bluuebunny/crossref_metadata_2025 huggingface dataset:
Impacts of impaired mitochondrial dynamics in hearing loss: Potential therapeutic targets
Authors: Zou Tianyuan , Ye Bin , Chen Kaili , Zhang Andi , Guo Dongye , Pan Yi , Ding Rui , Hu Haixia , Sun Xingmei , Xiang Mingliang
Published: October 2022

Mitochondria are the powerhouse of the cells. Under physiological conditions, mitochondrial fission and fusion maintain a dynamic equilibrium in the cytoplasm, which is referred to as mitochondrial dynamics. As an important approach to regulating mitochondrial function and quantity, the role of mitochondrial dynamics has been demonstrated in the pathogenesis of various disease models, including brain damage, neurodegeneration, and stress. As the vital organ of the peripheral auditory system, the cochlea consumes a significant amount of energy, and the maintenance of mitochondrial homeostasis is essential for the cochlear auditory capacity. OPA1 functions as both a necessary gene regulating mitochondrial fusion and a pathogenic gene responsible for auditory neuropathy, suggesting that an imbalance in mitochondrial dynamics may play a critical role in hearing loss, but relevant studies are few. In this review, we summarize recent evidence regarding the role of mitochondrial dynamics in the pathogenesis of noise-induced hearing loss (NIHL), drug-induced hearing loss, hereditary hearing loss, and age-related hearing loss. The impacts of impaired mitochondrial dynamics on hearing loss are discussed, and the potential of mitochondrial dynamics for the prevention and treatment of hearing loss is considered.
“Natural Laboratory Complex” for novel primate neuroscience
Authors: Iriki Atsushi , Tramacere Antonella
Published: October 2022

We propose novel strategies for primate experimentation that are ethically valuable and pragmatically useful for cognitive neuroscience and neuropsychiatric research. Specifically, we proposeNatural Laboratory ComplexorNatural Labs, which are a combination of indoor-outdoor structures for studying free moving and socially housed primates in natural or naturalistic environment. We contend thatNatural Labsare pivotal to improve primate welfare, and at the same time to implement longitudinal and socio-ecological studies of primate brain and behavior. Currently emerging advanced technologies and social systems (includingrecent COVID-19 induced “remote” infrastructures) can speed-up cognitive neuroscience approaches in freely behaving animals. Experimental approaches in natural(istic) settings are not in competition with conventional approaches of laboratory investigations, and could establish several benefits at the ethical, experimental, and economic levels.
Generalized resistance to pruritogen-induced scratching in the C3H/HeJ strain
Authors: Zhang Yanbin , Richter Nicole , König Christine , Kremer Andreas E. , Zimmermann Katharina
Published: October 2022

Previously the effect of the pruritogens, such as histamine and chloroquine, was tested in 11 inbred mouse strains, and this study aimed to identify resistant and sensitive strains, consistent with the observation that underlies the large variability in human populations. In the present study, we used the low responder C3H/HeJ (C3H) and the more sensitive C57BL/6J (C57) strain to find out if resistance and sensitivity to develop pruritus is restricted to only histamine and chloroquine or extends to other known pruritogens as well. We tested five additional commonly known pruritogens. We established dose-response relationships by injecting four concentrations of the pruritogens in the range of 0.3, 1, 3, and ten-fold in the nuchal fold. Then we assessed the scratching behavior for 30 min after injection with an automated custom-designed device based on the bilateral implantation of mini-magnets in the hind paws and on single cages placed within a magnetic coil. We found that the resistance to pruritogens is a general phenotype of the C3H strain and extends to all pruritogens tested, including not only histamine and chloroquine, but also endothelin, trypsin, 5-HT (serotonin), the short peptide SLIGRL, and Lysophosphatidic acid (LPA). C57 was more sensitive to all pruritogens and, in contrast to C3H, dose-response relationships were evident for some of the pruritogens. In general, comparable peak scratch responses were observed for the 0.3-fold concentrations of the pruritogens in C57 whereas C3H required at least the ten-fold concentration and still displayed only between 5 and 33% of the scratch responses observed in C57 for the respective pruritogen. The general resistance to pruritogens and the low level of scratching behavior found in the C3H strain is an interesting trait and represents a model for the study of the heritability of itch. It is accompanied in C3H with a higher sensitivity in assays of nociception.
Tsc2 shapes olfactory bulb granule cell molecular and morphological characteristics
Authors: Riley Victoria A. , Holmberg Jennie C. , Sokolov Aidan M. , Feliciano David M.
Published: October 2022

