldehyde 3-phosphate dehydrogenase (GAPDH), one of the central enzymes in glycolysis. GAPDH has a key role in metabolism, catalyzing the sixth step in glycolysis and generating NADH. GAPDH also has a surprisingly diverse number of localizations, including the nucleus, where it performs multiple functions, and the plasma membrane. One membrane-associated function of GAPDH is stimulating glucose uptake, consistent with a role for GAPDH in energy and metabolite production. The plasma membrane localization of GAPDH and its role in glucose uptake have been verified in neuroblastoma. Membrane-associated GAPDH also participates in iron uptake, although this has not been tested in neuroblastoma. Finally, GAPDH activates autophagy through a nuclear complex with Sirtuin. This review will discuss these activities and their potential role in cancer metabolism, treatment and drug resistance.
Gonadotropin-releasing hormone analog therapies for children with central precocious puberty in the United States
Authors: Popovic Jadranka , Geffner Mitchell E. , Rogol Alan D. , Silverman Lawrence A. , Kaplowitz Paul B. , Mauras Nelly , Zeitler Philip , Eugster Erica A. , Klein Karen O.
Published: October 2022

Gonadotropin-releasing hormone agonists (GnRHa's) are the standard treatment for children with central precocious puberty (CPP). We aim to present data on available GnRHa options with an easy-to-review table and discuss factors that influence treatment selection. Five GnRHa's are currently FDA-approved and prescribed in the US and published data suggest similar safety and efficacy profiles over the first year of treatment. One- and 3-month intramuscular (IM) leuprolide acetate (LA) have long-term safety and efficacy data and allow for flexible dosing. Six-month IM triptorelin pamoate offers a longer duration of treatment, but without long-term efficacy and outcome data. Six-month subcutaneous (SQ) LA combines a SQ route of injection and long duration of action but lacks long-term efficacy and outcome data. The 12-month SQ histrelin acetate implant avoids injections and offers the longest duration of action, but requires a minor surgical procedure with local or general anesthesia. Factors in treatment selection include route of administration, needle size, injection volume, duration of action, and cost. The current GnRHa landscape provides options with varying benefits and risks, allowing physicians and caregivers to select the most appropriate therapy based on the specific needs and concerns of the child and the caregiver. Agents have different advantages and disadvantages for use, with no one agent displaying superiority.
Development of a drug risk analysis and assessment system and its application in signal excavation and analysis of 263 cases of fluoroquinolone-induced adverse reactions
Authors: Guan Yuyao , Ji Lei , Zheng Lei , Yang Jing , Qin Yizhuo , Ding Ning , Miao Ting , Liu Xuemei
Published: October 2022

Background: Adverse drug reaction (ADR) signal mining is essential for assessing drug safety. However, the currently available methods for this are rather cumbersome.

Objective: We aimed to develop a drug risk analysis and assessment system using Java language and conduct pharmacovigilance data mining for fluoroquinolones at our hospital.

Methods: We used ADR data reported by Shandong Provincial Third Hospital between July 2007 and August 2021. The signal detection methods included proportional reporting ratio (PRR), reporting odds ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN), Medicines and Healthcare products Regulatory Agency (MHRA). The BCPNN method was used as the reference standard for comparing the remaining three signal detection methods based on sensitivity, specificity, positive predictive value, negative predictive value, and Jorden index.

Results: The hospital database contained a total of 2,621 ADR reports, among which 263 were attributed to fluoroquinolones. There were 391 fluoroquinolone-ADR pairs. Using the PRR, ROR, MHRA, and BCPNN method, we detected 13 signals, 13 signals, 10 signals, and 11 weak signals, respectively. After signal detection, levofloxacin and moxifloxacin were shown to induce high risk signals for mental and sleep disorders, with the signal intensity of moxifloxacin being the most significant. Compared with BCPNN, the PRR and ROR methods showed better sensitivity, whereas the MHRA method showed better specificity.

