Biomedicines

17 pages, 1653 KiB

Open AccessArticle

Butyrate Protects against Diet-Induced NASH and Liver Fibrosis and Suppresses Specific Non-Canonical TGF-β Signaling Pathways in Human Hepatic Stellate Cells

by Eveline Gart, Wim van Duyvenvoorde, Karin Toet, Martien P. M. Caspers, Lars Verschuren, Mette Juul Nielsen, Diana Julie Leeming, Everton Souto Lima, Aswin Menke, Roeland Hanemaaijer, Jaap Keijer, Kanita Salic, Robert Kleemann and Martine C. Morrison

Biomedicines 2021, 9(12), 1954; https://doi.org/10.3390/biomedicines9121954 - 20 Dec 2021

Cited by 23 | Viewed by 3620

Abstract

In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, which is the main determinant of NASH-associated mortality. The short-chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver [...] Read more.

In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, which is the main determinant of NASH-associated mortality. The short-chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver fibrosis remain unclear. Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared with a HFD-control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). HFD-fed mice developed obesity, insulin resistance, increased plasma leptin levels, adipose tissue inflammation, gut permeability, dysbiosis, and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels, and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 levels and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways Rho-like GTPases and PI3K/AKT and other important pro-fibrotic regulators (e.g., YAP/TAZ, MYC) by butyrate, providing a potential rationale for its antifibrotic effects. In conclusion, butyrate protects against obesity development, insulin resistance-associated NASH, and liver fibrosis. These antifibrotic effects are at least partly attributable to a direct effect of butyrate on collagen production in hepatic stellate cells, involving inhibition of non-canonical TGF-β signaling pathways. Full article

(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)

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Graphical abstract

13 pages, 3204 KiB

Open AccessArticle

Controlled Synthesis of Up-Conversion NaYF₄:Yb,Tm Nanoparticles for Drug Release under Near IR-Light Therapy

by Edelweiss Moyano Rodríguez, Miguel Gomez-Mendoza, Raúl Pérez-Ruiz, Beatriz Peñín, Diego Sampedro, Antonio Caamaño and Víctor A. de la Peña O’Shea

Biomedicines 2021, 9(12), 1953; https://doi.org/10.3390/biomedicines9121953 - 20 Dec 2021

Cited by 2 | Viewed by 2477

Abstract

Up-Conversion materials have received great attention in drug delivery applications in recent years. A specifically emerging field includes the development of strategies focusing on photon processes that promote the development of novel platforms for the efficient transport and the controlled release of drug [...] Read more.

Up-Conversion materials have received great attention in drug delivery applications in recent years. A specifically emerging field includes the development of strategies focusing on photon processes that promote the development of novel platforms for the efficient transport and the controlled release of drug molecules in the harsh microenvironment. Here, modified reaction time, thermal treatment, and pH conditions were controlled in the synthesis of NaYF₄:Yb,Tm up-converted (UC) material to improve its photoluminescence properties. The best blue-emission performance was achieved for the UC3 sample prepared through 24 h-synthesis without thermal treatment at a pH of 5, which promotes the presence of the β-phase and smaller particle size. NaYF₄:Yb,Tm has resulted in a highly efficient blue emitter material for light-driven drug release under near-IR wavelength. Thus, NaYF₄:Yb,Tm up-converted material promotes the N-O bond cleavage of the oxime ester of Ciprofloxacin (prodrug) as a highly efficient photosensitized drug delivery process. HPLC chromatography and transient absorption spectroscopy measurements were performed to evaluate the drug release conversion rate. UC3 has resulted in a very stable and easily recovered material that can be used in several reaction cycles. This straightforward methodology can be extended to other drugs containing photoactive chromophores and is present as an alternative for drug release systems. Full article

(This article belongs to the Special Issue Optical Nanoparticles for Biomedicine)

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16 pages, 20738 KiB

Open AccessArticle

Improving Generation of Cardiac Organoids from Human Pluripotent Stem Cells Using the Aurora Kinase Inhibitor ZM447439

by Su-Jin Lee, Hyeon-A Kim, Sung-Joon Kim and Hyang-Ae Lee

Biomedicines 2021, 9(12), 1952; https://doi.org/10.3390/biomedicines9121952 - 20 Dec 2021

Cited by 6 | Viewed by 2822

Abstract

Drug-induced cardiotoxicity reduces the success rates of drug development. Thus, the limitations of current evaluation methods must be addressed. Human cardiac organoids (hCOs) derived from induced pluripotent stem cells (hiPSCs) are useful as an advanced drug-testing model; they demonstrate similar electrophysiological functionality and [...] Read more.

Drug-induced cardiotoxicity reduces the success rates of drug development. Thus, the limitations of current evaluation methods must be addressed. Human cardiac organoids (hCOs) derived from induced pluripotent stem cells (hiPSCs) are useful as an advanced drug-testing model; they demonstrate similar electrophysiological functionality and drug reactivity as the heart. How-ever, similar to other organoid models, they have immature characteristics compared to adult hearts, and exhibit batch-to-batch variation. As the cell cycle is important for the mesodermal differentiation of stem cells, we examined the effect of ZM447439, an aurora kinase inhibitor that regulates the cell cycle, on cardiogenic differentiation. We determined the optimal concentration and timing of ZM447439 for the differentiation of hCOs from hiPSCs and developed a novel protocol for efficiently and reproducibly generating beating hCOs with improved electrophysiological functionality, contractility, and yield. We validated their maturity through electro-physiological- and image-based functional assays and gene profiling with next-generation sequencing, and then applied these cells to multi-electrode array platforms to monitor the cardio-toxicity of drugs related to cardiac arrhythmia; the results confirmed the drug reactivity of hCOs. These findings may enable determination of the regulatory mechanism of cell cycles underlying the generation of iPSC-derived hCOs, providing a valuable drug testing platform. Full article

(This article belongs to the Special Issue Drug Screening or Toxicology Research Based on 3D-Cultured Cell Models)

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13 pages, 2624 KiB

Open AccessSystematic Review

The Effect of a Multimodal Occupational Therapy Program with Cognition-Oriented Approach on Cognitive Function and Activities of Daily Living in Patients with Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

by Min-Joo Ham, Sujin Kim, Ye-Ji Jo, Chisoo Park, Yunkwon Nam, Doo-Han Yoo and Minho Moon

Biomedicines 2021, 9(12), 1951; https://doi.org/10.3390/biomedicines9121951 - 20 Dec 2021

Cited by 7 | Viewed by 5621

Abstract

Non-pharmacological intervention, which includes a broad range of approaches, may be an alternative treatment for Alzheimer’s disease (AD). Multimodal non-pharmacological intervention alleviates cognitive dysfunction and the impairment of activities of daily living (ADL) in AD patients. However, it is still unclear which combination [...] Read more.

Non-pharmacological intervention, which includes a broad range of approaches, may be an alternative treatment for Alzheimer’s disease (AD). Multimodal non-pharmacological intervention alleviates cognitive dysfunction and the impairment of activities of daily living (ADL) in AD patients. However, it is still unclear which combination of non-pharmacological interventions is preferred. We selected a non-pharmacological intervention combined with occupational therapy (OT). We investigated the effect of a multimodal OT program with cognition-oriented approach on cognitive dysfunction and impairments of ADL in patients with AD. Four electronic databases were searched from January 2000 to August 2020. The studies were assessed for heterogeneity, quality assessment, effect size and publication bias. A total of seven randomized controlled trials examining multimodal OT programs with cognition-oriented approach in AD patients were included in the meta-analysis. Compared with the control group, the multimodal OT program with cognition-oriented approach group was statistically beneficial for cognitive dysfunction (95% CI: 0.25–0.91). However, compared with the control group, the multimodal OT program with cognition-oriented approach group tended to be beneficial for basic ADL, and instrumental ADL. These results suggest that the multimodal OT program with cognition-oriented approach might be the optimal multimodal non-pharmacological intervention for improving cognitive dysfunction in AD patients. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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15 pages, 1231 KiB

Open AccessReview

Complement and Coagulation System Crosstalk in Synaptic and Neural Conduction in the Central and Peripheral Nervous Systems

by Shani Berkowitz, Joab Chapman, Amir Dori, Shany Guly Gofrit, Nicola Maggio and Efrat Shavit-Stein

Biomedicines 2021, 9(12), 1950; https://doi.org/10.3390/biomedicines9121950 - 20 Dec 2021

Cited by 10 | Viewed by 3491

Abstract

Complement and coagulation are both key systems that defend the body from harm. They share multiple features and are similarly activated. They each play individual roles in the systemic circulation in physiology and pathophysiology, with significant crosstalk between them. Components from both systems [...] Read more.