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations that inactivate TSC1 or TSC2. Hamartin and tuberin are encoded by TSC1 and TSC2 which form a GTPase activating protein heteromer that inhibits the Rheb GTPase from activating a growth promoting protein kinase called mammalian target of rapamycin (mTOR). Growths and lesions occur in the ventricular-subventricular zone (V-SVZ), cortex, olfactory tract, and olfactory bulbs (OB) in TSC. A leading hypothesis is that mutations in inhibitory neural progenitor cells cause brain growths in TSC. OB granule cells (GCs) are GABAergic inhibitory neurons that are generated through infancy by inhibitory progenitor cells along the V-SVZ. Removal of Tsc1 from mouse OB GCs creates cellular phenotypes seen in TSC lesions. However, the role of Tsc2 in OB GC maturation requires clarification. Here, it is demonstrated that conditional loss of Tsc2 alters GC development. A mosaic model of TSC was created by performing neonatal CRE recombinase electroporation into inhibitory V-SVZ progenitors yielded clusters of ectopic cytomegalic neurons with hyperactive mTOR complex 1 (mTORC1) in homozygous Tsc2 mutant but not heterozygous or wild type mice. Similarly, homozygous Tsc2 mutant GC morphology was altered at postnatal days 30 and 60. Tsc2 mutant GCs had hypertrophic dendritic arbors that were established by postnatal day 30. In contrast, loss of Tsc2 from mature GCs had negligible effects on mTORC1, soma size, and dendrite arborization. OB transcriptome profiling revealed a network of significantly differentially expressed genes following loss of Tsc2 during development that altered neural circuitry. These results demonstrate that Tsc2 has a critical role in regulating neural development and shapes inhibitory GC molecular and morphological characteristics.
Potential effects of commonly applied drugs on neural stem cell proliferation and viability: A hypothesis-generating systematic review and meta-analysis
Authors: Mortimer Katherine R. H. , Vernon-Browne Hannah , Zille Marietta , Didwischus Nadine , Boltze Johannes
Published: October 2022

Neural stem cell (NSC) transplantation is an emerging and promising approach to combat neurodegenerative diseases. While NSCs can differentiate into neural cell types, many therapeutic effects are mediated by paracrine, “drug-like” mechanisms. Neurodegenerative diseases are predominantly a burden of the elderly who commonly suffer from comorbidities and thus are subject to pharmacotherapies. There is substantial knowledge about drug-drug interactions but almost nothing is known about a potential impact of pharmacotherapy on NSCs. Such knowledge is decisive for designing tailored treatment programs for individual patients. Previous studies revealed preliminary evidence that the anti-depressants fluoxetine and imipramine may affect NSC viability and proliferation. Here, we derive a hypothesis on how commonly applied drugs, statins and antihypertensives, may affect NSC viability, proliferation, and differentiation. We conducted a systematic review and meta-analysis looking at potential effects of commonly prescribed antihypertensive and antihyperlipidemic medication on NSC function. PubMed and Web of Science databases were searched on according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Publications were assessed against a priori established selection criteria for relevancy. A meta-analysis was then performed on data extracted from publications eligible for full text review to estimate drug effects on NSC functions. Our systematic review identified 1,017 potential studies, 55 of which were eligible for full text review. Out of those, 21 were included in the qualitative synthesis. The meta-analysis was performed on 13 publications; the remainder were excluded as they met exclusion criteria or lacked sufficient data to perform a meta-analysis. The meta-analysis revealed that alpha-2 adrenoceptor agonists, an anti-hypertensive drug class [p < 0.05, 95% confidence intervals (CI) = –1.54; –0.35], and various statins [p < 0.05, 95% CI = –3.17; –0.0694] had an inhibiting effect on NSC proliferation. Moreover, we present preliminary evidence that L-type calcium channel blockers and statins, particularly lovastatin, may reduce NSC viability. Although the data available in the literature is limited, there are clear indications for an impact of commonly applied drugs, in particular statins, on NSC function. Considering the modes of action of the respective drugs, we reveal plausible mechanisms by which this impact may be mediated, creating a testable hypothesis, and providing insights into how future confirmative research on this topic may be conducted.
Contributions of extracellular-signal regulated kinase 1/2 activity to the memory trace
Authors: Ojea Ramos Santiago , Feld Mariana , Fustiñana María Sol
Published: October 2022

The ability to learn from experience and consequently adapt our behavior is one of the most fundamental capacities enabled by complex and plastic nervous systems. Next to cellular and systems-level changes, learning and memory formation crucially depends on molecular signaling mechanisms. In particular, the extracellular-signal regulated kinase 1/2 (ERK), historically studied in the context of tumor growth and proliferation, has been shown to affect synaptic transmission, regulation of neuronal gene expression and protein synthesis leading to structural synaptic changes. However, to what extent the effects of ERK are specifically related to memory formation and stabilization, or merely the result of general neuronal activation, remains unknown. Here, we review the signals leading to ERK activation in the nervous system, the subcellular ERK targets associated with learning-related plasticity, and how neurons with activated ERK signaling may contribute to the formation of the memory trace.
Phillyrin restores metabolic disorders in mice fed with high-fat diet through inhibition of interleukin-6-mediated basal lipolysis
Authors: Fang Zhizheng , Wei Lu , Lv Yanping , Wang Tongsheng , Hamezah Hamizah Shahirah , Han Rongchun , Tong Xiaohui
Published: October 2022

The function of white adipose tissue as an energy reservoir is impaired in obesity, leading to lipid spillover and ectopic lipid deposition. Adipose tissue inflammation can reduce the efficacy of lipid storage in adipocytes by augmenting basal lipolysis through producing interleukin-6 (IL-6). Therefore, pharmacological compounds targeting adipose tissue inflammation or IL-6 signaling might have the potential to combat obesity. This study aims to investigate the impact of Phillyrin, which is frequently used for treating respiratory infections in clinics in China, on obesity-related metabolic dysfunctions. Firstly, a mouse model of diet-induced obesity is used to assess the pharmacological applications of Phillyrin on obesity in vivo. Secondly, ex vivo culture of adipose tissue explants is utilized to investigate actions of Phillyrin on IL-6-linked basal lipolysis. Thirdly, a mouse model of IL-6 injection into visceral adipose tissue is explored to confirm the anti-basal lipolytic effect of Phillyrin against IL-6 in vivo. The results show that Phillyrin treatment reduces circulating level of glycerol, decreases hepatic steatosis and improves insulin sensitivity in obese mice. Meanwhile, Phillyrin attenuates obesity-related inflammation and IL-6 production in adipose tissue in obese mice. Furthermore, Phillyrin treatment results in resistance to IL-6-induced basal lipolysis in adipose tissue through suppressing expression of adipose triglyceride lipase (ATGL) both in vivo and in vitro. Collectively, these findings suggest that Phillyrin can restrain lipid efflux from inflamed adipose tissue in obesity by inhibiting IL-6-initiated basal lipolysis and ATGL expression, and thus is a potential candidate in the treatment of obesity-associated complications.
A comparative review on the anti-nutritional factors of herbal tea concoctions and their reduction strategies
Authors: Pathaw Neeta , Devi Konjengbam Sarda , Sapam Redina , Sanasam Jyotsana , Monteshori Sapam , Phurailatpam Sumitra , Devi Huirem Chandrajini , Chanu Wangkhem Tampakleima , Wangkhem Baby , Mangang Naorem Loya
Published: October 2022