Conclusion: We developed a drug risk analysis and assessment system that can help hospitals and other medical institutions to detect and analyse ADR signals in the self-reporting system database, and thus improve drug safety. Further, it indicates that the central nervous system damage caused by fluoroquinolones should be monitored closely, and thus provides a reference for the clinical application of these drugs.
Hypericin, a potential new BH3 mimetic
Authors: Doroshenko Anastasia , Tomkova Silvia , Kozar Tibor , Stroffekova Katarina
Published: October 2022

Many types of cancer such as prostate cancer, myeloid leukemia, breast cancer, glioblastoma display strong chemo resistance, which is supported by enhanced expression of multiple anti-apoptotic Bcl-2, Bcl-XL and Mcl-1 proteins. The viable anti-cancer strategies are based on developing anti-apoptotic Bcl-2 proteins inhibitors, BH3 mimetics. Our focus in past years has been on the investigating a new potential BH3 mimetic, Hypericin (Hyp). Hyp is a naturally occurring photosensitive compound used in photodynamic therapy and diagnosis. We have demonstrated that Hyp can cause substantial effects in cellular ultrastructure, mitochondria function and metabolism, and distribution of Bcl2 proteins in malignant and non-malignant cells. One of the possible mechanisms of Hyp action could be the direct interactions between Bcl-2 proteins and Hyp. We investigated this assumption by in silico computer modelling and in vitro fluorescent spectroscopy experiments with the small Bcl2 peptide segments designed to correspond to Bcl2 BH3 and BH1 domains. We show here that Hyp interacts with BH3 and BH1 peptides in concentration dependent manner, and shows the stronger interactions than known BH3 mimetics, Gossypol (Goss) and ABT-263. In addition, interactions of Hyp, Goss and ABT263, with whole purified proteins Bcl-2 and Mcl-1 by fluorescence spectroscopy show that Hyp interacts stronger with the Bcl-2 and less with Mcl-1 protein than Goss or ABT-263. This suggest that Hyp is comparable to other BH3 mimetics and could be explore as such. Hyp cytotoxicity was low in human U87 MG glioma, similar to that of ABT263, where Goss exerted sufficient cytotoxicity, suggesting that Hyp acts primarily on Bcl-2, but not on Mcl-1 protein. In combination therapy, low doses of Hyp with Goss effectively decreased U87 MG viability, suggesting a possible synergy effect. Overall, we can conclude that Hyp as BH3 mimetic acts primarily on Bcl-2 protein and can be explored to target cells with Bcl-2 over-expression, or in combination with other BH3 mimetics, that target Mcl-1 or Bcl-XL proteins, in dual therapy.
2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside ameliorates bleomycin-induced pulmonary fibrosis via regulating pro-fibrotic signaling pathways
Authors: Huang Tsung-Teng , Chen Chuan-Mu , Chen Lih-Geeng , Lan Ying-Wei , Huang Tse-Hung , Choo Kong Bung , Chong Kowit-Yu
Published: October 2022

2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-Glucoside (THSG) is the main active ingredient extracted fromPolygonum multiflorumThunb. (PMT), which has been reported to possess extensive pharmacological properties. Nevertheless, the exact role of THSG in pulmonary fibrosis has not been demonstrated yet. The main purpose of this study was to investigate the protective effect of THSG against bleomycin (BLM)-induced lung fibrosis in a murine model, and explore the underlying mechanisms of THSG in transforming growth factor-beta 1 (TGF-β1)-induced fibrogenesis using MRC-5 human lung fibroblast cells. We found that THSG significantly attenuated lung injury by reducing fibrosis and extracellular matrix deposition. THSG treatment significantly downregulated the expression levels of TGF-β1, fibronectin, α-SMA, CTGF, and TGFBR2, however, upregulated the expression levels of antioxidants (SOD-1 and catalase) and LC3B in the lungs of BLM-treated mice. THSG treatment decreased the expression levels of fibronectin, α-SMA, and CTGF in TGF-β1-stimulated MRC-5 cells. Conversely, THSG increased the expression levels of SOD-1 and catalase. Furthermore, treatment of THSG profoundly reduced the TGF-β1-induced generation of reactive oxygen species (ROS). In addition, THSG restored TGF-β1-induced impaired autophagy, accompany by increasing the protein levels of LC3B-II and Beclin 1. Mechanism study indicated that THSG significantly reduced TGF-β1-induced increase of TGFBR2 expression and phosphorylation of Smad2/3, Akt, mTOR, and ERK1/2 in MRC-5 cells. These findings suggest that THSG may be considered as an anti-fibrotic drug for the treatment of pulmonary fibrosis.
Advancement in understanding the role of ferroptosis in rheumatoid arthritis
Authors: Long Li , Guo Hongmei , Chen Xixi , Liu Yan , Wang Ruyi , Zheng Xiaomei , Huang Xiaobo , Zhou Qiao , Wang Yi
Published: October 2022

