bluuebunny/crossref_metadata_2025 huggingface dataset:
Paracrine secretion of IL8 by breast cancer stem cells promotes therapeutic resistance and metastasis of the bulk tumor cells
Authors: Wu Mingming , Zhang Xiao , Zhang Weijie , Yan Linlin , Liu Xiangtian , Zhang Min , Pan Yueyin , Lobie Peter E. , Han Xinghua , Zhu Tao
Published: March 2023

Background

Breast tumors consist of heterogeneous cellular subpopulations that differ in molecular properties and functional attributes. Cancer stem cells (CSCs) play pivotal roles in cancer therapeutic failure and metastasis. However, it remains indeterminate how CSCs determine the progression of the bulk cancer cell population.

Methods

Co-culture systems in vitro and co-implantation systems in vivo were designed to characterize the interactions between breast cancer stem cells (BCSCs) and bulk cancer cells. RNA sequencing was performed to study the functional and mechanistic implications of the BCSC secretome on bulk cancer cells. A cytokine antibody array was employed to screen the differentially secreted cytokines in the BCSC secretome. Tail vein injection metastatic models and orthotopic xenograft models were applied to study the therapeutic potential of targeting IL8.

Results

We identified that the BCSC secretome potentiated estrogen receptor (ER) activity in the bulk cancer cell population. The BCSC secretome rendered the bulk cancer cell population resistant to anti-estrogen and CDK4/6 inhibitor therapy; as well as increased the metastatic burden attributable to bulk cancer cells. Screening of the BCSC secretome identified IL8 as a pivotal factor that potentiated ERα activity, endowed tamoxifen resistance and enhanced metastatic burden by regulation of bulk cancer cell behavior. Pharmacological inhibition of IL8 increased the efficacy of fulvestrant and/or palbociclib by reversing tamoxifen resistance and abrogated metastatic burden.

Conclusion

Taken together, this study delineates the mechanism by which BCSCs determine the therapeutic response and metastasis of bulk cancer cells; and thereby suggests potential therapeutic strategies to ameliorate breast cancer outcomes.
FGF19 increases mitochondrial biogenesis and fusion in chondrocytes via the AMPKα-p38/MAPK pathway
Authors: Kan Shiyi , Pi Caixia , Zhang Li , Guo Daimo , Niu Zhixing , Liu Yang , Duan Mengmeng , Pu Xiahua , Bai Mingru , Zhou Chenchen , Zhang Demao , Xie Jing
Published: March 2023

Fibroblast growth factor 19 (FGF19) is recognized to play an essential role in cartilage development and physiology, and has emerged as a potential therapeutic target for skeletal metabolic diseases. However, FGF19-mediated cellular behavior in chondrocytes remains a big challenge. In the current study, we aimed to investigate the role of FGF19 on chondrocytes by characterizing mitochondrial biogenesis and fission–fusion dynamic equilibrium and exploring the underlying mechanism. We first found that FGF19 enhanced mitochondrial biogenesis in chondrocytes with the help of β Klotho (KLB), a vital accessory protein for assisting the binding of FGF19 to its receptor, and the enhanced biogenesis accompanied with a fusion of mitochondria, reflecting in the elongation of individual mitochondria and the up-regulation of mitochondrial fusion proteins. We then revealed that FGF19-mediated mitochondrial biogenesis and fusion required the binding of FGF19 to the membrane receptor, FGFR4, and the activation of AMP-activated protein kinase alpha (AMPKα)/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α)/sirtuin 1 (SIRT1) axis. Finally, we demonstrated that FGF19-mediated mitochondrial biogenesis and fusion was mainly dependent on the activation of p-p38 signaling. Inhibition of p38 signaling largely reduced the high expression of AMPKα/PGC-1α/SIRT1 axis, decreased the up-regulation of mitochondrial fusion proteins and impaired the enhancement of mitochondrial network morphology in chondrocytes induced by FGF19. Taking together, our results indicate that FGF19 could increase mitochondrial biogenesis and fusion via AMPKα-p38/MAPK signaling, which enlarge the understanding of FGF19 on chondrocyte metabolism.
The prognostic and therapeutic potential of HO-1 in leukemia and MDS
Authors: Sadeghi Mohammad , Fathi Mehrdad , Gholizadeh Navashenaq Jamshid , Mohammadi Hamed , Yousefi Mehdi , Hojjat-Farsangi Mohammad , Namdar Afshin , Movasaghpour Akbari Ali Akbar , Jadidi-Niaragh Farhad
Published: March 2023

Background

Heme oxygenase-1 (HO-1), a heme-degrading enzyme, is proven to have anti-apoptotic effects in several malignancies. In addition, HO-1 is reported to cause chemoresistance and increase cell survival. Growing evidence indicates that HO-1 contributes to the course of hematological malignancies as well. Here, the expression pattern, prognostic value, and the effect of HO-1 targeting in HMs are discussed.

Main body

According to the recent literature, it was discovered that HO-1 is overexpressed in myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), acute myeloblastic leukemia (AML), and acute lymphoblastic leukemia (ALL) cells and is associated with high-risk disease. Furthermore, in addition to HO-1 expression by leukemic and MDS cells, CML, AML, and ALL leukemic stem cells express this protein as well, making it a potential target for eliminating minimal residual disease (MRD). Moreover, it was concluded that HO-1 induces tumor progression and prevents apoptosis through various pathways.

