Biomolecules
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Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 107
Author(s):  
Giorgio Santoni ◽  
Consuelo Amantini ◽  
Federica Maggi ◽  
Oliviero Marinelli ◽  
Matteo Santoni ◽  
...  

Multiple myeloma (MM) is a haematological B cell malignancy characterised by clonal proliferation of plasma cells and their accumulation in the bone marrow. The aim of the present study is the evaluation of biological effects of Ibrutinib in human MM cell lines alone or in combination with different doses of Bortezomib. In addition, the relationship between the expression of TRPML2 channels and chemosensitivity of different MM cell lines to Ibrutinib administered alone or in combination with Bortezomib has been evaluated. By RT-PCR and Western blot analysis, we found that the Ibrutinib-resistant U266 cells showed lower TRPML2 expression, whereas higher TRPML2 mRNA and protein levels were evidenced in RPMI cells. Moreover, TRPML2 gene silencing in RPMI cells markedly reverted the effects induced by Ibrutinib alone or in combination with Bortezomib suggesting that the sensitivity to Ibrutinib is TRPML2 mediated. In conclusion, this study suggests that the expression of TRPML2 in MM cells increases the sensitivity to Ibrutinib treatment, suggesting for a potential stratification of Ibrutinib sensitivity of MM patients on the basis of the TRPML2 expression. Furthermore, studies in vitro and in vivo should still be necessary to completely address the molecular mechanisms and the potential role of TRPML2 channels in therapy and prognosis of MM patients.


Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 104
Author(s):  
Elisa Fernández-Millán ◽  
Carlos Guillén

Type 2 diabetes (T2D) results from impaired beta-cell function and insufficient beta-cell mass compensation in the setting of insulin resistance. Current therapeutic strategies focus their efforts on promoting the maintenance of functional beta-cell mass to ensure appropriate glycemic control. Thus, understanding how beta-cells communicate with metabolic and non-metabolic tissues provides a novel area for investigation and implicates the importance of inter-organ communication in the pathology of metabolic diseases such as T2D. In this review, we provide an overview of secreted factors from diverse organs and tissues that have been shown to impact beta-cell biology. Specifically, we discuss experimental and clinical evidence in support for a role of gut to beta-cell crosstalk, paying particular attention to bacteria-derived factors including short-chain fatty acids, lipopolysaccharide, and factors contained within extracellular vesicles that influence the function and/or the survival of beta cells under normal or diabetogenic conditions.


Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 106
Author(s):  
Pavel V. Ershov ◽  
Yuri V. Mezentsev ◽  
Alexis S. Ivanov

The identification of disease-related protein-protein interactions (PPIs) creates objective conditions for their pharmacological modulation. The contact area (interfaces) of the vast majority of PPIs has some features, such as geometrical and biochemical complementarities, “hot spots”, as well as an extremely low mutation rate that give us key knowledge to influence these PPIs. Exogenous regulation of PPIs is aimed at both inhibiting the assembly and/or destabilization of protein complexes. Often, the design of such modulators is associated with some specific problems in targeted delivery, cell penetration and proteolytic stability, as well as selective binding to cellular targets. Recent progress in interfacial peptide design has been achieved in solving all these difficulties and has provided a good efficiency in preclinical models (in vitro and in vivo). The most promising peptide-containing therapeutic formulations are under investigation in clinical trials. In this review, we update the current state-of-the-art in the field of interfacial peptides as potent modulators of a number of disease-related PPIs. Over the past years, the scientific interest has been focused on following clinically significant heterodimeric PPIs MDM2/p53, PD-1/PD-L1, HIF/HIF, NRF2/KEAP1, RbAp48/MTA1, HSP90/CDC37, BIRC5/CRM1, BIRC5/XIAP, YAP/TAZ–TEAD, TWEAK/FN14, Bcl-2/Bax, YY1/AKT, CD40/CD40L and MINT2/APP.


Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 102
Author(s):  
Xiaohong Liu ◽  
Hui Yin ◽  
Xia Song ◽  
Zhongxing Zhang ◽  
Jun Li

Lignin is a natural renewable biomass resource with great potential for applications, while its development into high value-added molecules or materials is rare. The development of biomass lignin as potential nonviral gene delivery carriers was initiated by our group through the “grafting-from” approach. Firstly, the lignin was modified into macroinitiator using 2-bromoisobutyryl bromide. Then cationic polymer chains of poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) were grown from the lignin backbone using atom transfer radical polymerization (ATRP) to yield lignin-PDMAEMA graft copolymers (LPs) with branched structure. To gain a deep understanding of the relationship between the nonviral gene transfection efficiency of such copolymers and their structural and compositional factors, herein eight lignin-based macroinitiators with different modification degrees (MDs, from 3.0 to 100%) were synthesized. Initiated by them, a series of 20 LPs were synthesized with varied structural factors such as grafting degree (GD, which is equal to MD, determining the cationic chain number per lignin macromolecule), cationic chain length (represented by number of repeating DMAEMA units per grafted arm or degree of polymerization, DP) as well as the content of N element (N%) which is due to the grafted PDMAEMA chains and proportional to molecular weight of the LPs. The in vitro gene transfection capability of these graft copolymers was evaluated by luciferase assay in HeLa, COS7 and MDA-MB-231cell lines. Generally, the copolymers LP-12 (N% = 7.28, MD = 36.7%, DP = 13.6) and LP-14 (N% = 6.05, MD = 44.4%, DP = 5.5) showed good gene transfection capabilities in the cell lines tested. Overall, the performance of LP-12 was the best among all the LPs in the three cell lines at the N/P ratios from 10 to 30, which was usually several times higher than PEI standard. However, in MDA-MB-231 at N/P ratio of 30, LP-14 showed the best gene transfection performance among all the LPs. Its gene transfection efficiency was ca. 11 times higher than PEI standard at this N/P ratio. This work demonstrated that, although the content of N element (N%) which is due to the grafted PDMAEMA chains primarily determines the gene transfection efficiency of the LPs, it is not the only factor in explaining the performance of such copolymers with the branched structure. Structural factors of these copolymers such as grafting degree and cationic chain length could have a profound effect on the copolymer performance on gene transfection efficiency. Through carefully adjusting these factors, the gene transfection efficiency of the LPs could be modulated and optimized for different cell lines, which could make this new type of biomass-based biomaterial an attractive choice for various gene delivery applications.


Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 103
Author(s):  
Dong Hyuk Jung ◽  
Byoungjin Park ◽  
Yong Jae Lee

Serum calcium and phosphate levels are controlled by a regulatory system, but their individual concentration tendencies and interactions may affect long-term vascular health. This study aimed to assess the effects of serum calcium and phosphate levels on incident ischemic heart disease (IHD) in a large-scale community-dwelling Korean cohort. We evaluated 15,259 non-diabetic individuals (median age, 45 years; range, 30–85) without previous IHD or ischemic stroke using the Korean National Health Insurance data. The study population was classified based on the calcium, phosphate, and calcium/phosphate ratios. Using Cox proportional hazards regression models, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for IHD over 50 months after baseline enrolment. The age- and sex-adjusted incidence of IHD gradually increased with serum calcium and phosphate quartiles and decreased with calcium/phosphate ratio quartiles, with an overall crude rate of 2.1% (315/15,259). After setting the lowest calcium, phosphate, and calcium/phosphate ratio quartiles as a reference group, the HRs (95% CIs) of the highest calcium, phosphate, and calcium/phosphate ratio quartiles for IHD were 1.77 (1.15–2.72), 1.73 (1.18–2.55), and 0.58 (0.39–0.87), respectively, after adjusting for potential confounding variables. Serum calcium and phosphate levels were positively associated with IHD incidence, while the serum calcium/phosphate ratio exhibited an inverse relationship. Serum calcium and phosphate homeostasis may merit serious consideration to understand the pathogenesis of coronary atherosclerosis as a risk modifier for IHD.


Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 101
Author(s):  
Zhangsheng Yang ◽  
Milomir O. Simovic ◽  
Peter R. Edsall ◽  
Bin Liu ◽  
Tomas S. Cancio ◽  
...  

Several preclinical and clinical reports have demonstrated that levels of circulating high mobility group box 1 protein (HMGB1) are increased early after trauma and are associated with systemic inflammation and clinical outcomes. However, the mechanisms of the interaction between HMGB1 and inflammatory mediators that lead to the development of remote organ damage after trauma remain obscure. HMGB1 and inflammatory mediators were analyzed in plasma from 54 combat casualties, collected on admission to a military hospital in Iraq, and at 8 and 24 h after admission. In total, 45 (83%) of these patients had traumatic brain injury (TBI). Nine healthy volunteers were enrolled as controls. HMGB1 plasma levels were significantly increased in the first 8 h after admission, and were found to be associated with systemic inflammatory responses, injury severity score, and presence of TBI. These data provided the rationale for designing experiments in rats subjected to blast injury and hemorrhage, to explore the effect of HMGB1 inhibition by CX-01 (2-O, 3-O desulfated heparin). Animals were cannulated, then recovered for 5–7 days before blast injury in a shock tube and volume-controlled hemorrhage. Blast injury and hemorrhage induced an early increase in HMGB1 plasma levels that coincided with severity of tissue damage and mortality. CX-01 inhibited systemic HMGB1 activity, decreased local and systemic inflammatory responses, significantly reduced tissue and organ damage, and tended to increase survival. These data suggest that CX-01 has potential as an adjuvant treatment for traumatic hemorrhage.


Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 105
Author(s):  
Stefano Ciardullo ◽  
Cinzia Ballabeni ◽  
Roberto Trevisan ◽  
Gianluca Perseghin

An association between liver stiffness, a surrogate measure of liver fibrosis, and chronic kidney disease (CKD) in patients with nonalcoholic fatty liver disease (NAFLD) has been proposed. However, most studies were small and had low statistical power. We systematically searched PubMed-MEDLINE and Scopus from inception to August 2021 for cross-sectional or cohort studies reporting the association between liver stiffness diagnosed by vibration controlled transient elastography (VCTE) and renal dysfunction. The primary outcome was CKD, defined as a composite of urinary albumin to creatinine ratio (UACR) ≥ 30 mg/g and estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Measures of association from individual studies were meta-analyzed using random effects models. Of the 526 titles initially scrutinized, 7 cross-sectional studies fulfilled the criteria and were included. For CKD, risk was higher in patients with liver fibrosis assessed by VCTE, compared with patients without (n = 5 studies: OR 2.49, 95% CI 1.89–3.29; test for overall effect z = 6.475, p < 0.001). When increased UACR was considered as an outcome, elevated liver stiffness was associated with a significantly increased risk as well (n = 3 studies: OR 1. 98 95% CI 1.29–3.05; test for overall effect z = 3.113, p = 0.002). Neither analysis showed significant heterogeneity (I2 = 0% and I2 = 46.5%, respectively for the two outcomes). This meta-analysis indicates that elevated liver stiffness is associated with increased odds of kidney outcomes among patients with NAFLD. Wider use of VCTE to screen for advanced fibrosis might help identify patients at risk of end-stage renal disease.


Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 100
Author(s):  
Anna Alwani ◽  
Aneta Andreasik ◽  
Rafał Szatanek ◽  
Maciej Siedlar ◽  
Monika Baj-Krzyworzeka

Monocytes represent a heterogeneous population of blood cells that provide a link between innate and adaptive immunity. The unique potential of monocytes as both precursors (e.g., of macrophages) and effector cells (as phagocytes or cytotoxic cells) makes them an interesting research and therapeutic target. At the site of a tumor, monocytes/macrophages constitute a major population of infiltrating leukocytes and, depending on the type of tumor, may play a dual role as either a bad or good indicator for cancer recovery. The functional activity of monocytes and macrophages derived from them is tightly regulated at the transcriptional and post-transcriptional level. This review summarizes the current understanding of the role of small regulatory miRNA in monocyte formation, maturation and function in health and cancer development. Additionally, signatures of miRNA-based monocyte subsets and the influence of exogenous miRNA generated in the tumor environment on the function of monocytes are discussed.


Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 96
Author(s):  
Anton Meinicke ◽  
Wolfgang Härtig ◽  
Karsten Winter ◽  
Joana Puchta ◽  
Bianca Mages ◽  
...  

The classic surfactant proteins (SPs) A, B, C, and D were discovered in the lungs, where they contribute to host defense and regulate the alveolar surface tension during breathing. Their additional importance for brain physiology was discovered decades later. SP-G, a novel amphiphilic SP, was then identified in the lungs and is mostly linked to inflammation. In the brain, it is also present and significantly elevated after hemorrhage in premature infants and in distinct conditions affecting the cerebrospinal fluid circulation of adults. However, current knowledge on SP-G-expression is limited to ependymal cells and some neurons in the subventricular and superficial cortex. Therefore, we primarily focused on the distribution of SP-G-immunoreactivity (ir) and its spatial relationships with components of the neurovascular unit in murine forebrains. Triple fluorescence labeling elucidated SP-G-co-expressing neurons in the habenula, infundibulum, and hypothalamus. Exploring whether SP-G might play a role in Alzheimer’s disease (AD), 3xTg-AD mice were investigated and displayed age-dependent hippocampal deposits of β-amyloid and hyperphosphorylated tau separately from clustered, SP-G-containing dots with additional Reelin-ir—which was used as established marker for disease progression in this specific context. Semi-quantification of those dots, together with immunoassay-based quantification of intra- and extracellular SP-G, revealed a significant elevation in old 3xTg mice when compared to age-matched wildtype animals. This suggests a role of SP-G for the pathophysiology of AD, but a confirmation with human samples is required.


Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 99
Author(s):  
Anella Saviano ◽  
Simona De Vita ◽  
Maria Giovanna Chini ◽  
Noemi Marigliano ◽  
Gianluigi Lauro ◽  
...  

Tanshinone IIA (TIIA) and cryptotanshinone (CRY) from Salvia miltiorrhiza Bunge were investigated for their inhibitory activity against the cyclooxygenase-2 (COX-2)/microsomal prostaglandin E synthase-1 (mPGES-1)/endothelial prostaglandin 3 (EP3) pathway using in silico, in vitro, in vivo, and ex vivo assays. From the analysis of the docking poses, both diterpenoids were able to interact significantly with COX-2, 5-lipoxygenase (5-LO), platelet-activating factor receptor (PAFR), and mPGES-1. This evidence was further corroborated by data obtained from a cell-free assay, where CRY displayed a significant inhibitory potency against mPGES-1 (IC50 = 1.9 ± 0.4 µM) and 5-LO (IC50 = 7.1 µM), while TIIA showed no relevant inhibition of these targets. This was consistent with their activity to increase mice bleeding time (CRY: 2.44 ± 0.13 min, p ≤ 0.001; TIIA: 2.07 ± 0.17 min p ≤ 0.01) and with the capability to modulate mouse clot retraction (CRY: 0.048 ± 0.011 g, p ≤ 0.01; TIIA: 0.068 ± 0.009 g, p ≤ 0.05). For the first time, our results show that TIIA and, in particular, CRY are able to interact significantly with the key proteins involved not only in the onset of inflammation but also in platelet activity (and hyper-reactivity). Future preclinical and clinical investigations, together with this evidence, could provide the scientific basis to consider these compounds as an alternative therapeutic approach for thrombotic- and thromboembolic-based diseases.


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