Complement and coagulation are both key systems that defend the body from harm. They share multiple features and are similarly activated. They each play individual roles in the systemic circulation in physiology and pathophysiology, with significant crosstalk between them. Components from both systems are mapped to important structures in the central nervous system (CNS) and peripheral nervous system (PNS). Complement and coagulation participate in critical functions in neuronal development and synaptic plasticity. During pathophysiological states, complement and coagulation factors are upregulated and can modulate synaptic transmission and neuronal conduction. This review summarizes the current evidence regarding the roles of the complement system and the coagulation cascade in the CNS and PNS. Possible crosstalk between the two systems regarding neuroinflammatory-related effects on synaptic transmission and neuronal conduction is explored. Novel treatment based on the modulation of crosstalk between complement and coagulation may perhaps help to alleviate neuroinflammatory effects in diseased states of the CNS and PNS. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)

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13 pages, 541 KiB

Open AccessReview

YAP/Hippo Pathway and Cancer Immunity: It Takes Two to Tango

by Dimitrios Matthaios, Maria Tolia, Davide Mauri, Konstantinos Kamposioras and Michalis Karamouzis

Biomedicines 2021, 9(12), 1949; https://doi.org/10.3390/biomedicines9121949 - 20 Dec 2021

Cited by 16 | Viewed by 5519

Abstract

Hippo pathway with its main molecule YAP is a crucial pathway for development, tissue homeostasis, wound healing, tissue regeneration, and cancer. In this review, we discuss the multiple effects of the YAP/Hippo pathway in the immune system and cancer. We analyzed a series [...] Read more.

Hippo pathway with its main molecule YAP is a crucial pathway for development, tissue homeostasis, wound healing, tissue regeneration, and cancer. In this review, we discuss the multiple effects of the YAP/Hippo pathway in the immune system and cancer. We analyzed a series of effects: extracellular vesicles enhanced immunity through inhibition of LATS1/2, ways of modulation of the tumor microenvironment, YAP- and TAZ-mediated upregulation of PDL1, high expression of YAP and PDL1 in EGFR-TKI-resistant cells, enhanced YAP activity in inflammation, and the effect of the Hippo pathway on T cells, B cells, Tregs, macrophages, and myeloid-derived suppressor cells (MDSCs). These pleiotropic effects render the YAP and Hippo pathway a key pathway for exploitation in the future, in order to enhance our immunotherapy treatment strategies in oncology. Full article

(This article belongs to the Special Issue New Advance in Immuno-Oncology)

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12 pages, 628 KiB

Open AccessArticle

The Change in Metabolic Syndrome Status and the Risk of Nonviral Liver Cirrhosis

by Goh-Eun Chung, Young Chang, Yuri Cho, Eun-Ju Cho, Jeong-Ju Yoo, Sang-Hyun Park, Kyungdo Han, Dong-Wook Shin, Su-Jong Yu, Yoon-Jun Kim and Jung-Hwan Yoon

Biomedicines 2021, 9(12), 1948; https://doi.org/10.3390/biomedicines9121948 - 20 Dec 2021

Cited by 3 | Viewed by 2502

Abstract

Background: Nonalcoholic fatty liver disease is considered to be the hepatic component of metabolic syndrome (MetS). However, the association between changes in MetS status and the risk of liver cirrhosis (LC) has not been investigated to date. This study assessed the association between [...] Read more.

Background: Nonalcoholic fatty liver disease is considered to be the hepatic component of metabolic syndrome (MetS). However, the association between changes in MetS status and the risk of liver cirrhosis (LC) has not been investigated to date. This study assessed the association between changes in MetS and subsequent nonviral LC development. Methods: Data were obtained from the Korean National Health Insurance Service. Individuals who participated in health screenings from both 2009 to 2010 and 2011 to 2012 were included. The primary outcome was LC development according to the static and dynamic MetS status. Subjects were stratified into four groups according to the change in MetS status observed from the two-year interval screening (2009–2011). Cox regression analysis was used to examine the hazard ratios of LC. Results: During a median of 7.3 years of follow-up, 24,923 incident LC cases developed among 5,975,308 individuals. After adjusting for age, sex, smoking, alcohol, regular exercise, and body mass index, the adjusted hazard ratios (95% confidence intervals) for LC development were 1.39 (1.33–1.44) for the MetS-Developed group, 1.32 (1.26–1.37) for the MetS-Recovered group, and 1.51 (1.45–1.56) for the MetS-Sustained group, relative to the MetS-Free group. Stratified analyses according to age, sex, smoking, alcohol intake, exercise, diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease showed similar results. Conclusions: Both static and dynamic MetS status are independent risk factors for LC development. The risk of LC was the highest in people with sustained MetS and was lower in the MetS-Recovered group than in the MetS-Sustained group. These results suggest that improving a person’s MetS status may be helpful in preventing LC. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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10 pages, 639 KiB

Open AccessArticle

Inverse Association between High-Density Lipoprotein Cholesterol and Adverse Outcomes among Acute Ischemic Stroke Patients with Diabetes Mellitus

by Guoliang Hu, Yuesong Pan, Mengxing Wang, Xia Meng, Yong Jiang, Zixiao Li, Hao Li, Yongjun Wang and Yilong Wang

Biomedicines 2021, 9(12), 1947; https://doi.org/10.3390/biomedicines9121947 - 20 Dec 2021

Cited by 4 | Viewed by 2535

Abstract

A low high-density lipoprotein cholesterol (HDL-C) level is an identified risk factor for cardiovascular diseases. However, results on the association between HDL-C levels and adverse outcomes in diabetic status still remain limited and controversial. Herein, we evaluated the association between HDL-C levels and [...] Read more.

A low high-density lipoprotein cholesterol (HDL-C) level is an identified risk factor for cardiovascular diseases. However, results on the association between HDL-C levels and adverse outcomes in diabetic status still remain limited and controversial. Herein, we evaluated the association between HDL-C levels and adverse outcomes among acute ischemic stroke (AIS) patients with diabetes mellitus. The cohort comprised 3824 AIS patients with diabetes mellitus (62.7 ± 10.5 years; 34.2% women) from the Third China National Stroke Registry (n = 15,166). Patients were classified into five groups by quintiles of HDL-C. The outcomes included recurrent stroke and major adverse cardiovascular events (MACEs) within 1 year. The relationship between HDL-C levels and the risk of adverse outcomes was analyzed by Cox proportional hazards models. Patients in the lowest quintile of HDL-C had a higher risk of recurrent stroke (hazard ratio (HR) 1.59, 95% confidence interval (CI), 1.12–2.25) and MACEs (HR 1.53, 95% CI, 1.09–2.15) during 1-year follow-up compared with those in the highest quintile of HDL-C. There were linear associations between HDL-C levels and the risks of both recurrent stroke and MACEs. Low HDL-C levels were associated with higher risks of recurrent stroke and MACEs within 1 year in AIS patients with diabetes mellitus. Full article

(This article belongs to the Special Issue Lipids and Lipoproteins in Atherosclerosis: A Commemorative Issue in Honor of Dr. Vladimir V Tertov)

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24 pages, 10337 KiB

Open AccessArticle

Peripheral Infection after Traumatic Brain Injury Augments Excitability in the Perilesional Cortex and Dentate Gyrus

by Ying Wang, Pedro Andrade and Asla Pitkänen

Biomedicines 2021, 9(12), 1946; https://doi.org/10.3390/biomedicines9121946 - 19 Dec 2021

Cited by 6 | Viewed by 2487

Abstract

Peripheral infections occur in up to 28% of patients with traumatic brain injury (TBI), which is a major etiology for structural epilepsies. We hypothesized that infection occurring after TBI acts as a “second hit” and facilitates post-traumatic epileptogenesis. Adult male Sprague–Dawley rats were [...] Read more.