Rheumatoid arthritis (RA) is a chronic, systemic disease of unknown etiology. The primary manifestation of RA is inflammatory synovitis, which eventually leads to deformity and functional loss. Ferroptosis is a non-apoptosis form of cell death that depends on intracellular iron accumulation. This leads to an increase in reactive oxygen species (ROS) induced-lipid peroxidation. The underlying mechanisms of ferroptosis are System Xc- and Glutathione metabolism, regulation of glutathione peroxidase 4 activity, and ROS generation. Recent studies have shown an association between the pathogenesis of RA and ferroptosis, suggesting the involvement of ferroptosis in the onset and progression of RA. In this review, we have focused on the mechanism of ferroptosis and its association with RA pathogenesis. Further, we discuss the status of therapeutics targeting ferroptosis in the treatment of patients with RA. Targeting ferroptosis could be a potential therapeutic approach for RA treatment.
Short total sleep duration and poor sleep quality might be associated with asthenozoospermia risk: A case-control study
Authors: Li Xiaoying , Wang Xiaobin , Wu Qijun , Guo Renhao , Leng Xu , Du Qiang , Pan Bochen , Zhao Yuhong
Published: October 2022

Sleep has been related to a variety of health outcomes. However, no association between sleep and asthenozoospermia has been reported. The aim of this study is to first investigate the relationship between sleep status and asthenozoospermia risk. A case-control study, including 540 asthenozoospermia cases and 579 controls, was performed from June 2020 to December 2020 in the infertility clinic from Shengjing Hospital of China Medical University. Data on sleep status were collected by Pittsburgh sleep quality index questionnaires and asthenozoospermia was diagnosed based on the World Health Organization guidelines. Odds ratio (OR) with 95% confidence interval (95% CI) was calculated by logistic regression analysis to assess the aforementioned association. Results of this study demonstrated that compared with total sleep duration of 8–9 h/day, < 8 h/day was related to asthenozoospermia risk (OR: 1.44, 95% CI: 1.05–1.99); compared to good sleep quality, poor sleep quality was associated with asthenozoospermia risk (OR: 1.35; 95% CI: 1.04–1.77). There were multiplicative model interaction effects between sleep quality and tea drinking (p = 0.04), rotating night shift work (p < 0.01) on asthenozoospermia risk. However, we failed to detect any associations between night sleep duration, daytime napping duration, night bedtime, wake-up time, sleep pattern and asthenozoospermia risk. In conclusion, short total sleep duration and poor sleep quality might be related to asthenozoospermia risk. Further well-designed prospective studies are warranted to confirm our findings.
Atlas of human dental pulp cells at multiple spatial and temporal levels based on single-cell sequencing analysis
Authors: Ren Huihui , Wen Quan , Zhao Qingxuan , Wang Nan , Zhao Yuming
Published: October 2022

The dental pulp plays a crucial role in the long-term maintenance of tooth function. The progress of endodontic treatment and pulp tissue regeneration engineering has made pulp-regeneration therapy promising in clinical practice. However, the mechanisms of pulp regeneration and the role of dental stem cells in development and regeneration have not been fully elucidated. Bridging the gaps between clinical operation and basic research is urgently needed. With the application of single-cell sequencing technology in dental research, the landscapes of human dental pulp cells have begun being outlined. However, the specific cellular heterogeneity of dental pulp cells, especially that of dental stem cells, at different spatial and temporal levels, is still unclear. In this study, we used single-cell RNA sequencing analysis of pulp samples at four different developmental stages and combined the findings with immunohistochemical staining to explore the development of dental pulp and stem cells. The results revealed temporal changes in the proportion of pulp cells during development. For example, mononuclear phagocytes accounted for a higher proportion in early samples. Odontoblasts identified by DMP1 had a higher expression of ion channel-related and neurodevelopment-related genes. Subpopulations were identified in fibroblasts, odontoblasts, and mesenchymal stem cells. We identified a subclass of odontoblasts that expresses DGKI and RRBP1 present in early developmental samples. A population of earlier mesenchymal stem cells expressed the SEPTIN gene, which may have greater proliferative and differentiation potential. Furthermore, dental pulp stem cells can differentiate into two directions: mineralization and myogenesis. In summary, the specific cellular heterogeneity of dental pulp cells was revealed at different spatial and temporal levels. These findings may shed light on the mechanism of tooth development. The gene expression profile of developing pulp cells may help to select cells for regenerative engineering and improve the success of dental pulp regeneration.
Proteomic and metabolomic studies on chilling injury in peach and nectarine
Authors: Lurie Susan
Published: October 2022