Tea is an important beverage consumed worldwide. Of the different types of tea available, herbal tea is an important beverage consumed owing to its popularity as a drink and stress relieving factors, several different herbal concoctions made from seeds, leaves, or roots are currently consumed and sold as herbal teas. The herbal teas are not the usual tea but “tisanes.” They are caffeine free and popular for their medicinal property or immune boosters. Herbal tea formulations are popularly sold and consumed by millions owing to their health benefits as they are rich in antioxidants and minerals. However, plants are also known to contain toxic and anti-nutritional factors. Anti-nutritional factors are known to interfere with the metabolic process and hamper the absorption of important nutrients in the body. These anti-nutritional factors include saponins, tannins, alkaloids, oxalates, lectins, goitrogens, cyanogens, and lethogens. These chemicals are known to have deleterious effects on human health. Therefore, it is important to understand and assess the merits and demerits before consumption. Also, several techniques are currently used to process and reduce the anti-nutrients in foods. This review is focused on comparing the contents of various anti-nutritional factors in some underutilized plants of North-East India used as herbal tea along with processing methods that can be used to reduce the level of these anti-nutrients.
Identification of bromodomain-containing proteins prognostic value and expression significance based on a genomic landscape analysis of ovarian serous cystadenocarcinoma
Authors: Zhang Juan , Li Yan , Fan Ting-yu , Liu Dan , Zou Wen-da , Li Hui , Li Yu-kun
Published: October 2022

Background

Ovarian serous cystadenocarcinoma (OSC), a common gynecologic tumor, is characterized by high mortality worldwide. Bromodomain (BRD)-containing proteins are a series of evolutionarily conserved proteins that bind to acetylated Lys residues of histones to regulate the transcription of multiple genes. The ectopic expression of BRDs is often observed in multiple cancer types, but the role of BRDs in OSC is still unclear.

Methods

We performed the differential expression, GO enrichment, GSEA, immune infiltration, risk model, subtype classification, stemness feature, DNA alteration, and epigenetic modification analysis for these BRDs based on multiple public databases.

Results

Most BRDs were dysregulated in OSC tissues compared to normal ovary tissues. These BRDs were positively correlated with each other in OSC patients. Gene alteration and epigenetic modification were significant for the dysregulation of BRDs in OSC patients. GO enrichment suggested that BRDs played key roles in histone acetylation, viral carcinogenesis, and transcription coactivator activity. Two molecular subtypes were classified by BRDs for OSC, which were significantly correlated with stemness features, m6A methylation, ferroptosis, drug sensitivity, and immune infiltration. The risk model constructed by LASSO regression with BRDs performed moderately well in prognostic predictions for OSC patients. Moreover, BRPF1 plays a significant role in these BRDs for the development and progression of OSC patients.

Conclusion

BRDs are potential targets and biomarkers for OSC patients, especially BRPF1.
A comparative study of robotics and laparoscopic in minimally invasive pancreatoduodenectomy: A single-center experience
Authors: Zong Ke , Luo Kai , Chen Kunlun , Ye Jianwen , Liu Wentao , Zhai Wenlong
Published: October 2022

Objective

To retrospectively compare the short-term benefits of robotic surgery and laparoscopic in the perioperative period of minimally invasive pancreatoduodenectomy (MIPD).

Methods

This retrospective analysis evaluated patients who underwent laparoscopic pancreatoduodenectomy (LPD) or robotic pancreatoduodenectomy (RPD) from March 2018 to January 2022 in the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China). Perioperative data, including operating time, complications, morbidity and mortality, estimated blood loss (EBL), and postoperative length of stay, were analysed.

Result

A total of 190 cases of MIPD were included, of which 114 were LPD and 76 were RPD. There was no significant difference between the two groups in gender, age, previous history of upper abdominal operation, jaundice (>150 µmol/L), or diabetes (P > 0.05). The conversion rate to laparotomy was similar in the LPD and RPD groups (5.3% vs. 6.6%, P = 0.969). A total of 179 cases of minimally invasive pancreatoduodenectomy were successfully performed, including 108 cases of LPD and 71 cases of RPD. There were significant differences between the laparoscopic and robotic groups in operation time [mean, 5.97 h vs. 5.42 h, P < 0.05] and postoperative length of stay [mean, 15.3 vs. 14.6 day, P < 0.05]. No significant difference was observed between the two groups in terms of EBL, intraoperative transfusion, complication rate, mortality rate, or reoperation rate (P > 0.05). There were no significant differences in pathological type, number of lymph nodes harvested, or positive lymph node rate (P > 0.05).