Peripheral infections occur in up to 28% of patients with traumatic brain injury (TBI), which is a major etiology for structural epilepsies. We hypothesized that infection occurring after TBI acts as a “second hit” and facilitates post-traumatic epileptogenesis. Adult male Sprague–Dawley rats were subjected to lateral fluid-percussion injury or sham-operation. At 8 weeks post-injury, rats were treated with lipopolysaccharide (LPS, 5 mg/kg) to mimic Gram-negative peripheral infection. T2-weighted magnetic resonance imaging was used to detect the cortical lesion type (small focal inflammatory [TBI_FI] vs. large cavity-forming [TBI_CF]). Spontaneous seizures were detected with video-electroencephalography, and seizure susceptibility was determined by the pentylenetetrazole (PTZ) test. Post-PTZ neuronal activation was assessed using c-Fos immunohistochemistry. LPS treatment increased the percentage of rats with PTZ-induced seizures among animals with TBI_FI lesions (p < 0.05). It also increased the cumulative duration of PTZ-induced seizures (p < 0.01), particularly in the TBI_FI group (p < 0.05). The number of c-Fos immunopositive cells was higher in the perilesional cortex of injured animals compared with sham-operated animals (p < 0.05), particularly in the TBI-LPS group (p < 0.05). LPS treatment increased the percentage of injured rats with bilateral c-Fos staining in the dentate gyrus (p < 0.05), particularly in the TBI_FI group (p < 0.05). Our findings demonstrate that peripheral infection after TBI increases PTZ-induced seizure susceptibility and neuronal activation in the perilesional cortex and bilaterally in the dentate gyrus, particularly in animals with prolonged perilesional T2 enhancement. Our data suggest that treatment of infections and reduction of post-injury neuro-inflammation are important components of the treatment regimen aiming at preventing epileptogenesis after TBI. Full article

(This article belongs to the Special Issue Pathogenesis and Targeted Therapy of Epilepsy)

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13 pages, 2293 KiB

Open AccessReview

Neutrophils and Platelets: Immune Soldiers Fighting Together in Stroke Pathophysiology

by Junaid Ansari and Felicity N. E. Gavins

Biomedicines 2021, 9(12), 1945; https://doi.org/10.3390/biomedicines9121945 - 19 Dec 2021

Cited by 4 | Viewed by 3730

Abstract

Neutrophils and platelets exhibit a diverse repertoire of functions in thromboinflammatory conditions such as stroke. Most cerebral ischemic events result from longstanding chronic inflammation secondary to underlying pathogenic conditions, e.g., hypertension, diabetes mellitus, obstructive sleep apnea, coronary artery disease, atrial fibrillation, morbid obesity, [...] Read more.

Neutrophils and platelets exhibit a diverse repertoire of functions in thromboinflammatory conditions such as stroke. Most cerebral ischemic events result from longstanding chronic inflammation secondary to underlying pathogenic conditions, e.g., hypertension, diabetes mellitus, obstructive sleep apnea, coronary artery disease, atrial fibrillation, morbid obesity, dyslipidemia, and sickle cell disease. Neutrophils can enable, as well as resolve, cerebrovascular inflammation via many effector functions including neutrophil extracellular traps, serine proteases and reactive oxygen species, and pro-resolving endogenous molecules such as Annexin A1. Like neutrophils, platelets also engage in pro- as well as anti-inflammatory roles in regulating cerebrovascular inflammation. These anucleated cells are at the core of stroke pathogenesis and can trigger an ischemic event via adherence to the hypoxic cerebral endothelial cells culminating in aggregation and clot formation. In this article, we review and highlight the evolving role of neutrophils and platelets in ischemic stroke and discuss ongoing preclinical and clinical strategies that may produce viable therapeutics for prevention and management of stroke. Full article

(This article belongs to the Special Issue Stroke—Pathophysiology and New Therapeutic Strategies)

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12 pages, 2262 KiB

Open AccessArticle

Altered Metabolic Profiles of the Plasma of Patients with Amyotrophic Lateral Sclerosis

by Kuo-Hsuan Chang, Chia-Ni Lin, Chiung-Mei Chen, Rong-Kuo Lyu, Chun-Che Chu, Ming-Feng Liao, Chin-Chang Huang, Hong-Shiu Chang, Long-Sun Ro and Hung-Chou Kuo

Biomedicines 2021, 9(12), 1944; https://doi.org/10.3390/biomedicines9121944 - 18 Dec 2021

Cited by 6 | Viewed by 2212

Abstract

Currently, there is no objective biomarker to indicate disease progression and monitor therapeutic effects for amyotrophic lateral sclerosis (ALS). This study aimed to identify plasma biomarkers for ALS using a targeted metabolomics approach. Plasma levels of 185 metabolites in 36 ALS patients and [...] Read more.

Currently, there is no objective biomarker to indicate disease progression and monitor therapeutic effects for amyotrophic lateral sclerosis (ALS). This study aimed to identify plasma biomarkers for ALS using a targeted metabolomics approach. Plasma levels of 185 metabolites in 36 ALS patients and 36 age- and sex-matched normal controls (NCs) were quantified using an assay combining liquid chromatography with tandem mass spectrometry and direct flow injection. Identified candidates were correlated with the scores of the revised ALS Functional Rating Scale (ALSFRS-r). Support vector machine (SVM) learning applied to selected metabolites was used to differentiate ALS and NC subjects. Forty-four metabolites differed significantly between ALS and NC subjects. Significant correlations with ALSFRS-r score were seen in 23 metabolites. Six of them showing potential to distinguish ALS from NC—asymmetric dimethylarginine (area under the curve (AUC): 0.829), creatinine (AUC: 0.803), methionine (AUC: 0.767), PC-acyl-alkyl C34:2 (AUC: 0.808), C34:2 (AUC: 0.763), and PC-acyl-acyl C42:2 (AUC: 0.751)—were selected for machine learning. The SVM algorithm using selected metabolites achieved good performance, with an AUC of 0.945. In conclusion, our findings indicate that a panel of metabolites were correlated with disease severity of ALS, which could be potential biomarkers for monitoring ALS progression and therapeutic effects. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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18 pages, 4873 KiB

Open AccessArticle

Azadirachtin Attenuates Lipopolysaccharide-Induced ROS Production, DNA Damage, and Apoptosis by Regulating JNK/Akt and AMPK/mTOR-Dependent Pathways in Rin-5F Pancreatic Beta Cells

by Annie John and Haider Raza

Biomedicines 2021, 9(12), 1943; https://doi.org/10.3390/biomedicines9121943 - 18 Dec 2021

Cited by 9 | Viewed by 2604

Abstract

Pancreatic inflammation and the resulting cellular responses have been implicated in pancreatitis, diabetes, and pancreatic cancer. Inflammatory responses due to the bacterial endotoxin, lipopolysaccharide (LPS), have been demonstrated to alter cellular metabolism, autophagy, apoptosis, and cell proliferation in different cell populations, and hence [...] Read more.

