Biology, Volume 10, Issue 6 (June 2021) – 115 articles

Olivacine and its derivatives are characterized by multidirectional biological activity. Noteworthy is their antiproliferative effect related to various mechanisms, such as inhibition of growth factors, enzymes, kinases and others. The activity of these compounds was tested on cell lines of various tumors. In most publications, the most active olivacine derivatives exceeded the effects of doxorubicin (a commonly used anticancer drug), so in the future, they may become the main new anticancer drugs. In this publication, we present the groups of the most active olivacine derivatives obtained. In this work, the in vitro and in vivo activity of olivacine and its most active derivatives are presented. We describe olivacine derivatives that have been in clinical trials. We conducted a structure–activity relationship (SAR) analysis that may be used to obtain new olivacine derivatives with better properties than the available anticancer drugs. Full article

Inhibition of key metabolic enzymes linked to type-2-diabetes (T2D) by food-derived compounds is a preventive emerging strategy in the management of T2D. Here, the impact of Parmigiano-Reggiano (PR) cheese peptide fractions, at four different ripening times (12, 18, 24, and 30 months), on the enzymatic activity of α-glucosidase, α-amylase, and dipeptidyl peptidase-IV (DPP-IV) as well as on the formation of fluorescent advanced glycation end-products (fAGEs) was assessed. The PR peptide fractions were able to inhibit the selected enzymes and fAGEs formation. The 12-month-ripening PR sample was the most active against the three enzymes and fAGEs. Mass spectrometry analysis enabled the identification of 415 unique peptides, 54.9% of them common to the four PR samples. Forty-nine previously identified bioactive peptides were found, mostly characterized as angiotensin-converting enzyme-inhibitors. The application of an integrated approach that combined peptidomics, in silico analysis, and a structure–activity relationship led to an efficient selection of 6 peptides with potential DPP-IV and α-glucosidase inhibitory activities. Peptide APFPE was identified as a potent novel DPP-IV inhibitor (IC₅₀ = 49.5 ± 0.5 μmol/L). In addition, the well-known anti-hypertensive tripeptide, IPP, was the only one able to inhibit the three digestive enzymes, highlighting its possible new and pivotal role in diabetes management. Full article

Estimating the fitness effect conferred by a transgene introgressed into populations of wild relative species from a genetically engineered (GE) crop plays an important role in assessing the potential environmental risks caused by transgene flow. Such estimation has essentially focused on the survival and fecundity-related characteristics measured above the ground, but with little attention to the fate of GE seeds shattered in the soil seed banks after maturation. To explore the survival and longevity of GE seeds in soil, we examined the germination behaviors of crop–wild hybrid seeds (F₄–F₆) from the lineages of a GE herbicide-tolerant rice (Oryzasativa) line that contains an endogenous EPSPS transgene hybridized with two wild O. rufipogon populations after the seeds were buried in soil. The results showed significantly increased germination of the GE crop–wild hybrid seeds after soil burial, compared with that of the non-GE hybrid seeds. Additionally, the proportion of dormant seeds and the content of the growth hormone auxin (indole-3-acetic acid, IAA) in the GE crop–wild hybrid seeds significantly increased. Evidently, the EPSPS transgene enhances the survival and longevity of GE crop–wild rice seeds in the soil seed banks. The enhanced survival and longevity of the GE hybrid seeds is likely associated with the increases in seed dormancy and auxin (IAA) by overexpressing the rice endogenous EPSPS transgene. Thus, the fate of GE seeds in the soil seed banks should be earnestly considered when assessing the environmental risks caused by transgene flow. Full article

The advent of immunotherapy has changed the management and therapeutic methods for a variety of malignant tumors in the last decade. Unlike traditional cytotoxic chemotherapy, which works by interfering with cancer cell growth via various pathways and stages of the cell cycle, cancer immunotherapy uses the immune system to reduce malignant cells’ ability to escape the immune system and combat cell proliferation. The widespread use of immune checkpoint inhibitors (ICIs) over the past 10 years has presented valuable information on the profiles of toxic adverse effects. The attenuation of T-lymphocyte inhibitory mechanisms by ICIs results in immune system hyperactivation, which, as expected, is associated with various adverse events defined by inflammation. These adverse events, known as immune-related adverse events (ir-AEs), may affect any type of tissue throughout the human body, which includes the digestive tract, endocrine glands, liver and skin, with reports of cardiovascular, pulmonary and rheumatic ir-AEs as well. The adverse events that arise from ICI therapy are both novel and unique compared to those of the conventional treatment options. Thus, they require a multidisciplinary approach and continuous updates on the diagnostic approach and management. Full article