Conclusion

RPD had an advantage compared to LPD in reduced operation time and postoperative length of stay, technical feasibility, and safety.
Recurrent pyogenic infections caused by a novel Gln1420* mutation in the C3 gene
Authors: Coelho Pedro Simão , Gouveia Catarina , Pinto Marta Valente , Neves Conceição , Cordeiro Ana Isabel , Neves João Farela
Published: October 2022

C3 is a crucial protein of the complement system. Congenital C3 deficiency is extremely rare and manifests through recurrent, severe infections and should always be considered as a differential diagnosis of recurrent pyogenic infections. We report a case of a patient with a novel C3 gene mutation, responsible for complete C3 deficiency with impaired complement system activation and recurrent infections.
Trend in 167 cases of minors witnessing violence: The role played by COVID-19 pandemic
Authors: Focardi Martina , Grassi Simone , Raddi Silvia , Rosati Maria Elena , Cazzato Francesca , D’Onofrio Paola , Doretti Vittoria , Bianchi Ilenia , Vetrugno Giuseppe , Oliva Antonio , Pinchi Vilma
Published: October 2022

Background

There currently is no evidence that COVID-19 has had an impact on the rates of psychological abuses occurring when a minor witnesses interpersonal violence.

Aim

Our aim was to describe the accesses of the last four years to the Emergency Department of a tertiary hospital (Careggi University Hospital—Florence, Italy) due to this issue and then to evaluate whether the COVID-19 has had an impact on this trend.

Methods

We collected data regarding cases of abuse in which at least a minor had reportedly witnessed the event. Medical records stored between January 1, 2018 to January 1, 2022 were analyzed, extracting sex, age and nationality of the victim; sex of the perpetrator and relationship with the victim; known previous episodes of abuse in the medical history of the victim; setting of the abuse (domestic vs. non-domestic); type of abuse (physical, psychological, sexual); whether the perpetrator was under the influence of alcohol/drugs; whether the victim was hospitalized; prognosis of the victim; number, relation with the victim and involvement in the abuse (as co-victim) of the minor(s) who witnessed the abuse.

Results

A total of 167 eligible cases were registered. 69% of victims had previous episodes of abuse. The perpetrators were all known and mainly males (96%).The abuses were mainly domestic (79%). In 74% of the cases only a type of violence was perpetrated. In 12% of the cases, the minors were also victims of physical abuse. No statistically significant relationships were found between the start of the COVID-19 pandemic and the changes in the number of cases of domestic abuse (p = 0.07), physical abuse (p = 0.62), psychological abuse (p = 0.83) or sexual abuse (p = 0.88). However, during the institutional lockdown in Italy (March-May 2022) only two cases occurred – a number that did not allow period-specific statistical inference.

Conclusions

Empowering the hospital policies specifically aimed at identifying and protecting the victims of violence/witnessed violence remains a critical goal from both a public health and medico-legal point of view.
Mingmu Xiaoyao granules regulate the PI3K/Akt/mTOR signaling pathway to reduce anxiety and depression and reverse retinal abnormalities in rats
Authors: Ma Qiuyan , Zhou Jian , Yang Ziyi , Xue Yuxin , Xie Xinran , Li Tiejun , Yang Yingxin
Published: October 2022

Objective: To investigate the effects of Mingmu Xiaoyao granules (MMXY) on the morphology and function of the retina and the mechanism of PI3K/Akt/mTOR pathway-related proteins in rats with anxiety and depression induced by chronic unpredictable mild stress (CUMS).

Methods: Fifty-two male Sprague Dawley rats were randomly allocated to either a control (n = 14) or a simulated CUMS group (n = 38). The CUMS model was established successfully at 4 weeks. Six rats in each group were randomly selected to be sacrificed and their retinas isolated for histological examination. At 5 weeks, rats in the CUMS group were randomly allocated to the following groups: Model (CUMS + pure water), MMXY-H (CUMS + MMXY 7.2 g/kg/d), MMXY-L (CUMS + MMXY 3.6 g/kg/d), and CBZ (CUMS + Carbamazepine 20 mg/kg/d), with eight rats in each group. All rats were given the relevant intervention once a day. At 12 weeks, sucrose preference and open field tests were performed to evaluate the anxiety and depression status of rats. In live rats, optical coherence tomography angiography was used to measure retinal thickness and blood flow, while electroretinograms (ERGs) and visual evoked potentials (VEPs) were used to evaluate retinal function. The next day, the specimens were sacrificed for serological, histological, immunofluorescence, Western blot and transmission electron microscopy examinations to explore the mechanism of MMXY in CUMS rats.

Results: MMXY improved the anxiety and depression-like behavior of rats. Results of optical coherence tomography angiography showed that MMXY improved retinal inner thickness and blood flow in CUMS rats. MMXY improved the amplitude of a- and b-waves in the scotopic and photopic ERG, as well as N2 and P2 peak time and amplitude in the flash-VEP in CUMS rats. Retinal histological staining and transmission electron microscopy showed that MMXY reversed retinal morphology and ultrastructure in CUMS rats. MMXY reduced the expression of Beclin1 and LC3I/II proteins, regulated the PI3K/Akt/mTOR pathway, inhibited autophagy, and had a protective effect on the retina in CUMS rats.