Pancreatic inflammation and the resulting cellular responses have been implicated in pancreatitis, diabetes, and pancreatic cancer. Inflammatory responses due to the bacterial endotoxin, lipopolysaccharide (LPS), have been demonstrated to alter cellular metabolism, autophagy, apoptosis, and cell proliferation in different cell populations, and hence increases the risks for organ toxicity including cancer. The exact molecular mechanism is however not clear. In the present study, we investigated the role and mechanism of an antioxidant, azadirachtin (AZD), a limonoid extracted from the neem tree (Azadirachta indica), against LPS-induced oxidative stress in the pancreatic β-cell line, Rin-5F. We demonstrated that cells treated with LPS (1 µg/mL for 24 h) showed increased reactive oxygen species (ROS) production, DNA damage, cell cycle arrest, and apoptosis. Our results also showed that LPS induced alterations in the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathways, suppressing autophagy and augmenting apoptosis. Treatment with Azadirachtin (25 µM for 24 h), on the other hand, rendered some degree of protection to the pancreatic cells from apoptosis by inducing the autophagy signals required for cell survival. These results may have significance in elucidating the mechanisms of pancreatic β-cell survival and death by balancing the molecular communication between autophagy and apoptosis under inflammatory and pathological conditions. Full article

(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)

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34 pages, 2628 KiB

Open AccessReview

Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path

by Elisabetta Iessi, Rosa Vona, Camilla Cittadini and Paola Matarrese

Biomedicines 2021, 9(12), 1942; https://doi.org/10.3390/biomedicines9121942 - 18 Dec 2021

Cited by 6 | Viewed by 3633

Abstract

In cancer cells, metabolic adaptations are often observed in terms of nutrient absorption, biosynthesis of macromolecules, and production of energy necessary to meet the needs of the tumor cell such as uncontrolled proliferation, dissemination, and acquisition of resistance to death processes induced by [...] Read more.

In cancer cells, metabolic adaptations are often observed in terms of nutrient absorption, biosynthesis of macromolecules, and production of energy necessary to meet the needs of the tumor cell such as uncontrolled proliferation, dissemination, and acquisition of resistance to death processes induced by both unfavorable environmental conditions and therapeutic drugs. Many oncogenes and tumor suppressor genes have a significant effect on cellular metabolism, as there is a close relationship between the pathways activated by these genes and the various metabolic options. The metabolic adaptations observed in cancer cells not only promote their proliferation and invasion, but also their survival by inducing intrinsic and acquired resistance to various anticancer agents and to various forms of cell death, such as apoptosis, necroptosis, autophagy, and ferroptosis. In this review we analyze the main metabolic differences between cancer and non-cancer cells and how these can affect the various cell death pathways, effectively determining the susceptibility of cancer cells to therapy-induced death. Targeting the metabolic peculiarities of cancer could represent in the near future an innovative therapeutic strategy for the treatment of those tumors whose metabolic characteristics are known. Full article

(This article belongs to the Special Issue Cancer Metabolism and Resistance to Cell Death: Novel Therapeutic Perspectives)

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10 pages, 267 KiB

Open AccessArticle

An Untargeted Lipidomic Analysis Reveals Depletion of Several Phospholipid Classes in Patients with Familial Hypercholesterolemia on Treatment with Evolocumab

by Andrea Anesi, Alessandro Di Minno, Ilenia Calcaterra, Viviana Cavalca, Maria Tripaldella, Benedetta Porro and Matteo Nicola Dario Di Minno

Biomedicines 2021, 9(12), 1941; https://doi.org/10.3390/biomedicines9121941 - 17 Dec 2021

Cited by 2 | Viewed by 2648

Abstract

Rationale: Familial hypercholesterolemia (FH) is caused by mutations in genes involved in low-density lipoprotein cholesterol (LDL-C) metabolism, including those for pro-protein convertase subtilisin/kexin type 9 (PCSK-9). The effect of PCSK-9 inhibition on the plasma lipidome has been poorly explored. Objective: Using an ultra-high-performance [...] Read more.

Rationale: Familial hypercholesterolemia (FH) is caused by mutations in genes involved in low-density lipoprotein cholesterol (LDL-C) metabolism, including those for pro-protein convertase subtilisin/kexin type 9 (PCSK-9). The effect of PCSK-9 inhibition on the plasma lipidome has been poorly explored. Objective: Using an ultra-high-performance liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry method, the plasma lipidome of FH subjects before and at different time intervals during treatment with the PCSK-9 inhibitor Evolocumab was explored. Methods and Results: In 25 FH subjects, heterozygotes or compound heterozygotes for different LDL receptor mutations, untargeted lipidomic revealed significant reductions in 26 lipid classes belonging to phosphatidylcholine (PC), sphingomyelin (SM), ceramide (CER), cholesteryl ester (CE), triacylglycerol (TG) and phosphatidylinositol (PI). Lipid changes were graded between baseline and 4- and 12-week treatment. At 12-week treatment, five polyunsaturated diacyl PC, accounting for 38.6 to 49.2% of total PC at baseline; two ether/vinyl ether forms; seven SM; five CER and glucosyl/galactosyl-ceramide (HEX-CER) were reduced, as was the unsaturation index of HEX-CER and lactosyl—CER (LAC-CER). Although non quantitative modifications were observed in phosphatidylethanolamine (PE) during treatment with Evolocumab, shorter and more saturated fatty acyl chains were documented. Conclusions: Depletion of several phospholipid classes occurs in plasma of FH patients during treatment with the PCSK-9 inhibitor Evolocumab. The mechanism underlying these changes likely involves the de novo synthesis of SM and CER through the activation of the key enzyme sphingomyelin synthase by oxidized LDL and argues for a multifaceted system leading to vascular improvement in users of PCSK-9 inhibitors. Full article

(This article belongs to the Section Molecular and Translational Medicine)

29 pages, 1825 KiB

Open AccessReview

Antimicrobial and Prebiotic Activity of Lactoferrin in the Female Reproductive Tract: A Comprehensive Review

by Jolanta Artym and Michał Zimecki

Biomedicines 2021, 9(12), 1940; https://doi.org/10.3390/biomedicines9121940 - 17 Dec 2021

Cited by 19 | Viewed by 6565

Abstract

Women’s intimate health depends on several factors, such as age, diet, coexisting metabolic disorders, hormonal equilibrium, sexual activity, drug intake, contraception, surgery, and personal hygiene. These factors may affect the homeostasis of the internal environment of the genital tract: the vulva, vagina and [...] Read more.

Women’s intimate health depends on several factors, such as age, diet, coexisting metabolic disorders, hormonal equilibrium, sexual activity, drug intake, contraception, surgery, and personal hygiene. These factors may affect the homeostasis of the internal environment of the genital tract: the vulva, vagina and cervix. This equilibrium is dependent on strict and complex mutual interactions between epithelial cells, immunocompetent cells and microorganisms residing in this environment. The microbiota of the genital tract in healthy women is dominated by several species of symbiotic bacteria of the Lactobacillus genus. The bacteria inhibit the growth of pathogenic microorganisms and inflammatory processes by virtue of direct and multidirectional antimicrobial action and, indirectly, by the modulation of immune system activity. For the homeostasis of the genital tract ecosystem, antimicrobial and anti-inflammatory peptides, as well as proteins secreted by mucus cells into the cervicovaginal fluid, have a fundamental significance. Of these, a multifunctional protein known as lactoferrin (LF) is one of the most important since it bridges innate and acquired immunity. Among its numerous properties, particular attention should be paid to prebiotic activity, i.e., exerting a beneficial action on symbiotic microbiota of the gastrointestinal and genital tract. Such activity of LF is associated with the inhibition of bacterial and fungal infections in the genital tract and their consequences, such as endometritis, pelvic inflammation, urinary tract infections, miscarriage, premature delivery, and infection of the fetus and newborns. The aim of this article is to review the results of laboratory as well as clinical trials, confirming the prebiotic action of LF on the microbiota of the lower genital tract. Full article

(This article belongs to the Section Microbiology in Human Health and Disease)

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13 pages, 2667 KiB

Open AccessArticle

Red Blood Cell-Derived Iron Alters Macrophage Function in COPD

by James M. Baker, Molly Hammond, Josiah Dungwa, Rajesh Shah, Angeles Montero-Fernandez, Andrew Higham, Simon Lea and Dave Singh

Biomedicines 2021, 9(12), 1939; https://doi.org/10.3390/biomedicines9121939 - 17 Dec 2021

Cited by 10 | Viewed by 2718

Abstract

Lung macrophage iron levels are increased in COPD patients. Lung macrophage iron levels are thought to be increased by cigarette smoke, but the role of red blood cells (RBCs) as a source of iron has not been investigated. We investigate RBCs as a [...] Read more.