Conclusion

HO-1 has great potential in determining the prognosis of leukemia and MDS patients. HO-1 induces resistance to several chemotherapeutic agents as well as tyrosine kinase inhibitors and following its inhibition, chemo-sensitivity increases. Moreover, the exact role of HO-1 in Chronic Lymphocytic Leukemia (CLL) is yet unknown. While findings illustrate that MDS and other leukemic patients could benefit from HO-1 targeting. Future studies can help broaden our knowledge regarding the role of HO-1 in MDS and leukemia.
iRGD-modified memory-like NK cells exhibit potent responses to hepatocellular carcinoma
Authors: Dong Yanbing , Huang Ying , Zhang Zhe , Chen Aoxing , Li Lin , Tian Manman , Shen Jie , Shao Jie
Published: March 2023

Background

Cytokine-induced memory-like natural killer (CIML NK) cells have been found to possess potent antitumor responses and induce complete remissions in patients with leukemia. However, the poor infiltration of transferred NK cells is a major obstacle in developing adoptive cell immunotherapy for solid tumors. In our study, we explored the potential of using the tumor-penetrating peptide iRGD to deliver activated CIML NK cells deep into tumor tissues.

Methods

After being briefly stimulated with interleukin-12 (IL-12), IL-15, and IL-18, CIML NK cells were assessed for their phenotype and function with flow cytometry. The penetrating and killing capability of iRGD-modified CIML NK cells in tumor spheroids was revealed by confocal microscopy. The anti-tumor efficacy of these modified CIML NK cells was tested in hepatocellular carcinoma (HCC) xenograft mouse models.

Results

Treating NK cells with cytokines led to a substantial activation, which was evidenced by the upregulation of CD25 and CD137. After a resting period of six days, CIML NK cells were still able to display strong activation when targeting HepG2 and SK-Hep-1 HCC cell lines. Additionally, CIML NK cells produced increased amounts of cytokines (interferon-gamma and tumor necrosis factor alpha) and exhibited heightened cytotoxicity towards HCC cell lines. The iRGD modification enabled CIML NK cells to infiltrate multicellular spheroids (MCSs) and, consequently, to induce cytotoxicity against the target cancer cells. Moreover, the CIML NK cells modified with iRGD significantly decreased tumor growth in a HCC xenograft mouse model.

Conclusion

Our findings demonstrate that CIML NK cells possess augmented potency and durability against HCC cell lines in vitro. Additionally, we have seen that the incorporation of iRGD to CIML NK cells facilitates enhanced infiltration and targeted destruction of MCSs. Moreover, the application of iRGD-modified CIML NK cells reveal remarkable anti-tumor efficacy against HCC in vivo.
Plasma gelsolin levels are associated with diabetes, sex, race, and poverty
Authors: Noren Hooten Nicole , Mode Nicolle A. , Kowalik Edward , Omoniyi Victor , Zonderman Alan B. , Ezike Ngozi , DiNubile Mark J. , Levinson Susan L. , Evans Michele K.
Published: March 2023

Background

The growing epidemic of the inflammation-related metabolic disease, type 2 diabetes mellitus, presents a challenge to improve our understanding of potential mechanisms or biomarkers to prevent or better control this age-associated disease. A gelsolin isoform is secreted into the plasma as part of the extracellular actin scavenger system which serves a protective role by digesting and removing actin filaments released from damaged cells. Recent data indicate a role for decreased plasma gelsolin (pGSN) levels as a biomarker of inflammatory conditions. Extracellular vesicles (EVs), a heterogeneous group of cell-derived membranous structures involved in intercellular signaling, have been implicated in metabolic and inflammatory diseases including type 2 diabetes mellitus. We examined whether pGSN levels were associated with EV concentration and inflammatory plasma proteins in individuals with or without diabetes.

Methods

We quantified pGSN longitudinally (n = 104) in a socioeconomically diverse cohort of middle-aged African American and White study participants with and without diabetes mellitus. Plasma gelsolin levels were assayed by ELISA. EV concentration (sub-cohort n = 40) was measured using nanoparticle tracking analysis. Inflammatory plasma proteins were assayed on the SomaScan® v4 proteomic platform.

Results

pGSN levels were lower in men than women. White individuals with diabetes had significantly lower levels of pGSN compared to White individuals without diabetes and to African American individuals either with or without diabetes. For adults living below poverty, those with diabetes had lower pGSN levels than those without diabetes. Adults living above poverty had similar pGSN levels regardless of diabetes status. No correlation between EV concentrations and pGSN levels was identified (r = − 0.03; p = 0.85). Large-scale exploratory plasma protein proteomics revealed 47 proteins that significantly differed by diabetes status, 19 of which significantly correlated with pGSN levels, including adiponectin.

Conclusions

In this cohort of racially diverse individuals with and without diabetes, we found differences in pGSN levels with diabetes status, sex, race, and poverty. We also report significant associations of pGSN with the adipokine, adiponectin, and other inflammation- and diabetes-related proteins. These data provide mechanistic insights into the relationship of pGSN and diabetes.
Targeting KK-LC-1 inhibits malignant biological behaviors of triple-negative breast cancer
Authors: Zhu Xudong , Bu Jiawen , zhu Tong , Jiang Yi
Published: March 2023

Background

Cancer/testis antigens (CTAs) participate in the regulation of malignant biological behaviors in breast cancer. However, the function and mechanism of KK-LC-1, a member of the CTA family, in breast cancer are still unclear.

Methods

Bioinformatic tools, immunohistochemistry, and western blotting were utilized to detect the expression of KK-LC-1 in breast cancer and to explore the prognostic effect of KK-LC-1 expression in breast cancer patients. Cell function assays, animal assays, and next-generation sequencing were utilized to explore the function and mechanism of KK-LC-1 in the malignant biological behaviors of triple-negative breast cancer. Small molecular compounds targeting KK-LC-1 were also screened and drug susceptibility testing was performed.