Conclusion: MMXY may effectively improve retinal morphology and function as well as anxiety and depression-like behaviors in CUMS rats by regulating the PI3K/Akt/mTOR signaling pathway.
Predictive performance and verification of physiologically based pharmacokinetic model of propylthiouracil
Authors: Shen Chaozhuang , Liang Dahu , Wang Xiaohu , Shao Wenxin , Geng Kuo , Wang Xingwen , Sun Hua , Xie Haitang
Published: October 2022

Background: Propylthiouracil (PTU) treats hyperthyroidism and thyroid crisis in all age groups. A variety of serious adverse effects can occur during clinical use and require attention to its pharmacokinetic and pharmacodynamic characteristics in various populations.

Objective: To provide information for individualized dosing and clinical evaluation of PTU in the clinical setting by developing a physiologically based pharmacokinetic (PBPK) model, predicting ADME characteristics, and extrapolating to elderly and pediatric populations.

Methods: Relevant databases and literature were retrieved to collect PTU’s pharmacochemical properties and ADME parameters, etc. A PBPK model for adults was developed using PK-Sim® software to predict tissue distribution and extrapolated to elderly and pediatric populations. The mean fold error (MFE) method was used to compare the differences between predicted and observed values to assess the accuracy of the PBPK model. The model was validated using PTU pharmacokinetic data in healthy adult populations.

Result: The MFE ratios of predicted to observed values of AUC0-t, Cmax, and Tmax were mainly within 0.5 and 2. PTU concentrations in various tissues are lower than venous plasma concentrations. Compared to healthy adults, the pediatric population requires quantitative adjustment to the appropriate dose to achieve the same plasma exposure levels, while the elderly do not require dose adjustments.

Conclusion: The PBPK model of PTU was successfully developed, externally validated, and applied to tissue distribution prediction and special population extrapolation, which provides a reference for clinical individualized drug administration and evaluation.
In vitro effects of European and Latin-American medicinal plants in CYP3A4 gene expression, glutathione levels, and P-glycoprotein activity
Authors: Mazzari Andre Luis Dias Araujo , Lacerda Mariella Guimarães , Milton Flora Aparecida , Mulin Montechiari Machado João Augusto , Sinoti Simone Batista Pires , Toullec Anne-Soulene , Rodrigues Patricia Marquez , Neves Francisco de Assis Rocha , Simeoni Luiz Alberto , Silveira Dâmaris , Prieto Jose Maria
Published: October 2022

Many medicinal plants species from European -such as Artemisia absinthium, Equisetum arvense, Lamium album, Malva sylvestris, Morus nigra, Passiflora incarnata, Frangula purshiana, and Salix alba- as well as Latin American traditions -such as Libidibia ferrea, Bidens pilosa, Casearia sylvestris, Costus spicatus, Monteverdia ilicifolia, Persea americana, Schinus terebinthifolia, Solidago chilensis, Syzygium cumini, Handroanthus impetiginosus, and Vernonanthura phosphorica- are shortlisted by the Brazilian National Health System for future clinical use. However, they lack many data on their action upon some key ADME targets. In this study, we assess non-toxic concentrations (up to100 μg/ml) of their infusions for in vitro ability to modulate CYP3A4 mRNA gene expression and intracellular glutathione levels in HepG2 cells, as well as P-glycoprotein (P-gp) activity in vincristine-resistant Caco-2 cells (Caco-2 VCR). We further investigated the activation of human pregnane X receptor (hPXR) in transiently co-transfected HeLa cells and the inhibition of Gamma-glutamyl transferase (GGT) in HepG2 cells. Our results demonstrate L. ferrea, C. sylvestris, M. ilicifolia, P. americana, S. terebinthifolia, S. cumini, V. phosphorica, E. arvense, P. incarnata, F. purshiana, and S. alba can significantly increase CYP3A4 mRNA gene expression in HepG2 cells. Only F. purshiana shown to do so likely via hPXR activation. P-gp activity was affected by L. ferrea, F. purshiana, S. terebinthifolia, and S. cumini. Total intracellular glutathione levels were significantly depleted by exposure to all extracts except S. alba and S. cumini This was accompanied by a lower GGT activity in the case of C. spicatus, P. americana, S. alba, and S. terebinthifolia, whilst L. ferrea, P. incarnata and F. purshiana increased it. Surprisingly, S. cumini aqueous extract drastically decreased GGT activity (−48%, p < 0.01). In conclusion, this preclinical study shows that the administration of some of these herbal medicines causes in vitro disturbances to key drug metabolism mechanisms. We recommend active pharmacovigilance for Libidibia ferrea (Mart.) L. P. Queiroz, Frangula purshiana Cooper, Schinus terebinthifolia Raddi, and Salix alba L. which were able to alter all targets in our preclinical study.
Identification of minimum essential therapeutic mixtures from cannabis plant extracts by screening in cell and animal models of Parkinson’s disease
Authors: Morash Michael G. , Nixon Jessica , Shimoda Lori M. N. , Turner Helen , Stokes Alexander J. , Small-Howard Andrea L. , Ellis Lee D.
Published: October 2022