Lung macrophage iron levels are increased in COPD patients. Lung macrophage iron levels are thought to be increased by cigarette smoke, but the role of red blood cells (RBCs) as a source of iron has not been investigated. We investigate RBCs as a potential source of alveolar iron in COPD, and determine the effect of RBC-derived iron on macrophage function. We used lung tissue sections to assess RBC coverage of the alveolar space, iron and ferritin levels in 11 non-smokers (NS), 15 smokers (S) and 32 COPD patients. Lung macrophages were isolated from lung resections (n = 68) and treated with hemin or ferric ammonium citrate (50, 100 or 200 μM). Lung macrophage phenotype marker gene expression was measured by qPCR. The phagocytosis of Non-typeable Haemophilus influenzae (NTHi) was measured by flow cytometry. Cytokine production in response to NTHi in iron-treated macrophages was measured by ELISA. Lung macrophage iron levels were significantly correlated with RBC coverage of the alveolar space (r = 0.31, p = 0.02). Furthermore, RBC coverage and lung macrophage iron were significantly increased in COPD patients and correlated with airflow obstruction. Hemin treatment downregulated CD36, CD163, HLA-DR, CD38, TLR4, CD14 and MARCO gene expression. Hemin-treated macrophages also impaired production of pro-inflammatory cytokines in response to NTHi exposure, and decreased phagocytosis of NTHi (200 μM: 35% decrease; p = 0.03). RBCs are a plausible source of pulmonary iron overload in COPD. RBC-derived iron dysregulates macrophage phenotype and function. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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20 pages, 3161 KiB

Open AccessReview

Discovery, Development, Inventions, and Patent Trends on Mobocertinib Succinate: The First-in-Class Oral Treatment for NSCLC with EGFR Exon 20 Insertions

by Mohd Imran, Shah Alam Khan, Mohammed Kanan Alshammari, Meshal Ayedh Alreshidi, Abeer Abdullah Alreshidi, Rawan Sulaiman Alghonaim, Fayez Aboud Alanazi, Sultan Alshehri, Mohammed M. Ghoneim and Faiyaz Shakeel

Biomedicines 2021, 9(12), 1938; https://doi.org/10.3390/biomedicines9121938 - 17 Dec 2021

Cited by 16 | Viewed by 4664

Abstract

The majority of lung cancers are non-small-cell lung cancer (NSCLC) having a low survival rate. Recent studies have indicated the involvement of epidermal growth factor receptor (EGFR) oncogene mutations like EGFR exon 20 insertions (EGFRex20ins) mutation among NSCLC patients. The response of patients [...] Read more.

The majority of lung cancers are non-small-cell lung cancer (NSCLC) having a low survival rate. Recent studies have indicated the involvement of epidermal growth factor receptor (EGFR) oncogene mutations like EGFR exon 20 insertions (EGFRex20ins) mutation among NSCLC patients. The response of patients of NSCLC with the EGFRex20ins mutation to the currently available EGFR inhibitor is negligible. Mobocertinib is the first oral treatment that has been approved by the USFDA, on 15 September 2021, to treat NSCLC with the EGFRex20ins mutation. This patent review discusses the inventions and patent literature of mobocertinib that will help the scientific community to develop additional and improved inventions related to mobocertinib. The structure of mobocertinib was first reported in 2015. Therefore, this article covered the patents/patent applications related to mobocertinib from 2015 to 25 October 2021. The patent search revealed 27 patents/patent applications related to compound, method of treatment, salt, polymorph, process, composition, and drug combinations of mobocertinib. The authors foresee an exciting prospect for developing a treatment for NSCLC with EGFRex20ins mutation, and other cancers employing a combination of mobocertinib with other approved anticancer agents. The inventions related to novel dosage forms, processes, and intermediates used in the synthesis of mobocertinib are also anticipated. Full article

(This article belongs to the Section Drug Discovery and Development)

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14 pages, 2760 KiB

Open AccessArticle

A Gene-Based Machine Learning Classifier Associated to the Colorectal Adenoma—Carcinoma Sequence

by Antonio Lacalamita, Emanuele Piccinno, Viviana Scalavino, Roberto Bellotti, Gianluigi Giannelli and Grazia Serino

Biomedicines 2021, 9(12), 1937; https://doi.org/10.3390/biomedicines9121937 - 17 Dec 2021

Cited by 5 | Viewed by 2967

Abstract

Colorectal cancer (CRC) carcinogenesis is generally the result of the sequential mutation and deletion of various genes; this is known as the normal mucosa–adenoma–carcinoma sequence. The aim of this study was to develop a predictor-classifier during the “adenoma-carcinoma” sequence using microarray gene expression [...] Read more.

Colorectal cancer (CRC) carcinogenesis is generally the result of the sequential mutation and deletion of various genes; this is known as the normal mucosa–adenoma–carcinoma sequence. The aim of this study was to develop a predictor-classifier during the “adenoma-carcinoma” sequence using microarray gene expression profiles of primary CRC, adenoma, and normal colon epithelial tissues. Four gene expression profiles from the Gene Expression Omnibus database, containing 465 samples (105 normal, 155 adenoma, and 205 CRC), were preprocessed to identify differentially expressed genes (DEGs) between adenoma tissue and primary CRC. The feature selection procedure, using the sequential Boruta algorithm and Stepwise Regression, determined 56 highly important genes. K-Means methods showed that, using the selected 56 DEGs, the three groups were clearly separate. The classification was performed with machine learning algorithms such as Linear Model (LM), Random Forest (RF), k-Nearest Neighbors (k-NN), and Artificial Neural Network (ANN). The best classification method in terms of accuracy (88.06 ± 0.70) and AUC (92.04 ± 0.47) was k-NN. To confirm the relevance of the predictive models, we applied the four models on a validation cohort: the k-NN model remained the best model in terms of performance, with 91.11% accuracy. Among the 56 DEGs, we identified 17 genes with an ascending or descending trend through the normal mucosa–adenoma–carcinoma sequence. Moreover, using the survival information of the TCGA database, we selected six DEGs related to patient prognosis (SCARA5, PKIB, CWH43, TEX11, METTL7A, and VEGFA). The six-gene-based classifier described in the current study could be used as a potential biomarker for the early diagnosis of CRC. Full article

(This article belongs to the Special Issue Omics Data Analysis and Integration in Complex Diseases)

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31 pages, 2668 KiB

Open AccessReview

Analytical Techniques for the Characterization of Bioactive Coatings for Orthopaedic Implants

by Katja Andrina Kravanja and Matjaž Finšgar

Biomedicines 2021, 9(12), 1936; https://doi.org/10.3390/biomedicines9121936 - 17 Dec 2021

Cited by 15 | Viewed by 3406

Abstract

The development of bioactive coatings for orthopedic implants has been of great interest in recent years in order to achieve both early- and long-term osseointegration. Numerous bioactive materials have been investigated for this purpose, along with loading coatings with therapeutic agents (active compounds) [...] Read more.

The development of bioactive coatings for orthopedic implants has been of great interest in recent years in order to achieve both early- and long-term osseointegration. Numerous bioactive materials have been investigated for this purpose, along with loading coatings with therapeutic agents (active compounds) that are released into the surrounding media in a controlled manner after surgery. This review initially focuses on the importance and usefulness of characterization techniques for bioactive coatings, allowing the detailed evaluation of coating properties and further improvements. Various advanced analytical techniques that have been used to characterize the structure, interactions, and morphology of the designed bioactive coatings are comprehensively described by means of time-of-flight secondary ion mass spectrometry (ToF-SIMS), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), scanning electron microscopy (SEM), transmission electron microscopy (TEM), 3D tomography, quartz crystal microbalance (QCM), coating adhesion, and contact angle (CA) measurements. Secondly, the design of controlled-release systems, the determination of drug release kinetics, and recent advances in drug release from bioactive coatings are addressed as the evaluation thereof is crucial for improving the synthesis parameters in designing optimal bioactive coatings. Full article

(This article belongs to the Special Issue New Techniques and Materials for Biomedical Applications)

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21 pages, 24532 KiB

Open AccessArticle

Epigenetic Dysregulation of Trophoblastic Gene Expression in Gestational Trophoblastic Disease

by Zoltan Szabolcsi, Amanda Demeter, Peter Kiraly, Andrea Balogh, Melissa L. Wilson, Jennifer R. King, Szabolcs Hetey, Zsolt Gelencser, Koji Matsuo, Beata Hargitai, Paulette Mhawech-Fauceglia, Petronella Hupuczi, Andras Szilagyi, Zoltan Papp, Lynda D. Roman, Victoria K. Cortessis and Nandor Gabor Than

Biomedicines 2021, 9(12), 1935; https://doi.org/10.3390/biomedicines9121935 - 17 Dec 2021

Cited by 7 | Viewed by 3007

Abstract

Gestational trophoblastic diseases (GTDs) have not been investigated for their epigenetic marks and consequent transcriptomic changes. Here, we analyzed genome-wide DNA methylation and transcriptome data to reveal the epigenetic basis of disease pathways that may lead to benign or malignant GTDs. RNA-Seq, mRNA [...] Read more.