The current study addressed the heavy metals accumulation potentials of seven perennial aquatic macrophytes (Cyperus alopecuroides, Echinochloa stagnina, Eichhornia crassipes, Ludwigia stolonifera, Phragmites australis, Ranunculus sceleratus and Typha domingensis) and the pollution status of three drains (Amar, El-Westany and Omar-Beck) in the Nile Delta of Egypt. Nine sites at each drain were sampled for sediment and plant analyses. Concentrations of eight metals (Fe, Cu, Zn, Mn, Co, Cd, Ni, and Pb) were determined in the sediment and the aboveground and belowground tissues of the selected macrophytes. Bioaccumulation factor (BF) and translocation factor (TF) were computed for each species. The sediment heavy metals concentrations of the three drains occurred in the following order: El-Westany > Amar > Omar-Beck. The concentrations of sediment heavy metals in the three drains were ordered as follows: Fe (438.45–615.17 mg kg⁻¹) > Mn (341.22–481.09 mg kg⁻¹) > Zn (245.08–383.19 mg kg⁻¹) > Cu (205.41–289.56 mg kg⁻¹) > Pb (31.49–97.73 mg kg⁻¹) > Cd (13.97–55.99 mg kg⁻¹) > Ni (14.36–39.34 mg kg⁻¹) > Co (1.25–3.51 mg kg⁻¹). The sediment exceeded the worldwide permissible ranges of Cu, Zn and Pb, but ranged within safe limits for Mn, Cd, Ni and Co. P. australis accumulated the highest concentrations of Fe, Co, Cd and Ni, while E. crassipes contained the highest concentrations of Cu, Zn, Mn, and Pb. Except for C. alopecuroides and Cu metal, the studied species had BF values greater than one for the investigated heavy metals. Nevertheless, the TFs of all species (except Cd in L. stolonifera) were less than one. Hence, the studied species are appropriate for accumulation, biomonitoring, and phytostabilization of the investigated metals. Full article

Butyrate has a central function in the regulation of energy metabolism as a metabolite of bacterial fermentation. This study evaluated the effects of intravenous sodium butyrate (SB) administration on the transcriptome of muscle and adipose tissue of pigs. Twelve crossbred barrows (Duroc × Landrace × Large White) were fitted with a medical polyethylene cannula via the internal jugular vein and were daily infused with 10 mL SB (200 mmol/L) or the same volume of physiological saline. Muscle transcriptome showed 11 DEGs related to carbohydrate metabolism, 28 DEGs related to lipid metabolism, and 10 DEGs related to amino acid metabolism. Among these, carbohydrate catabolic process-related genes (PPP1R3B, PRPS2, ALDOC), fatty acid synthase (FASN), and lipolysis-related genes (PLIN1) were upregulated, while the carbohydrate biosynthetic process-related genes (PCK1) and most amino acid metabolism-related genes were downregulated. Adipose transcriptome showed 12 DEGs related to carbohydrate metabolism, 27 DEGs related to lipid metabolism, and 10 DEGs related to amino acid metabolism. Among these, carbohydrate metabolism-related genes (IGF1, LEP, SLC2A4) and lipolysis-related genes (LPL) were upregulated, while lipolysis-related genes (ANGPTL4) and most amino acid metabolism-related genes were downregulated. The results suggest that short-term intravenous SB infusion could modulate the muscle and adipose tissue metabolism at the transcriptional level by decreasing amino acid metabolism pathways. Additionally, intravenous SB increased the glucose catabolism in muscle tissue and decreased the glucose utilization in adipose tissue. Intravenous SB increased the fatty acid synthesis, decreased the lipolysis in muscle tissue, and increased the lipolysis in adipose tissue. This suggests that systemic butyrate may display discriminative metabolic regulation in different tissues of barrows. Full article

In the city of Maputo, Mozambique, food and water are often sold on the streets. Street water is packaged, distributed, and sold not paying attention to good hygienic practices, and its consumption is often associated with the occurrence of diarrheal diseases. Coincidentally, the increase of diarrheal diseases promotes the inappropriate use of antibiotics that might cause the emergence of antibiotic-resistant bacterial strains. In this context, the present study aimed to assess the microbiological quality of water sold on the streets of Maputo, as well as the antibiotic resistance profile of selected Enterobacteriaceae isolates. The 118 water samples analyzed were from street home-bottled water (n = 81), municipal water distribution systems (tap water) (n = 25), and selected supply wells in several neighborhoods (n = 12). The samples were analyzed for total mesophilic microorganisms, fecal enterococci, fecal coliforms, Escherichia coli, and Vibrio spp. The results showed a high level of fecal contamination in all types of water samples. In home-bottled water, fecal coliforms were found in 88% of the samples, and E. coli in 66% of the samples. In tap water, fecal coliforms were found in 64%, and E. coli in 28% of the samples. In water from supply wells, fecal coliforms and E. coli were found in 83% of the samples. From 33 presumptive Vibrio spp. colonies, only three were identified as V. fluvialis. The remaining isolates belonged to Aeromonas spp. (n = 14) and Klebsiella spp. (n = 16). Of 44 selected Enterobacteriaceae isolates from water samples (28 isolates of E. coli and 16 isolates of Klebsiella spp.), 45.5% were not susceptible to the beta-lactams ampicillin and imipenem, 43.2% to amoxicillin, and 31.8% to amoxicillin/clavulanic acid. Regarding non-beta-lactam antibiotics, there was a high percentage of isolates with tolerance to tetracycline (52.3%) and azithromycin (31.8%). In conclusion, water in Maputo represents a risk for human health due to its high fecal contamination. This situation is made more serious by the fact that a relatively high percentage of isolates with multidrug resistance (40%) were found among Enterobacteriaceae. The dissemination of these results can raise awareness of the urgent need to reduce water contamination in Maputo and other cities in Mozambique. Full article