Results

KK-LC-1 was significantly highly expressed in triple-negative breast cancer tissues than in normal breast tissues. KK-LC-1 high expression was related to poor survival outcomes in patients with breast cancer. In vitro studies suggested that KK-LC-1 silencing can inhibit triple-negative breast cancer cell proliferation, invasion, migration, and scratch healing ability, increase cell apoptosis ratio, and arrest the cell cycle in the G0–G1 phase. In vivo studies have suggested that KK-LC-1 silencing decreases tumor weight and volume in nude mice. Results showed that KK-CL-1 can regulate the malignant biological behaviors of triple-negative breast cancer via the MAL2/MUC1-C/PI3K/AKT/mTOR pathway. The small-molecule compound Z839878730 had excellent KK-LC-1 targeting ability and cancer cell killing ability. The EC50 value was 9.7 μM for MDA-MB-231 cells and 13.67 µM for MDA-MB-468 cells. Besides, Z839878730 has little tumor-killing effect on human normal mammary epithelial cells MCF10A and can inhibit the malignant biological behaviors of triple-negative breast cancer cells by MAL2/MUC1-C/PI3K/AKT/mTOR pathway.

Conclusions

Our findings suggest that KK-LC-1 may serve as a novel therapeutic target for triple-negative breast cancer. Z839878730, which targets KK-LC-1, presents a new path for breast cancer clinical treatment.
EGR1 induces EMT in pancreatic cancer via a P300/SNAI2 pathway
Authors: Wang Yuanyang , Qin Cheng , Zhao Bangbo , Li Zeru , Li Tianyu , Yang Xiaoying , Zhao Yutong , Wang Weibin
Published: March 2023

Background

The prognosis of pancreatic cancer patients remains relatively poor. Although some patients would receive surgical resection, distant metastasis frequently occurs within one year. Epithelial-mesenchymal transition (EMT), as a pathological mechanism in cancer progression, contributed to the local and distant metastasis of pancreatic cancer.

Methods

Tissue microarray analysis and immunohistochemistry assays were used to compare the expression of EGR1 in pancreatic cancer and normal pancreatic tissues. Transwell chambers were used to evaluated the migration and invasion ability of cancer cells. Immunofluorescence was utilized to assess the expression of E-cadherin. ChIP-qPCR assay was applied to verify the combination of EGR1 and SNAI2 promoter sequences. Dual-luciferase reporter assay was used to detect the gene promoter activation. Co-IP assay was conducted to verify the interaction of EGR1 and p300/CBP.

Results

EGR1 was highly expressed in pancreatic cancer rather than normal pancreatic tissues and correlated with poor prognosis and cancer metastasis. EGR1 was proved to enhance the migration and invasion ability of pancreatic cells. Besides, EGR1 was positively correlated with EMT process in pancreatic cancer, via a SNAI2-dependent pathway. P300/CBP was found to play an auxiliary role in the transcriptional activation of the SNAI2 gene by EGR1. Finally, in vivo experiments also proved that EGR1 promoted liver metastasis of pancreatic cancer.

Conclusion

Our findings implied the EMT-promoting effect of EGR1 in pancreatic cancer and revealed the intrinsic mechanism. Blocking the expression of EGR1 may be a new anticancer strategy for pancreatic cancer.

Graphical Abstract
Identification of the MMP family as therapeutic targets and prognostic biomarkers in the microenvironment of head and neck squamous cell carcinoma
Authors: Liu Maohua , Huang Lijuan , Liu Yunling , Yang Sen , Rao Yong , Chen Xiao , Nie Minhai , Liu Xuqian
Published: March 2023

Background

Head and Neck Squamous Cell Carcinoma is a malignant tumor with high morbidity and mortality. The MMP family plays an important role in tumor invasion and metastasis. However, the mechanistic value of the MMP family as a therapeutic target and prognostic biomarker in HNSC has not been fully elucidated.

Methods

Oncomine, UALCAN, GEPIA, cBioportal, GeneMANIA, STRING, DAVID6.8, TRRUST, TIMER and Linkedomics were used for analysis.

Results

The mRNA expression levels of MMP1, MMP3, ILF3, MMP7, MMP9, MMP10, MMP11, MMP12, MMP13 and MMP16 were higher in HNSC than those in normal tissues, while the mRNA expression level of MMP15 was reduced. The relative expression levels of MMP1 and MMP14 were the highest in HNSC tissues. A significant correlation was found between the expression of MMP3, MMP11, MMP25 and the pathological stage of HNSC patients. There was no significant associations between all the MMP family members expression levels and DFS. Increased mRNA levels of MMP1, MMP8 and MMP25 were significantly associated with OS. In addition, we investigated the genetic changes of the MMP family in HNSC and found that all the MMP family members had genetic changes, most of which were amplification and depth loss. In the analysis of neighbor gene network and protein interaction, we found that the MMP family interacted with 25 neighboring genes, except for ILF3, MMP19, MMP20, MMP21, MMP23B, MMP27 and MMP28, other MMP proteins interacted with each other. Functional enrichment analysis showed that the MMP family could be present in the extracellular matrix, regulate peptidase activity, and participate in the catabolism of collagen. Meanwhile, we identified the transcription factor targets and kinase targets of the MMP family and found that ATM and ATR were the two most common kinase targets in the MMP family. We also found a significant correlation between the MMP family expression and immune cell infiltration. Cox proportional risk model analysis showed that macrophages, MMP14, MMP16, and MMP19 were significantly associated with clinical outcomes in HNSC patients.