Peaches and nectarines are temperate climate stone fruits, which should be stored at 0°C to prevent the ripening of these climacteric fruits. However, if stored for too long or if stored at a higher temperature (4 or 5°C), they develop chilling injury. Chilling injury damage includes (1) dry, mealy, wooly (lack of juice) fruits, (2) hard-textured fruits with no juice (leatheriness), (3) flesh browning, and (4) flesh bleeding or internal reddening. There are genetic components to these disorders in that early season fruits are generally more resistant than late season fruits, and white-fleshed fruits are more susceptible to internal browning than yellow-fleshed fruits. A recent review covered the recent research in genomic and transcriptomic studies, and this review examines findings from proteomic and metabolomics studies. Proteomic studies found that the ethylene synthesis proteins are decreased in cold compromised fruits, and this affects the processes initiated by ethylene including cell wall and volatile changes. Enzymes in metabolic pathways were both higher and lower in abundance in CI fruits, an indication of an imbalance in energy production. Stress proteins increased in both fruits with or without CI, but were higher in damaged fruits. Metabolomics showed the role of levels of sugars, sucrose, raffinose, galactinol, and glucose-6-phosphate in protection against chilling injury, along with other membrane stabilizers such as polyamines. Amino acid changes were inconsistent among the studies. Lipid species changes during storage could be correlated with sensitivity or resistance to CI, but more studies are needed.
Effects of gibberellins on important agronomic traits of horticultural plants
Authors: Zhang Xiaojia , Zhao Baolin , Sun Yibo , Feng Yulong
Published: October 2022

Horticultural plants such as vegetables, fruits, and ornamental plants are crucial to human life and socioeconomic development. Gibberellins (GAs), a class of diterpenoid compounds, control numerous developmental processes of plants. The roles of GAs in regulating growth and development of horticultural plants, and in regulating significant progress have been clarified. These findings have significant implications for promoting the quality and quantity of the products of horticultural plants. Here we review recent progress in determining the roles of GAs (including biosynthesis and signaling) in regulating plant stature, axillary meristem outgrowth, compound leaf development, flowering time, and parthenocarpy. These findings will provide a solid foundation for further improving the quality and quantity of horticultural plants products.
Root hair-specific transcriptome reveals response to low phosphorus in Cicer arietinum
Authors: Kohli Pawandeep Singh , Pazhamala Lekha T. , Mani Balaji , Thakur Jitendra Kumar , Giri Jitender
Published: October 2022

Root hairs (RH) are a single-cell extension of root epidermal cells. In low phosphorus (LP) availability, RH length and density increase thus expanding the total root surface area for phosphate (Pi) acquisition. However, details on genes involved in RH development and response to LP are missing in an agronomically important leguminous crop, chickpea. To elucidate this response in chickpea, we performed tissue-specific RNA-sequencing and analyzed the transcriptome modulation for RH and root without RH (Root-RH) under LP. Root hair initiation and cellular differentiation genes like RSL TFs and ROPGEFs are upregulated in Root-RH, explaining denser, and ectopic RH in LP. In RH, genes involved in tip growth processes and phytohormonal biosynthesis like cell wall synthesis and loosening (cellulose synthase A catalytic subunit, CaEXPA2, CaGRP2, and CaXTH2), cytoskeleton/vesicle transport, and ethylene biosynthesis are upregulated. Besides RH development, genes involved in LP responses like lipid and/or pectin P remobilization and acid phosphatases are induced in these tissues summarizing a complete molecular response to LP. Further, RH displayed preferential enrichment of processes involved in symbiotic interactions, which provide an additional benefit during LP. In conclusion, RH shows a multi-faceted response that starts with molecular changes for epidermal cell differentiation and RH initiation in Root-RH and later induction of tip growth and various LP responses in elongated RH.