Gestational trophoblastic diseases (GTDs) have not been investigated for their epigenetic marks and consequent transcriptomic changes. Here, we analyzed genome-wide DNA methylation and transcriptome data to reveal the epigenetic basis of disease pathways that may lead to benign or malignant GTDs. RNA-Seq, mRNA microarray, and Human Methylation 450 BeadChip data from complete moles and choriocarcinoma cells were bioinformatically analyzed. Paraffin-embedded tissues from complete moles and control placentas were used for tissue microarray construction, DNMT3B immunostaining and immunoscoring. We found that DNA methylation increases with disease severity in GTDs. Differentially expressed genes are mainly upregulated in moles while predominantly downregulated in choriocarcinoma. DNA methylation principally influences the gene expression of villous trophoblast differentiation-related or predominantly placenta-expressed genes in moles and choriocarcinoma cells. Affected genes in these subsets shared focal adhesion and actin cytoskeleton pathways in moles and choriocarcinoma. In moles, cell cycle and differentiation regulatory pathways, essential for trophoblast/placental development, were enriched. In choriocarcinoma cells, hormone biosynthetic, extracellular matrix-related, hypoxic gene regulatory, and differentiation-related signaling pathways were enriched. In moles, we found slight upregulation of DNMT3B protein, a developmentally important de novo DNA methylase, which is strongly overexpressed in choriocarcinoma cells that may partly be responsible for the large DNA methylation differences. Our findings provide new insights into the shared and disparate molecular pathways of disease in GTDs and may help in designing new diagnostic and therapeutic tools. Full article

(This article belongs to the Special Issue Gynecological Tumor and Placenta Development)

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24 pages, 1261 KiB

Open AccessReview

Competitive Endogenous RNA Network Involving miRNA and lncRNA in Non-Hodgkin Lymphoma: Current Advances and Clinical Perspectives

by Mara Fernandes, Herlander Marques, Ana Luísa Teixeira and Rui Medeiros

Biomedicines 2021, 9(12), 1934; https://doi.org/10.3390/biomedicines9121934 - 17 Dec 2021

Cited by 1 | Viewed by 2710

Abstract

Non-Hodgkin lymphoma (NHL) is a heterogeneous malignancy with variable patient outcomes. There is still a lack of understanding about the different players involved in lymphomagenesis, and the identification of new diagnostic and prognostic biomarkers is urgent. MicroRNAs and long non-coding RNAs emerged as [...] Read more.

Non-Hodgkin lymphoma (NHL) is a heterogeneous malignancy with variable patient outcomes. There is still a lack of understanding about the different players involved in lymphomagenesis, and the identification of new diagnostic and prognostic biomarkers is urgent. MicroRNAs and long non-coding RNAs emerged as master regulators of B-cell development, and their deregulation has been associated with the initiation and progression of lymphomagenesis. They can function by acting alone or, as recently proposed, by creating competing endogenous RNA (ceRNA) networks. Most studies have focused on individual miRNAs/lncRNAs function in lymphoma, and there is still limited data regarding their interactions in lymphoma progression. The study of miRNAs’ and lncRNAs’ deregulation in NHL, either alone or as ceRNAs networks, offers new insights into the molecular mechanisms underlying lymphoma pathogenesis and opens a window of opportunity to identify potential diagnostic and prognostic biomarkers. In this review, we summarized the current knowledge regarding the role of miRNAs and lncRNAs in B-cell lymphoma, including their interactions and regulatory networks. Finally, we summarized the studies investigating the potential of miRNAs and lncRNAs as clinical biomarkers, with a special focus on the circulating profiles, to be applied as a non-invasive, easy-to-obtain, and reproducible liquid biopsy for dynamic management of NHL patients. Full article

(This article belongs to the Special Issue MicroRNA in Solid Tumor and Hematological Diseases 2.0)

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14 pages, 453 KiB

Open AccessReview

Towards Personalized Antioxidant Use in Female Infertility: Need for More Molecular and Clinical Studies

by Jan Tesarik

Biomedicines 2021, 9(12), 1933; https://doi.org/10.3390/biomedicines9121933 - 17 Dec 2021

Cited by 8 | Viewed by 3572

Abstract

Treatment with antioxidants is increasingly used to slow down aging processes in different organs of the human body, including those implicated in female fertility. There is a plethora of different natural, synthetic or semi-synthetic medicines available on the market; most of them can [...] Read more.

Treatment with antioxidants is increasingly used to slow down aging processes in different organs of the human body, including those implicated in female fertility. There is a plethora of different natural, synthetic or semi-synthetic medicines available on the market; most of them can be purchased without medical prescription. Even though the use of antioxidants, even under conditions of auto-medication, was shown to improve many functions related to female infertility related to oxidative stress, the lack of medical control and supervision can lead to an overmedication resulting in an opposite extreme, reductive stress, which can be counterproductive with regard to reproductive function and produce various adverse health effects in general. This paper reviews the current knowledge relative to the effects of different antioxidants on female reproductive function. The persisting gaps in this knowledge are also highlighted, and the need for medical supervision and personalization of antioxidant prescription is underscored. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation: From Mechanisms to Therapeutic Approaches 3.0)

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15 pages, 2004 KiB

Open AccessReview

The Immune Regulatory Role of Protein Kinase CK2 and Its Implications for Treatment of Cancer

by Huixian Hong and Etty N. Benveniste

Biomedicines 2021, 9(12), 1932; https://doi.org/10.3390/biomedicines9121932 - 17 Dec 2021

Cited by 12 | Viewed by 6795

Abstract

Protein Kinase CK2, a constitutively active serine/threonine kinase, fulfills its functions via phosphorylating hundreds of proteins in nearly all cells. It regulates a variety of cellular signaling pathways and contributes to cell survival, proliferation and inflammation. CK2 has been implicated in the pathogenesis [...] Read more.

Protein Kinase CK2, a constitutively active serine/threonine kinase, fulfills its functions via phosphorylating hundreds of proteins in nearly all cells. It regulates a variety of cellular signaling pathways and contributes to cell survival, proliferation and inflammation. CK2 has been implicated in the pathogenesis of hematologic and solid cancers. Recent data have documented that CK2 has unique functions in both innate and adaptive immune cells. In this article, we review aspects of CK2 biology, functions of the major innate and adaptive immune cells, and how CK2 regulates the function of immune cells. Finally, we provide perspectives on how CK2 effects in immune cells, particularly T-cells, may impact the treatment of cancers via targeting CK2. Full article

(This article belongs to the Special Issue CK2 Regulation of Cell Death and Targeting in Cancer Treatment)

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16 pages, 1449 KiB

Open AccessEditor’s ChoiceArticle

Post-COVID-19 Patients Who Develop Lung Fibrotic-like Changes Have Lower Circulating Levels of IFN-β but Higher Levels of IL-1α and TGF-β

by Chiara Colarusso, Angelantonio Maglio, Michela Terlizzi, Carolina Vitale, Antonio Molino, Aldo Pinto, Alessandro Vatrella and Rosalinda Sorrentino

Biomedicines 2021, 9(12), 1931; https://doi.org/10.3390/biomedicines9121931 - 17 Dec 2021

Cited by 44 | Viewed by 3470

Abstract

Purpose: SARS-CoV-2 infection induces in some patients a condition called long-COVID-19, herein post-COVID-19 (PC), which persists for longer than the negative oral-pharyngeal swab. One of the complications of PC is pulmonary fibrosis. The purpose of this study was to identify blood biomarkers to [...] Read more.