Medicinal cannabis has shown promise for the symptomatic treatment of Parkinson’s disease (PD), but patient exposure to whole plant mixtures may be undesirable due to concerns around safety, consistency, regulatory issues, and psychoactivity. Identification of a subset of components responsible for the potential therapeutic effects within cannabis represents a direct path forward for the generation of anti-PD drugs. Using an in silico database, literature reviews, and cell based assays, GB Sciences previously identified and patented a subset of five cannabinoids and five terpenes that could potentially recapitulate the anti-PD attributes of cannabis. While this work represents a critical step towards harnessing the anti-PD capabilities of cannabis, polypharmaceutical drugs of this complexity may not be feasible as therapeutics. In this paper, we utilize a reductionist approach to identify minimal essential mixtures (MEMs) of these components that are amenable to pharmacological formulation. In the first phase, cell-based models revealed that the cannabinoids had the most significant positive effects on neuroprotection and dopamine secretion. We then evaluated the ability of combinations of these cannabinoids to ameliorate a 6-hydroxydopmamine (OHDA)-induced change in locomotion in larval zebrafish, which has become a well-established PD disease model. Equimolar mixtures that each contained three cannabinoids were able to significantly reverse the OHDA mediated changes in locomotion and other advanced metrics of behavior. Additional screening of sixty-three variations of the original cannabinoid mixtures identified five highly efficacious mixtures that outperformed the original equimolar cannabinoid MEMs and represent the most attractive candidates for therapeutic development. This work highlights the strength of the reductionist approach for the development of ratio-controlled, cannabis mixture-based therapeutics for the treatment of Parkinson’s disease.
Study on the vasodilatory activity of lotus leaf extract and its representative substance nuciferine on thoracic aorta in rats
Authors: Deng Hao , Xu Qian , Sang Xiao-Tong , Huang Xing , Jin Li-Li , Chen Fen-Er , Shen Qing-Kun , Quan Zhe-Shan , Cao Li-Hua
Published: October 2022

Lotus (Nelumbo nucifera) leaves are widely used for both edible and medicinal applications. For its further utilization, we studied the vasodilatory activity of lotus leaf extract for the first time. In this study, we obtained the extracts using different ratios of water and ethanol, which was followed by polarity-dependent extraction. We found that the CH2Cl2 layer exhibited better vasodilatory activity (EC50 = 1.21 ± 0.10 μg/ml). HPLC and ESI-HRMS analysis of the CH2Cl2 layer using the standard product as a control revealed that nuciferine (Emax = 97.95 ± 0.76%, EC50 = 0.36 ± 0.02 μM) was the main component in this layer. Further research revealed that nuciferine exerts a multi-target synergistic effect to promote vasodilation, via the NO signaling pathway, K+ channel, Ca2+ channel, intracellular Ca2+ release, α and β receptors, etc. Nuciferine exhibits good vasodilatory activity, and it exhibits the potential to be utilized as a lead compound.
The efficacy and safety of intralesional injection of collagenase Clostridium histolyticum for Peyronie’s disease: A meta-analysis of published prospective studies
Authors: Zhang Fuxun , Xiong Yang , Wang Wei , Wu Changjing , Qin Feng , Yuan Jiuhong
Published: October 2022

Background: Peyronie’s disease (PD) is a progressive fibrotic disorder of the penis that is adverse to men’s health. Currently, effective and reliable non-surgical options for PD are limited. Since the Food and Drug Administration (FDA) approved it in 2013, intralesional injection of collagenase Clostridium histolyticum (CCH) became the only licensed treatment for PD. This meta-analysis aims to evaluate the clinical efficacy and safety of CCH in treating PD, predominantly based on post-FDA studies.

Methods: The primary outcome was clinical efficacy evaluated by the percentages of improvement in penile curvature (PC) and Peyronie’s disease symptom bother score (PD bother score). The secondary outcome was the safety assessed by treatment-related adverse events (TRAEs). Heterogeneity was assessed by Cochran’s Q and I2 tests. Sensitivity and subgroup analyses were performed to explore the source of heterogeneity. Funnel plots and Egger’s test were used to evaluate the publication bias.

Results: A total of 11 studies with 1,480 intentions to treat (ITT) population were included. The pooled effect of the improvement of PC was 35% (95% CI: 0.33–0.38), and the pooled improvement of the PD bother score was 41% (95% CI: 0.37–0.45). No heterogeneity was found at the pooled improvement of PC (p = 0.845, I2 = 0.00%). Meanwhile, some heterogeneity existed in the pooled improvement of the PD bother score (p = 0.069, I2 = 43.4%). The pooled effect of TRAEs was 93% (95% CI 0.88–0.97) with significant heterogeneity (p < 0.000, I2 = 92.3%).

Conclusion: The intralesional injection of CCH could significantly improve the penile deformity of PD patients. Meanwhile, CCH appears to ameliorate the PD bother score to some extent and has acceptable clinical safety. Future studies are required to clarify the long-term outcomes of CCH injection in the treatment of PD.
Associations between the use of aspirin or other antiplatelet drugs and all-cause mortality among patients with COVID-19: A meta-analysis
Authors: Su Wanting , Miao He , Guo Zhaotian , Chen Qianhui , Huang Tao , Ding Renyu
Published: October 2022

Introduction: Whether aspirin or other antiplatelet drugs can reduce mortality among patients with coronavirus disease (COVID-19) remains controversial.

Methods: We identified randomized controlled trials, prospective cohort studies, and retrospective studies on associations between aspirin or other antiplatelet drug use and all-cause mortality among patients with COVID-19 in the PubMed database between March 2019 and September 2021. Newcastle–Ottawa Scale and Cochrane Risk of Bias Assessment Tool were used to assess the risk of bias. The I2 statistic was used to assess inconsistency among trial results. The summary risk ratio (RR) and odds ratio (OR) were obtained through the meta-analysis.