Conclusion

The MMP family might serve as therapeutic target and prognostic biomarker in HNSC.
Prospective, longitudinal analysis of the gut microbiome in patients with locally advanced rectal cancer predicts response to neoadjuvant concurrent chemoradiotherapy
Authors: Sun Yi , Zhang Xiang , Jin Chuandi , Yue Kaile , Sheng Dashuang , Zhang Tao , Dou Xue , Liu Jing , Jing Hongbiao , Zhang Lei , Yue Jinbo
Published: March 2023

Background

Neoadjuvant concurrent chemoradiotherapy (nCCRT) is a standard treatment for locally advanced rectal cancer (LARC). The gut microbiome may be reshaped by radiotherapy through its effects on microbial composition, mucosal immunity, and the systemic immune system. We sought to clarify dynamic, longitudinal changes in the gut microbiome and blood immunomodulators throughout nCCRT and to explore the relationship of such changes with outcomes after nCCRT.

Methods

A total of 39 patients with LARC were recruited for this study. Fecal samples and peripheral blood samples were collected from all 39 patients before nCCRT, during nCCRT (at week 3), and after nCCRT (at week 5). The gut microbiota and the microbial community structure were analyzed by 16S rRNA sequencing of the V3–V4 region. Levels of blood immunomodulatory proteins were measured with a Millipore HCKPMAG-11 K kit and Luminex 200 platform (Luminex, USA).

Results

Cross-sectional and longitudinal analyses revealed that the gut microbiome profile and enterotype exhibited characteristic variations that could distinguish patients with good response (AJCC TRG classification 0–1) vs poor response (TRG 2–3) to nCCRT. Sparse partial least squares regression and canonical correspondence analyses showed multivariate associations between specific microbial taxa, host immunomodulatory proteins, immune cells, and outcomes after nCCRT. An integrated model consisting of baseline Clostridium sensu stricto 1 levels, fold changes in Intestinimonas, blood levels of the herpesvirus entry mediator (HVEM/CD270), and lymphocyte counts could predict good vs poor outcome after nCCRT [area under the receiver-operating characteristics curve (AUC)= 0.821; area under the precision-recall curve [AUPR] = 0.911].

Conclusions

Our results showed that longitudinal variations in specific gut taxa, associated host immune cells, and immunomodulatory proteins before and during nCCRT could be useful for early predictions of the efficacy of nCCRT, which could guide the choice of individualized treatment for patients with LARC.
A Chinese girl of Blau syndrome with renal arteritis and a literature review
Authors: Zeng Qiaoqian , Liu Haimei , Li Guomin , Li Yifan , Guan Wanzhen , Zhang Tao , Gong Yinv , Zhang Xiaomei , Lv Qianying , Wu Bingbing , Xu Hong , Sun Li
Published: March 2023

Background

Blau syndrome is a rare autoinflammatory disease caused by autosomal dominant mutations in the CARD15/NOD2 gene. Vascular involvement is a rare phenotype in Blau syndrome patients. In this study, we aimed to describe a 20-year- old Chinese girl with Blau syndrome complicated by renal arteritis. In addition, we summarized a literature review of published cases of vascular involvement in patients with Blau syndrome.

Case presentation

We describe a 20-year-old girl who was initially misdiagnosed with juvenile idiopathic arthritis (JIA) almost 15 years prior. In October 2019, she developed renal arteritis at the age of 17 years and was eventually diagnosed with Blau syndrome. A de-novo M513T mutation was found in her gene testing. A review of the literature on patients with Blau syndrome and vasculitis showed that a total of 18 cases were reported in the past 40 years. The vast majority of them were predominantly involved medium and large vessel arteritis. Of the 18 patients included in our literature review, 14 patients had aorto-arteritis, and 4 of them had renal artery involvement. Two patients presented with renal artery stenosis, 1with a sinus of Valsalva aneurysm, and 1 with retinal vasculitis.

Conclusion

A detailed medical history inquiry and a careful physical examination are helpful for the early identification of Blau syndrome, especially for infant onset refractory JIA. Medium-and large-vessel arteritis is a rare clinical manifestation in Blau syndrome patients. Careful examination of the peripheral pulse and measurement of blood pressure at every regular visit may be helpful in the early identification of Blau syndrome-arteritis. Early diagnosis and appropriate treatment may prevent or delay the occurrence of severe symptoms in patients to improve the patient’s quality of life.
Impaired cardiorespiratory and neuromuscular fitness in children and adolescents with juvenile idiopathic arthritis: a cross-sectional case–control study in the era of biologic drug therapies
Authors: Räsänen Kati , Markula-Patjas Kati , Kantanen Saija , Sipilä Kalle , Lakka Timo A. , Arikoski Pekka , Piippo-Savolainen Eija
Published: March 2023

Background

In recent years, biologic drug therapies have altered the course of juvenile idiopathic arthritis (JIA) possibly also improving the patients’ physical fitness. However, studies measuring both cardiorespiratory and muscular fitness in children with JIA are sparse and have failed to show consistent results.

Our aim was to assess both cardiorespiratory and neuromuscular fitness and contributing factors in children and adolescents with JIA in the era of biologic drug therapies.

Methods

This cross-sectional study consisted of 73 JIA patients (25 boys, 48 girls) aged 6.8- 17.5 years and 73 healthy age- and sex-matched controls, investigated in 2017–2019. Cardiorespiratory fitness was assessed by maximal ergospirometry and neuromuscular fitness by speed, agility, balance, and muscle strength tests.

Results

Means (± SD) of maximal workload (Wmax/kg) and peak oxygen uptake (VO2peak/kg,) were lower in JIA patients than in controls (Wmax/kg: 2.80 ± 0.54 vs. 3.14 ± 0.50 Watts, p < 0.01; VO2peak/kg: 38.7 ± 7.53 vs. 45.8 ± 6.59 ml/min/kg, p < 0.01). Shuttle-run, sit-up and standing long jump test results were lower in JIA patients than in controls (p < 0.01). Mean (± SD) daily activity was lower (89.0 ± 44.7 vs. 112.7 ± 62.1 min/day, p < 0.05), and sedentary time was higher (427 ± 213 vs. 343 ± 211 min/day, p < 0.05) in JIA patients compared to controls. Physical activity and cardiorespiratory or neuromuscular fitness were not associated with disease activity.