Purpose: SARS-CoV-2 infection induces in some patients a condition called long-COVID-19, herein post-COVID-19 (PC), which persists for longer than the negative oral-pharyngeal swab. One of the complications of PC is pulmonary fibrosis. The purpose of this study was to identify blood biomarkers to predict PC patients undergoing pulmonary fibrosis. Patients and Methods: We analyzed blood samples of healthy, anti-SARS-CoV-2 vaccinated (VAX) subjects and PC patients who were stratified according to the severity of the disease and chest computed tomography (CT) scan data. Results: The inflammatory C reactive protein (CRP), complement complex C5b-9, LDH, but not IL-6, were higher in PC patients, independent of the severity of the disease and lung fibrotic areas. Interestingly, PC patients with ground-glass opacities (as revealed by chest CT scan) were characterized by higher plasma levels of IL-1α, CXCL-10, TGF-β, but not of IFN-β, compared to healthy and VAX subjects. In particular, 19 out of 23 (82.6%) severe PC and 8 out of 29 (27.6%) moderate PC patients presented signs of lung fibrosis, associated to lower levels of IFN-β, but higher IL-1α and TGF-β. Conclusions: We found that higher IL-1α and TGF-β and lower plasma levels of IFN-β could predict an increased relative risk (RR = 2.8) of lung fibrosis-like changes in PC patients. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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17 pages, 1954 KiB

Open AccessArticle

Reduced Interleukin-17-Expressing Cells in Cutaneous Melanoma

by Anna Tosi, Lavinia Nardinocchi, Maria Luigia Carbone, Lorena Capriotti, Elena Pagani, Simona Mastroeni, Cristina Fortes, Fernanda Scopelliti, Caterina Cattani, Francesca Passarelli, Antonio Rosato, Stefania D’Atri, Cristina Maria Failla and Andrea Cavani

Biomedicines 2021, 9(12), 1930; https://doi.org/10.3390/biomedicines9121930 - 16 Dec 2021

Cited by 3 | Viewed by 2306

Abstract

Characterization of tumor associated lymphocytes (TILs) in tumor lesions is important to obtain a clear definition of their prognostic value and address novel therapeutic opportunities. In this work, we examined the presence of T helper (Th)17 lymphocytes in cutaneous melanoma. We performed an [...] Read more.

Characterization of tumor associated lymphocytes (TILs) in tumor lesions is important to obtain a clear definition of their prognostic value and address novel therapeutic opportunities. In this work, we examined the presence of T helper (Th)17 lymphocytes in cutaneous melanoma. We performed an immunohistochemical analysis of a small cohort of primary melanomas, retrospectively selected. Thereafter, we isolated TILs from seven freshly surgically removed melanomas and from three basal cell carcinomas (BCC), as a comparison with a non-melanoma skin cancer known to retain a high amount of Th17 cells. In both studies, we found that, differently from BCC, melanoma samples showed a lower percentage of Th17 lymphocytes. Additionally, TIL clones could not be induced to differentiate towards the Th17 phenotype in vitro. The presence or absence of Th17 cells did not correlate with any patient characteristics. We only observed a lower amount of Th17 cells in samples from woman donors. We found a tendency towards an association between expression by melanoma cells of placenta growth factor, angiogenic factors able to induce Th17 differentiation, and presence of Th17 lymphocytes. Taken together, our data indicate the necessity of a deeper analysis of Th17 lymphocytes in cutaneous melanoma before correlating them with prognosis or proposing Th17-cell based therapeutic approaches. Full article

(This article belongs to the Special Issue Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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13 pages, 1371 KiB

Open AccessArticle

Increased Plasma Soluble PD-1 Concentration Correlates with Disease Progression in Patients with Cancer Treated with Anti-PD-1 Antibodies

by Ryotaro Ohkuma, Katsuaki Ieguchi, Makoto Watanabe, Daisuke Takayanagi, Tsubasa Goshima, Rie Onoue, Kazuyuki Hamada, Yutaro Kubota, Atsushi Horiike, Tomoyuki Ishiguro, Yuya Hirasawa, Hirotsugu Ariizumi, Junji Tsurutani, Kiyoshi Yoshimura, Mayumi Tsuji, Yuji Kiuchi, Shinichi Kobayashi, Takuya Tsunoda and Satoshi Wada

Biomedicines 2021, 9(12), 1929; https://doi.org/10.3390/biomedicines9121929 - 16 Dec 2021

Cited by 15 | Viewed by 3187

Abstract

Immune checkpoint inhibitors (ICIs) confer remarkable therapeutic benefits to patients with various cancers. However, many patients are non-responders or develop resistance following an initial response to ICIs. There are no reliable biomarkers to predict the therapeutic effect of ICIs. Therefore, this study investigated [...] Read more.

Immune checkpoint inhibitors (ICIs) confer remarkable therapeutic benefits to patients with various cancers. However, many patients are non-responders or develop resistance following an initial response to ICIs. There are no reliable biomarkers to predict the therapeutic effect of ICIs. Therefore, this study investigated the clinical implications of plasma levels of soluble anti-programmed death-1 (sPD-1) in patients with cancer treated with ICIs. In total, 22 patients (13 with non-small-cell lung carcinoma, 8 with gastric cancer, and 1 with bladder cancer) were evaluated for sPD-1 concentration using enzyme-linked immunosorbent assays for diagnostic and anti-PD-1 antibody analyses. sPD-1 levels were low before the administration of anti-PD-1 antibodies. After two and four cycles of anti-PD-1 antibody therapy, sPD-1 levels significantly increased compared with pretreatment levels (p = 0.0348 vs. 0.0232). We observed an increased rate of change in plasma sPD-1 concentrations after two and four cycles of anti-PD-1 antibody therapy that significantly correlated with tumor size progression (p = 0.024). sPD-1 may be involved in resistance to anti-PD-1 antibody therapy, suggesting that changes in sPD-1 levels can identify primary ICI non-responders early in treatment. Detailed analysis of each cancer type revealed the potential of sPD-1 as a predictive biomarker of response to ICI treatment in patients with cancer. Full article

(This article belongs to the Special Issue Feature Papers in Cancer Biology and Therapeutics)

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19 pages, 9793 KiB

Open AccessArticle

A Hyaluronic Acid Demilune Scaffold and Polypyrrole-Coated Fibers Carrying Embedded Human Neural Precursor Cells and Curcumin for Surface Capping of Spinal Cord Injuries

by Hoda Elkhenany, Pablo Bonilla, Esther Giraldo, Ana Alastrue Agudo, Michael J. Edel, María Jesus Vicent, Fernando Gisbert Roca, Cristina Martínez Ramos, Laura Rodríguez Doblado, Manuel Monleón Pradas and Victoria Moreno Manzano

Biomedicines 2021, 9(12), 1928; https://doi.org/10.3390/biomedicines9121928 - 16 Dec 2021

Cited by 15 | Viewed by 4208

Abstract

Tissue engineering, including cell transplantation and the application of biomaterials and bioactive molecules, represents a promising approach for regeneration following spinal cord injury (SCI). We designed a combinatorial tissue-engineered approach for the minimally invasive treatment of SCI—a hyaluronic acid (HA)-based scaffold containing polypyrrole-coated [...] Read more.