Results: The 34 included studies comprised three randomized controlled trials, 27 retrospective studies, and 4 prospective cohort studies. The retrospective and prospective cohort studies showed low-to-moderate risks of bias per the Newcastle–Ottawa Scale score, while the randomized controlled trials showed low-to-high risks of bias per the Cochrane Risk of Bias Assessment Tool. The randomized controlled trials showed no significant effect of aspirin use on all-cause mortality in patients with COVID-19 {risk ratio (RR), 0.96 [95% confidence interval (CI) 0.90–1.03]}. In retrospective studies, aspirin reduced all-cause mortality in patients with COVID-19 by 20% [odds ratio (OR), 0.80 (95% CI 0.70–0.93)], while other antiplatelet drugs had no significant effects. In prospective cohort studies, aspirin decreased all-cause mortality in patients with COVID-19 by 15% [OR, 0.85 (95% CI 0.80–0.90)].

Conclusion: The administration of aspirin may reduce all-cause mortality in patients with COVID-19.
Impact of the expert consensus on polypharmacy and potentially inappropriate medication use in elderly lung cancer outpatients with multimorbidity: An interrupted time series analysis, 2016–2021
Authors: Tian Fangyuan , Chen Zhaoyan , Tang Rui , Feng Qiyi , Wu Fengbo
Published: October 2022

Objectives: Elderly lung cancer patients often have chronic diseases other than lung cancer. Therefore, this kind of population is often accompanied by polypharmacy. This situation and the resulting potentially inappropriate medication (PIM) use are an increasing global concern. In this context, the Chinese Association of Geriatric Research issued an expert consensus on the safety management of polypharmacy. However, the long- and short-term effects of the expert consensus on polypharmacy and PIM use are not clear.

Methods: The study was conducted in Chengdu, a city in southwestern China, consisting of prescriptions for elderly lung cancer outpatients with multimorbidity (cancer with other diseases) from January 2016 to December 2021. The 2019 Beers criteria were used to evaluate PIM use, and interrupted time series analysis was used to evaluate the longitudinal effectiveness of expert consensus by measuring the prevalence of polypharmacy and PIM use. We used R software version 4.2.0 for data analysis.

Results: A total of 7,238 elderly lung cancer outpatient prescriptions were included in the study. After the publication of the expert consensus, the level (β = -10.273, P < 0.001) of the prevalence of polypharmacy decreased, but the trend (β = 0.158, p = 0.855) of polypharmacy increased. The prevalence of PIM use decreased abruptly (β = -22.828, p < 0.001) after the intervention, but the long-term trend was still upward (β = 0.907, p = 0.916).

Conclusion: The long-term effects of the publication of the expert consensus on the prevalence of polypharmacy and PIM use in hospitals in Chengdu were not optimal. Future research on interventions rationing polypharmacy and PIM use is needed.
A structured-light 3D sensor-based shape measurement method for casting allowance evaluation
Authors: Luo Hua , Zhang Ke , Li Ruifeng , Xia Yu , Liang Peidong
Published: October 2022

The evaluation of casting allowance currently relies on manual operation, which is time-consuming and unstable. The structured-light three-dimensional (3D) sensor-based 3D shape measurement technology is characterized by non-contact, high accuracy, and fast measuring speed, which provides the complete 3D shape of casting for accurate allowance evaluation. However, measuring a complex shape casting still requires numerous manual operations, including attaching marks, planning the measurement process, and data processing. To solve these problems, a robot-driven structured-light 3D sensor-based measurement method is proposed, with a six-degree of freedom (6-DOF) industrial robot and a turntable to control the structured-light 3D measurement sensor, to transform the 3D results from different measuring viewpoints into a coherent coordinate system, and to form a complete 3D shape of the casting. Then, the mechanical processing allowance will be calculated by comparing the 3D measurement result and the standard CAD model automatically. The experiment results show that the proposed method is accurate and efficient, and the casting allowance evaluation time is about ten times faster than that of manual operation. Moreover, the proposed method would provide valuable experience for other industrial applications.
Ion channels as a therapeutic target for renal fibrosis
Authors: Yan Peng , Ke Ben , Fang Xiangdong
Published: October 2022

Renal ion channel transport and electrolyte disturbances play an important role in the process of functional impairment and fibrosis in the kidney. It is well known that there are limited effective drugs for the treatment of renal fibrosis, and since a large number of ion channels are involved in the renal fibrosis process, understanding the mechanisms of ion channel transport and the complex network of signaling cascades between them is essential to identify potential therapeutic approaches to slow down renal fibrosis. This review summarizes the current work of ion channels in renal fibrosis. We pay close attention to the effect of cystic fibrosis transmembrane conductance regulator (CFTR), transmembrane Member 16A (TMEM16A) and other Cl− channel mediated signaling pathways and ion concentrations on fibrosis, as well as the various complex mechanisms for the action of Ca2+ handling channels including Ca2+-release-activated Ca2+ channel (CRAC), purinergic receptor, and transient receptor potential (TRP) channels. Furthermore, we also focus on the contribution of Na+ transport such as epithelial sodium channel (ENaC), Na+, K+-ATPase, Na+-H+ exchangers, and K+ channels like Ca2+-activated K+ channels, voltage-dependent K+ channel, ATP-sensitive K+ channels on renal fibrosis. Proposed potential therapeutic approaches through further dissection of these mechanisms may provide new therapeutic opportunities to reduce the burden of chronic kidney disease.
Dynamic but discordant alterations in zDHHC5 expression and palmitoylation of its substrates in cardiac pathologies
Authors: Main Alice , Boguslavskyi Andri , Howie Jacqueline , Kuo Chien-Wen , Rankin Aileen , Burton Francis L. , Smith Godfrey L. , Hajjar Roger , Baillie George S. , Campbell Kenneth S. , Shattock Michael J. , Fuller William
Published: October 2022