Conclusions

JIA patients were physically less active and had lower cardiorespiratory and neuromuscular fitness than their same aged controls with no JIA. Therefore, JIA patients should be encouraged to engage in physical activities as a part of their multidisciplinary treatment protocols to prevent adverse health risks of low physical activity and fitness.
Cannabinoids modulate the microbiota–gut–brain axis in HIV/SIV infection by reducing neuroinflammation and dysbiosis while concurrently elevating endocannabinoid and indole-3-propionate levels
Authors: McDew-White Marina , Lee Eunhee , Premadasa Lakmini S. , Alvarez Xavier , Okeoma Chioma M. , Mohan Mahesh
Published: March 2023

Background

Although the advent of combination anti-retroviral therapy (cART) has transformed HIV into a manageable chronic disease, an estimated 30–50% of people living with HIV (PLWH) exhibit cognitive and motor deficits collectively known as HIV-associated neurocognitive disorders (HAND). A key driver of HAND neuropathology is chronic neuroinflammation, where proinflammatory mediators produced by activated microglia and macrophages are thought to inflict neuronal injury and loss. Moreover, the dysregulation of the microbiota–gut–brain axis (MGBA) in PLWH, consequent to gastrointestinal dysfunction and dysbiosis, can lead to neuroinflammation and persistent cognitive impairment, which underscores the need for new interventions.

Methods

We performed RNA-seq and microRNA profiling in basal ganglia (BG), metabolomics (plasma) and shotgun metagenomic sequencing (colon contents) in uninfected and SIV-infected rhesus macaques (RMs) administered vehicle (VEH/SIV) or delta-9-tetrahydrocannabinol (THC) (THC/SIV).

Results

Long-term, low-dose THC reduced neuroinflammation and dysbiosis and significantly increased plasma endocannabinoid, endocannabinoid-like, glycerophospholipid and indole-3-propionate levels in chronically SIV-infected RMs. Chronic THC potently blocked the upregulation of genes associated with type-I interferon responses (NLRC5, CCL2, CXCL10, IRF1, IRF7, STAT2, BST2), excitotoxicity (SLC7A11), and enhanced protein expression of WFS1 (endoplasmic reticulum stress) and CRYM (oxidative stress) in BG. Additionally, THC successfully countered miR-142-3p-mediated suppression of WFS1 protein expression via a cannabinoid receptor-1-mediated mechanism in HCN2 neuronal cells. Most importantly, THC significantly increased the relative abundance of Firmicutes and Clostridia including indole-3-propionate (C. botulinum, C. paraputrificum, and C. cadaveris) and butyrate (C. butyricum, Faecalibacterium prausnitzii and Butyricicoccus pullicaecorum) producers in colonic contents.

Conclusion

This study demonstrates the potential of long-term, low-dose THC to positively modulate the MGBA by reducing neuroinflammation, enhancing endocannabinoid levels and promoting the growth of gut bacterial species that produce neuroprotective metabolites, like indole-3-propionate. The findings from this study may benefit not only PLWH on cART, but also those with no access to cART and more importantly, those who fail to suppress the virus under cART.
Understanding microglial responses in large animal models of traumatic brain injury: an underutilized resource for preclinical and translational research
Authors: Grovola Michael R. , von Reyn Catherine , Loane David J. , Cullen D. Kacy
Published: March 2023

Traumatic brain injury (TBI) often results in prolonged or permanent brain dysfunction with over 2.8 million affected annually in the U.S., including over 56,000 deaths, with over 5 million total survivors exhibiting chronic deficits. Mild TBI (also known as concussion) accounts for over 75% of all TBIs every year. Mild TBI is a heterogeneous disorder, and long-term outcomes are dependent on the type and severity of the initial physical event and compounded by secondary pathophysiological consequences, such as reactive astrocytosis, edema, hypoxia, excitotoxicity, and neuroinflammation. Neuroinflammation has gained increasing attention for its role in secondary injury as inflammatory pathways can have both detrimental and beneficial roles. For example, microglia—resident immune cells of the central nervous system (CNS)—influence cell death pathways and may contribute to progressive neurodegeneration but also aid in debris clearance and neuroplasticity. In this review, we will discuss the acute and chronic role of microglia after mild TBI, including critical protective responses, deleterious effects, and how these processes vary over time. These descriptions are contextualized based on interspecies variation, sex differences, and prospects for therapy. We also highlight recent work from our lab that was the first to describe microglial responses out to chronic timepoints after diffuse mild TBI in a clinically relevant large animal model. The scaled head rotational acceleration of our large animal model, paired with the gyrencephalic architecture and appropriate white:gray matter ratio, allows us to produce pathology with the same anatomical patterns and distribution of human TBI, and serves as an exemplary model to examine complex neuroimmune response post-TBI. An improved understanding of microglial influences in TBI could aid in the development of targeted therapeutics to accentuate positive effects while attenuating detrimental post-injury responses over time.
Metabolic reprogramming and lipid droplets are involved in Zika virus replication in neural cells
Authors: Dias Suelen Silva Gomes , Cunha-Fernandes Tamires , Souza-Moreira Luciana , Soares Vinicius Cardoso , Lima Giselle Barbosa , Azevedo-Quintanilha Isaclaudia G. , Santos Julia , Pereira-Dutra Filipe , Freitas Caroline , Reis Patricia A. , Rehen Stevens Kastrup , Bozza Fernando A. , Souza Thiago M. Lopes , de Almeida Cecilia J. G. , Bozza Patricia T.
Published: March 2023