Tissue engineering, including cell transplantation and the application of biomaterials and bioactive molecules, represents a promising approach for regeneration following spinal cord injury (SCI). We designed a combinatorial tissue-engineered approach for the minimally invasive treatment of SCI—a hyaluronic acid (HA)-based scaffold containing polypyrrole-coated fibers (PPY) combined with the RAD16-I self-assembling peptide hydrogel (Corning^® PuraMatrix™ peptide hydrogel (PM)), human induced neural progenitor cells (iNPCs), and a nanoconjugated form of curcumin (CURC). In vitro cultures demonstrated that PM preserves iNPC viability and the addition of CURC reduces apoptosis and enhances the outgrowth of Nestin-positive neurites from iNPCs, compared to non-embedded iNPCs. The treatment of spinal cord organotypic cultures also demonstrated that CURC enhances cell migration and prompts a neuron-like morphology of embedded iNPCs implanted over the tissue slices. Following sub-acute SCI by traumatic contusion in rats, the implantation of PM-embedded iNPCs and CURC with PPY fibers supported a significant increase in neuro-preservation (as measured by greater βIII-tubulin staining of neuronal fibers) and decrease in the injured area (as measured by the lack of GFAP staining). This combination therapy also restricted platelet-derived growth factor expression, indicating a reduction in fibrotic pericyte invasion. Overall, these findings support PM-embedded iNPCs with CURC placed within an HA demilune scaffold containing PPY fibers as a minimally invasive combination-based alternative to cell transplantation alone. Full article

(This article belongs to the Special Issue Advancements in the Treatment of Spinal Cord Injury)

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24 pages, 5924 KiB

Open AccessArticle

Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells

by Ji Hee Ha, Muralidharan Jayaraman, Revathy Nadhan, Srishti Kashyap, Priyabrata Mukherjee, Ciro Isidoro, Yong Sang Song and Danny N. Dhanasekaran

Biomedicines 2021, 9(12), 1927; https://doi.org/10.3390/biomedicines9121927 - 16 Dec 2021

Cited by 7 | Viewed by 2754

Abstract

Focusing on defining metabolite-based inter-tumoral heterogeneity in ovarian cancer, we investigated the metabolic diversity of a panel of high-grade serous ovarian carcinoma (HGSOC) cell-lines using a metabolomics platform that interrogate 731 compounds. Metabolic fingerprinting followed by 2-dimensional and 3-dimensional principal component analysis established [...] Read more.

Focusing on defining metabolite-based inter-tumoral heterogeneity in ovarian cancer, we investigated the metabolic diversity of a panel of high-grade serous ovarian carcinoma (HGSOC) cell-lines using a metabolomics platform that interrogate 731 compounds. Metabolic fingerprinting followed by 2-dimensional and 3-dimensional principal component analysis established the heterogeneity of the HGSOC cells by clustering them into five distinct metabolic groups compared to the fallopian tube epithelial cell line control. An overall increase in the metabolites associated with aerobic glycolysis and phospholipid metabolism were observed in the majority of the cancer cells. A preponderant increase in the levels of metabolites involved in trans-sulphuration and glutathione synthesis was also observed. More significantly, subsets of HGSOC cells showed an increase in the levels of 5-Hydroxytryptamine, γ-aminobutyrate, or glutamate. Additionally, 5-hydroxytryptamin synthesis inhibitor as well as antagonists of γ-aminobutyrate and glutamate receptors prohibited the proliferation of HGSOC cells, pointing to their potential roles as oncometabolites and ligands for receptor-mediated autocrine signaling in cancer cells. Consistent with this role, 5-Hydroxytryptamine synthesis inhibitor as well as receptor antagonists of γ-aminobutyrate and Glutamate-receptors inhibited the proliferation of HGSOC cells. These antagonists also inhibited the three-dimensional spheroid growth of TYKNU cells, a representative HGSOC cell-line. These results identify 5-HT, GABA, and Glutamate as putative oncometabolites in ovarian cancer metabolic sub-type and point to them as therapeutic targets in a metabolomic fingerprinting-based therapeutic strategy. Full article

(This article belongs to the Special Issue Feature Papers in Cancer Biology and Therapeutics)

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20 pages, 6011 KiB

Open AccessArticle

miR-6315 Attenuates Methotrexate Treatment-Induced Decreased Osteogenesis and Increased Adipogenesis Potentially through Modulating TGF-β/Smad2 Signalling

by Ya-Li Zhang, Liang Liu, Yu-Wen Su and Cory J. Xian

Biomedicines 2021, 9(12), 1926; https://doi.org/10.3390/biomedicines9121926 - 16 Dec 2021

Cited by 3 | Viewed by 2181

Abstract

Methotrexate (MTX) treatment for childhood malignancies has shown decreased osteogenesis and increased adipogenesis in bone marrow stromal cells (BMSCs), leading to bone loss and bone marrow adiposity, for which the molecular mechanisms are not fully understood. Currently, microRNAs (miRNAs) are emerging as vital [...] Read more.

Methotrexate (MTX) treatment for childhood malignancies has shown decreased osteogenesis and increased adipogenesis in bone marrow stromal cells (BMSCs), leading to bone loss and bone marrow adiposity, for which the molecular mechanisms are not fully understood. Currently, microRNAs (miRNAs) are emerging as vital mediators involved in bone/bone marrow fat homeostasis and our previous studies have demonstrated that miR-6315 was upregulated in bones of MTX-treated rats, which might be associated with bone/fat imbalance by directly targeting Smad2. However, the underlying mechanisms by which miR-6315 regulates osteogenic and adipogenic differentiation require more investigations. Herein, we further explored and elucidated the regulatory roles of miR-6315 in osteogenesis and adipogenesis using in vitro cell models. We found that miR-6315 promotes osteogenic differentiation and it alleviates MTX-induced increased adipogenesis. Furthermore, our results suggest that the involvement of miR-6315 in osteogenesis/adipogenesis regulation might be partially through modulating the TGF-β/Smad2 signalling pathway. Our findings indicated that miR-6315 may be important in regulating osteogenesis and adipogenesis and might be a therapeutic target for preventing/attenuating MTX treatment-associated bone loss and marrow adiposity. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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18 pages, 1851 KiB

Open AccessArticle

C3d Elicits Neutrophil Degranulation and Decreases Endothelial Cell Migration, with Implications for Patients with Alpha-1 Antitrypsin Deficiency

by Laura T. Fee, Debananda Gogoi, Michael E. O’Brien, Emer McHugh, Michelle Casey, Ciara Gough, Mark Murphy, Ann M. Hopkins, Tomás P. Carroll, Noel G. McElvaney and Emer P. Reeves

Biomedicines 2021, 9(12), 1925; https://doi.org/10.3390/biomedicines9121925 - 16 Dec 2021

Cited by 5 | Viewed by 2660

Abstract

Alpha-1 antitrypsin (AAT) deficiency (AATD) is characterized by increased risk for emphysema, chronic obstructive pulmonary disease (COPD), vasculitis, and wound-healing impairment. Neutrophils play a central role in the pathogenesis of AATD. Dysregulated complement activation in AATD results in increased plasma levels of C3d. [...] Read more.

Alpha-1 antitrypsin (AAT) deficiency (AATD) is characterized by increased risk for emphysema, chronic obstructive pulmonary disease (COPD), vasculitis, and wound-healing impairment. Neutrophils play a central role in the pathogenesis of AATD. Dysregulated complement activation in AATD results in increased plasma levels of C3d. The current study investigated the impact of C3d on circulating neutrophils. Blood was collected from AATD (n = 88) or non-AATD COPD patients (n = 10) and healthy controls (HC) (n = 40). Neutrophils were challenged with C3d, and degranulation was assessed by Western blotting, ELISA, or fluorescence resonance energy transfer (FRET) substrate assays. Ex vivo, C3d levels were increased in plasma (p < 0.0001) and on neutrophil plasma membranes (p = 0.038) in AATD compared to HC. C3d binding to CR3 receptors triggered primary (p = 0.01), secondary (p = 0.004), and tertiary (p = 0.018) granule release and increased CXCL8 secretion (p = 0.02). Ex vivo plasma levels of bactericidal-permeability-increasing-protein (p = 0.02), myeloperoxidase (p < 0.0001), and lactoferrin (p < 0.0001) were significantly increased in AATD patients. In endothelial cell scratch wound assays, C3d significantly decreased cell migration (p < 0.0001), an effect potentiated by neutrophil degranulated proteins (p < 0.0001). In summary, AATD patients had increased C3d in plasma and on neutrophil membranes and, together with neutrophil-released granule enzymes, reduced endothelial cell migration and wound healing, with potential implications for AATD-related vasculitis. Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong)

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Biomedicines, Volume 9, Issue 12 (December 2021) – 210 articles

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