S-palmitoylation is an essential lipid modification catalysed by zDHHC-palmitoyl acyltransferases that regulates the localisation and activity of substrates in every class of protein and tissue investigated to date. In the heart, S-palmitoylation regulates sodium-calcium exchanger (NCX1) inactivation, phospholemman (PLM) inhibition of the Na+/K+ ATPase, Nav1.5 influence on membrane excitability and membrane localisation of heterotrimeric G-proteins. The cell surface localised enzyme zDHHC5 palmitoylates NCX1 and PLM and is implicated in injury during anoxia/reperfusion. Little is known about how palmitoylation remodels in cardiac diseases. We investigated expression of zDHHC5 in animal models of left ventricular hypertrophy (LVH) and heart failure (HF), along with HF tissue from humans. zDHHC5 expression increased rapidly during onset of LVH, whilst HF was associated with decreased zDHHC5 expression. Paradoxically, palmitoylation of the zDHHC5 substrate NCX1 was significantly reduced in LVH but increased in human HF, while palmitoylation of the zDHHC5 substrate PLM was unchanged in all settings. Overexpression of zDHHC5 in rabbit ventricular cardiomyocytes did not alter palmitoylation of its substrates or overall cardiomyocyte contractility, suggesting changes in zDHHC5 expression in disease may not be a primary driver of pathology. zDHHC5 itself is regulated by post-translational modifications, including palmitoylation in its C-terminal tail. We found that in HF palmitoylation of zDHHC5 changed in the same manner as palmitoylation of NCX1, suggesting additional regulatory mechanisms may be involved. This study provides novel evidence that palmitoylation of cardiac substrates is altered in the setting of HF, and that expression of zDHHC5 is dysregulated in both hypertrophy and HF.
Mild temperatures differentiate while extreme temperatures unify gene expression profiles among populations of Dicosmoecus gilvipes in California
Authors: King Emily E. , Stillman Jonathon H.
Published: October 2022

Accurately predicting the effects of future warming on aquatic ectotherms requires an understanding how thermal history, including average temperature and variation, affects populations of the same species. However, many laboratory studies simplify the thermal environment to focus on specific organismal responses and sacrifice environmental realism. Here, we paired laboratory-based transcriptomic RNA-seq analysis to identify thermally responsive genes with NanoString analysis of a subset of those genes to characterize natural field-based variation in thermal physiology among populations. We tested gene expression responses of three populations of field-acclimatized larval caddisflies (Dicosmoecus gilvipes) from streams in different eco-regions (mountain, valley, and coast) following exposure to current and future summertime temperatures. We hypothesized that distinct thermal histories across eco-regions could differentiate populations at baseline “control” levels of gene expression, as well as gene expression changes in response to daily warming and heat shock. Population-specific patterns of gene expression were apparent under the control and daily warming conditions suggesting that local acclimatization or local adaptation may differentiate populations, while responses to extreme temperatures were similar across populations, indicating that response to thermal stress is canalized. Underlying gene co-expression patterns in the daily warming and heat shock treatments were different, demonstrating the distinct physiological mechanisms involved with thermal acclimatization and response to thermal stress. These results highlight the importance and limitations of studies of the thermal biology of wild-caught organisms in their natural environment, and provide an important resource for researchers of caddisflies and aquatic insects in general.
Phylogenetic analysis and expression profiles of jasmonate ZIM-domain gene family provide insight into abiotic stress resistance in sunflower
Authors: Song Huifang , Fu Xinxuan , Li Juan , Niu Tianzeng , Shen Jie , Wang Xi , Li Yunling , Hou Qinwen , Liu Ake
Published: October 2022

Jasmonate ZIM-domain (JAZ) proteins act as inhibitory factors of the jasmonic acid (JA) pathway, which is involved in regulating plant development and defense responses. However, there are no extensive studies available on JAZ genes in sunflower (Helianthus annuus L.). In this study, the phylogenetic analysis of 139 putative JAZ genes from eight plants demonstrated that these JAZs could be divided into five groups (Groups I–V), and the 27 sunflower JAZs (HaJAZs) were classified into these five groups. All groups contained genes from both monocotyledons and dicotyledons, indicating that the emergence of JAZ genes predates the differentiation of monocotyledons and dicotyledons. Both segmental and tandem duplications contributed greatly to this gene family’s expansion in sunflower, especially in Group II. Moreover, the expression profiles of HaJAZ genes under normal conditions, hormone treatments or abiotic stresses were analyzed based on RNA-seq data. HaJAZ2 may be undergoing pseudogenization as a nonfunctional gene because it was not expressed in any tissue. Many HaJAZ genes in roots upregulated their expression when involved in responding to exogenous hormones, especially methyl-jasmonate. The abiotic stress treatments of sunflower showed that HaJAZ5, HaJAZ15, HaJAZ17, HaJAZ20, and HaJAZ21 tend to be sensitive to certain abiotic stresses. HaJAZs from different groups may share similar functions but also exercise their unique functions when responding to abiotic stresses. We speculated that this gene family was conserved in sequence but varied in its expression among duplicated HaJAZ genes, which implies that they may confer neofunctionalization in the adaptation to abiotic stresses; this work provides insight into the resistance of sunflowers and their adaptation to diverse environmental conditions.