Zika virus (ZIKV) infection is a global public health concern linked to adult neurological disorders and congenital diseases in newborns. Host lipid metabolism, including lipid droplet (LD) biogenesis, has been associated with viral replication and pathogenesis of different viruses. However, the mechanisms of LD formation and their roles in ZIKV infection in neural cells are still unclear. Here, we demonstrate that ZIKV regulates the expression of pathways associated with lipid metabolism, including the upregulation and activation of lipogenesis-associated transcription factors and decreased expression of lipolysis-associated proteins, leading to significant LD accumulation in human neuroblastoma SH-SY5Y cells and in neural stem cells (NSCs). Pharmacological inhibition of DGAT-1 decreased LD accumulation and ZIKV replication in vitro in human cells and in an in vivo mouse model of infection. In accordance with the role of LDs in the regulation of inflammation and innate immunity, we show that blocking LD formation has major roles in inflammatory cytokine production in the brain. Moreover, we observed that inhibition of DGAT-1 inhibited the weight loss and mortality induced by ZIKV infection in vivo. Our results reveal that LD biogenesis triggered by ZIKV infection is a crucial step for ZIKV replication and pathogenesis in neural cells. Therefore, targeting lipid metabolism and LD biogenesis may represent potential strategies for anti-ZIKV treatment development.
HMGB1 mediates synaptic loss and cognitive impairment in an animal model of sepsis-associated encephalopathy
Authors: Yin Xiao-Yu , Tang Xiao-Hui , Wang Shi-Xu , Zhao Yong-Chang , Jia Min , Yang Jian-Jun , Ji Mu-Huo , Shen Jin-Chun
Published: March 2023

Background

Microglial activation-mediated neuroinflammation is one of the essential pathogenic mechanisms of sepsis-associated encephalopathy (SAE). Mounting evidence suggests that high mobility group box-1 protein (HMGB1) plays a pivotal role in neuroinflammation and SAE, yet the mechanism by which HMGB1 induces cognitive impairment in SAE remains unclear. Therefore, this study aimed to investigate the mechanism of HMGB1 underlying cognitive impairment in SAE.

Methods

An SAE model was established by cecal ligation and puncture (CLP); animals in the sham group underwent cecum exposure alone without ligation and perforation. Mice in the inflachromene (ICM) group were continuously injected with ICM intraperitoneally at a daily dose of 10 mg/kg for 9 days starting 1 h before the CLP operation. The open field, novel object recognition, and Y maze tests were performed on days 14–18 after surgery to assess locomotor activity and cognitive function. HMGB1 secretion, the state of microglia, and neuronal activity were measured by immunofluorescence. Golgi staining was performed to detect changes in neuronal morphology and dendritic spine density. In vitro electrophysiology was performed to detect changes in long-term potentiation (LTP) in the CA1 of the hippocampus. In vivo electrophysiology was performed to detect the changes in neural oscillation of the hippocampus.

Results

CLP-induced cognitive impairment was accompanied by increased HMGB1 secretion and microglial activation. The phagocytic capacity of microglia was enhanced, resulting in aberrant pruning of excitatory synapses in the hippocampus. The loss of excitatory synapses reduced neuronal activity, impaired LTP, and decreased theta oscillation in the hippocampus. Inhibiting HMGB1 secretion by ICM treatment reversed these changes.

Conclusions

HMGB1 induces microglial activation, aberrant synaptic pruning, and neuron dysfunction in an animal model of SAE, leading to cognitive impairment. These results suggest that HMGB1 might be a target for SAE treatment.
Tregs dysfunction aggravates postoperative cognitive impairment in aged mice
Authors: Zhou Yile , Ju Huihui , Hu Yan , Li Tingting , Chen Zhouyi , Si Yuan , Sun Xia , Shi Yi , Fang Hao
Published: March 2023

Objectives

Enhanced neuroinflammation is an important mechanism underlying perioperative neurocognitive disorders. Regulatory T cells (Tregs) play a crucial role in regulating systemic immune responses. The present study was aimed to investigate the participation of Tregs in the development of postoperative cognitive dysfunction (POCD).

Methods

Surgery-associated neurocognitive disorder was induced in 18-month-old mice subjected to internal fixation of tibial fracture. Morris water maze was used to examine mice cognitive function. Splenic Tregs were collected for RNA sequencing and flow cytometry. Levels of inflammatory factors in the circulation and hippocampus were measured by enzyme-linked immunosorbent assay. Protein presences of tight junction proteins were detected by immunofluorescence.

Results

Surgery of internal fixation of tibial fracture induced cognitive impairment in aged mice, accompanied by elevated plasma levels of inflammatory factors and increased circulating Tregs. Transfusion of Tregs from young mice partially restored the structure of the blood–brain barrier and alleviated POCD in aged mice. Compared with young Tregs, differentially expressed genes in aged Tregs were enriched in tumor necrosis factor (TNF) signaling pathway and cytokine–cytokine receptor interaction. Flow cytometry revealed that aged Tregs had blunted functions under basal and stimulated conditions. Blockade of the CD25 epitope protected the blood–brain barrier structure, reduced TNF-α levels in the hippocampus, and improved surgery-associated cognition in aged mice.

Conclusions

Blocking peripheral regulatory T cells improves surgery-induced cognitive function in aged mice. Therefore, aged Tregs play an essential role in the occurrence of POCD.
Microglia sustain anterior cingulate cortex neuronal hyperactivity in nicotine-induced pain
Authors: Long Dan-dan , Zhang Yu-zhuo , Liu An , Shen Liang , Wei Hong-rui , Lou Qian-qian , Hu Shan-shan , Chen Dan-yang , Chai Xiao-qing , Wang Di
Published: March 2023

Background

Long-term smoking is a risk factor for chronic pain, and chronic nicotine exposure induces pain-like effects in rodents. The anterior cingulate cortex (ACC) has been demonstrated to be associated with pain and substance abuse. This study aims to investigate whether ACC microglia are altered in response to chronic nicotine exposure and their interaction with ACC neurons and subsequent nicotine-induced allodynia in mice.

Methods

We utilized a mouse model that was fed nicotine water for 28 days. Brain slices of the ACC were collected for morphological analysis to evaluate the impacts of chronic nicotine on microglia. In vivo calcium imaging and whole-cell patch clamp were used to record the excitability of ACC glutamatergic neurons.

Results

Compared to the vehicle control, the branch endpoints and the length of ACC microglial processes decreased in nicotine-treated mice, coinciding with the hyperactivity of glutamatergic neurons in the ACC. Inhibition of ACC glutamatergic neurons alleviated nicotine-induced allodynia and reduced microglial activation. On the other hand, reactive microglia sustain ACC neuronal excitability in response to chronic nicotine, and pharmacological inhibition of microglia by minocycline or liposome-clodronate reduces nicotine-induced allodynia. The neuron-microglia interaction in chronic nicotine-induced allodynia is mediated by increased expression of neuronal CX3CL1, which activates microglia by acting on CX3CR1 receptors on microglial cells.

Conclusion

Together, these findings underlie a critical role of ACC microglia in the maintenance of ACC neuronal hyperactivity and resulting nociceptive hypersensitivity in chronic nicotine-treated mice.
Natural IgG antibodies to β amyloid are decreased in patients with Parkinson’s disease
Authors: Paganelli Roberto , Paganelli Alessia , Pawelec Graham , Di Iorio Angelo
Published: March 2023

Natural antibodies (nAbs) against aggregation-prone proteins have been found in healthy normal subjects. These proteins likely have a pathogenetic role in neurodegenerative diseases of ageing. They include the amyloid β (Aβ) protein which may play an important role in Alzheimer’s dementia (AD), and α-synuclein, a major determinant of Parkinson’s disease (PD). We measured nAbs to Aβ in a group of Italian patients with AD, vascular dementia, non-demented PD patients and healthy elderly controls. We found that Aβ antibody levels in AD were similar to age- and sex-matched controls, but contrary to our expectations, they were significantly reduced in PD. This may identify patients that could be more prone to amyloid aggregation.
Virome of wild rats (Rattus norvegicus) captured far from pig farms in Jiangsu province of China reveals novel porcine circovirus type 2d (PCV2d) sequences
Authors: Zhao Min , Bao Siwen , Xu Diandian , He Jingxian , Zhang Han , Ji Likai , Yang Shixing , Wang Xiaochun , Shen Quan , Liu Jia , Zhang Qing , Ma Xiao , Zhang Wen , Shan Tongling
Published: March 2023

Background

Porcine circovirus type 2 (PCV2) has caused great economic losses in the global pig industry. There have been published records of wild rats acting as the reservoirs of PCV2 (only PCV2a and PCV2b), but almost all of which were related to the PCV2-infected swine herds.

Results

In this study, we carried out the detection, amplification, and characterization of novel PCV2 strains in wild rats that were captured far from pig farms. Nested PCR assay demonstrated that the kidney, heart, lung, liver, pancreas, and large and small intestines of rats were screened positive for PCV2. We subsequently sequenced two full genomes of PCV2 in positive sample pools, designated as js2021-Rt001 and js2021-Rt002. Genome sequence analysis indicated that they had the highest similarity to nucleotide sequences of porcine-origin PCV2 isolates in Vietnam. Phylogenetically, js2021-Rt001 and js2021-Rt002 were a part of the PCV2d genotype cluster, which is a predominant genotype circulating worldwide in recent years. The antibody recognition regions, immunodominant decoy epitope, and heparin sulfate binding motif of the two complete genome sequences coincided with those previously reported.

Conclusions

Our research reported the genomic characterization of two novel PCV2 strains (js2021-Rt001 and js2021-Rt002) and provided the first supported evidence that PCV2d could naturally infect wild rats in China. However, whether the newly identified strains have potential for circulating in nature in vertical and horizontal transmission or inter-species jumping between rats and pigs needs further research.
Characterization of a novel papillomavirus identified from a whale (Delphinapterus leucas) pharyngeal metagenomic library
Authors: Lu Xiang , Zhu Rong , Dai Ziyuan
Published: March 2023

Here, using viral metagenomic method, a novel whale papillomavirus (temporarily named wPV, GenBank accession number OP856597) was discovered in a whale (Delphinapterus leucas) pharyngeal metagenomic library. The complete genome size of wPV is 7179 bp, with GC content of 54.4% and a nucleotide composition of 23.4% A, 22.3% T, 28.4% G, and 25.9% C. The viral genome has a typical papillomavirus organization pattern, and five ORFs were predicted, including two late genes encoding L1 and L2, and three early genes encoding E1, E2, and E6. Pairwise sequence comparison and phylogenetic analysis based on the L1 gene sequence indicated that wPV may be a novel species within genus Dyodeltapapillomavirus. In addition, the E2 region of wPV was predicted to have a potential recombination event. The discovery of this novel papillomavirus increases our understanding of the viral ecology of marine mammals, providing insights into possible future infectious diseases.
Risk of subclinical atherosclerosis across metabolic transition in individuals with or without fatty liver disease: a prospective cohort study
Authors: Xin Zhuojun , Huang Jiaojiao , Cao Qiuyu , Wang Jialu , He Ruixin , Hou Tianzhichao , Ding Yi , Lu Jieli , Wang Tiange , Zhao Zhiyun , Wang Weiqing , Ning Guang , Xu Min , Bi Yufang , Xu Yu , Li Mian
Published: March 2023

Background

Metabolic dysfunction is a major determinant in the progression of fatty liver disease. It is pivotal to evaluate the metabolic status and subsequent transition in fatty liver population and to identify the risk of subclinical atherosclerosis.

Methods

The prospective cohort study included 6260 Chinese community residents during 2010–2015. Fatty liver was determined as hepatic steatosis (HS) by ultrasonography. Metabolic unhealthy (MU) status was defined as having diabetes and/or ≥ 2 metabolic risk factors. Participants were categorized into 4 groups according to the combination of metabolic healthy (MH)/MU and fatty liver status (MHNHS, MUNHS, MHHS and MUHS). Subclinical atherosclerosis was assessed by elevated brachial-ankle pulse wave velocity, pulse pressure and/or albuminuria.

Results

31.3% of the participants had fatty liver disease and 76.9% were in MU status. During a 4.3-year follow-up, 24.2% of participants developed composite subclinical atherosclerosis. Multivariable adjusted odds ratios for composite subclinical atherosclerosis risk were (1.66 [1.30–2.13]) in MUNHS group and (2.57 [1.90–3.48]) in MUHS group. It seemed that participants with fatty liver disease were more prone to be remained in MU status (90.7% vs.50.8%) and less likely to regress to MH status (4.0% vs. 8.9%). Fatty liver participants progressed to (3.11 [1.23–7.92]) or maintained MU status (4.87 [3.25–7.31]) significantly impelled the development of the composite risk, while regressing to MH status (0.15 [0.04–0.64]) were more intended to mitigate the risk.

Conclusions

The current study emphasized the importance of assessing metabolic status and its dynamic changes, especially in the fatty liver population. Regressing from MU to MH status not only benefited the systematic metabolic profile but also ameliorated future cardiometabolic complications.
Distinct reinforcement learning profiles distinguish between language and attentional neurodevelopmental disorders
Authors: Nissan Noyli , Hertz Uri , Shahar Nitzan , Gabay Yafit
Published: March 2023

Background

Theoretical models posit abnormalities in cortico-striatal pathways in two of the most common neurodevelopmental disorders (Developmental dyslexia, DD, and Attention deficit hyperactive disorder, ADHD), but it is still unclear what distinct cortico-striatal dysfunction might distinguish language disorders from others that exhibit very different symptomatology. Although impairments in tasks that depend on the cortico-striatal network, including reinforcement learning (RL), have been implicated in both disorders, there has been little attempt to dissociate between different types of RL or to compare learning processes in these two types of disorders. The present study builds upon prior research indicating the existence of two learning manifestations of RL and evaluates whether these processes can be differentiated in language and attention deficit disorders. We used a two-step RL task shown to dissociate model-based from model-free learning in human learners.

Results

Our results show that, relative to neurotypicals, DD individuals showed an impairment in model-free but not in model-based learning, whereas in ADHD the ability to use both model-free and model-based learning strategies was significantly compromised.

Conclusions

Thus, learning impairments in DD may be linked to a selective deficit in the ability to form action-outcome associations based on previous history, whereas in ADHD some learning deficits may be related to an incapacity to pursue rewards based on the tasks' structure. Our results indicate how different patterns of learning deficits may underlie different disorders, and how computation-minded experimental approaches can differentiate between them.
B7-H3 expression is associated with high PD-L1 expression in clear cell renal cell carcinoma and predicts poor prognosis
Authors: Lee Jung Hee , Kim Yong Jun , Ryu Hyun Woo , Shin Seung Won , Kim Eun Ji , Shin So Hyun , Park Joon Young , Kim So Young , Hwang Chung Su , Na Joo-Young , Shin Dong Hoon , Kim Jee Yeon , Lee Hyun Jung
Published: March 2023

Background

Clear cell Renal cell carcinoma (ccRCC) is an immunogenic tumor. B7 family members, such as CTLA-4, PD-1, and PD-L1, are the main components of immune checkpoints that regulate various immune responses. Specifically, B7-H3 regulates T cell-mediated immune responses against cancer. This study aimed to analyze the association between B7-H3 and CTLA-4 expression and the prognostic factors of ccRCC to provide a basis for their potential use as predictive factors and in immunotherapy.

Methods

Formalin-fixed paraffin-embedded specimens were obtained from 244 ccRCC patients, and B7-H3, CTLA-4, and PD-L1 expressions were evaluated using immunohistochemical staining.

Results

B7-H3 and CTLA-4 were positive in 73 (29.9%) and 57 (23.4%) of the 244 patients, respectively. B7-H3 expression was significantly associated with PD-L1 expression (P <  0.0001); however, CTLA-4 expression was not (P = 0.842). Kaplan–Meier analysis showed that positive B7-H3 expression was associated with poor progression-free survival (PFS) (P <  0.0001), whereas CTLA-4 expression was not (P = 0.457). Multivariate analysis revealed that B7-H3 was correlated with poor PFS (P = 0.031), whereas CTLA-4 was not (P = 0.173).

Conclusions

To the best of our knowledge, this study is the first to investigate B7-H3 and PD-L1 expression and survival in ccRCC. B7-H3 expression is an independent prognostic factor for ccRCC. Furthermore, multiple immune cell inhibitory targets, such as B7-H3 and PD-L1, can be used for therapeutic tumor regression in a clinical setting.