The prevention of muscle atrophy carries with it clinical significance for the control of increased morbidity and mortality following physical inactivity. While major transcriptional events associated with muscle atrophy-recovery processes are the subject of active research on the gene level, the contribution of non-coding regulatory elements and alternative promoter usage is a major source for both the production of alternative protein products and new insights into the activity of transcription factors. We used the cap-analysis of gene expression (CAGE) to create a genome-wide atlas of promoter-level transcription in fast (m. EDL) and slow (m. soleus) muscles in rats that were subjected to hindlimb unloading and subsequent recovery. We found that the genetic regulation of the atrophy-recovery cycle in two types of muscle is mediated by different pathways, including a unique set of non-coding transcribed regulatory elements. We showed that the activation of “shadow” enhancers is tightly linked to specific stages of atrophy and recovery dynamics, with the largest number of specific regulatory elements being transcriptionally active in the muscles on the first day of recovery after a week of disuse. The developed comprehensive database of transcription of regulatory elements will further stimulate research on the gene regulation of muscle homeostasis in mammals. Full article

The recognition and binding of host bacteria by bacteriophages is most often enabled by a highly specific receptor–ligand type of interaction, with the receptor-binding proteins (RBPs) of phages being the primary determinants of host specificity. Specifically modifying the RBPs could alter or extend the host range of phages otherwise exhibiting desired phenotypic properties. This study employed two different strategies to reprogram T7 phages ordinarily infecting commensal K12 Escherichia coli strains to infect pathogen-associated K1-capsule-expressing strains. The strategies were based on either plasmid-based homologous recombination or bacteriophage recombineering using electroporated DNA (BRED). Our work pursued the construction of two genetic designs: one replacing the gp17 gene of T7, the other replacing gp11, gp12, and gp17 of T7 with their K1F counterparts. Both strategies displayed successful integration of the K1F sequences into the T7 genome, detected by PCR screening. Multiple methods were utilised to select or enrich for chimeric phages incorporating the K1F gp17 alone, including trxA, host-specificity, and CRISPR-Cas-based selection. Irrespective of the selection method, the above strategy yielded poorly reproducible phage propagation on the new host, indicating that the chimeric phage was less fit than the wild type and could not promote continual autonomous reproduction. Chimeric phages obtained from BRED incorporating gp11-12 and gp17, however, all displayed infection in a 2-stage pattern, indicating the presence of both K1F and T7 phenotypes. This study shows that BRED can be used as a tool to quickly access the potential of new RBP constructs without the need to engineer sustainably replicating phages. Additionally, we show that solely repurposing the primary RBP is, in some cases, insufficient to produce a viable chimeric phage. Full article

The variation of diazotrophs has been elusive in multiple SCS and WPO regions due to insufficient data. Therefore, the dynamics of diazotrophic composition and distribution were investigated in this study, based on high-throughput sequencing and quantitative PCR of the nifH gene. We found that Proteobacteria dominated the diazotrophic community in the river-impacted SCS and cyanobacteria and Proteobacteria were more abundant in the ocean-dominated SCS and WPO. The qPCR analysis showed that cyanobacterial Trichodesmium was abundant in the Pearl River plume and in the SCS basin influenced by the Kuroshio intrusion, and it also thrived in the subequatorial region of the WPO. Unicellular cyanobacteria UCYN-A were mainly detected in the river-impacted area, UCYN-B was abundant in the WPO, UCYN-C had a relatively high abundance in the ocean-dominated area, and a preponderance of γ-Proteobacteria γ-24774A11 was observed in the ocean-dominated SCS and pelagic WPO. Diazotrophic communities had significant distance–decay relationships, reflecting clear biogeographic patterns in the study area. The variations of diazotrophic community structure were well explained by dissolved inorganic nitrogen, dissolved inorganic phosphate by an eigenvector spatial variable PCNM1. These results provide further information to help determine the ecological mechanism of elusive diazotrophic communities in different ocean ecosystems. Full article

Multiple sclerosis (MS) is a demyelinating disease characterized by chronic inflammation of the central nervous system, in which many factors can act together to influence disease susceptibility and progression. To date, the exact cause of MS is still unclear, but it is believed to result from an abnormal response of the immune system to one or more myelin antigens that develops in genetically susceptible individuals after their exposure to a, as yet undefined, causal agent. In our study, we assessed the effect of microRNAs on the expression level of neuroprotective proteins, including neurotrophins (BDNF and NT4/5), heat shock proteins (HSP70 and HSP27), and sirtuin (SIRT1) in peripheral blood mononuclear cells in the development of multiple sclerosis. The analysis of dysregulation of miRNA levels and the resulting changes in target mRNA/protein expression levels could contribute to a better understanding of the etiology of multiple sclerosis, as well as new alternative methods of diagnosis and treatment of this disease. The aim of this study was to find a link between neurotrophins (BDNF and NT4), SIRT1, heat shock proteins (HSP27 and HSP27), and miRNAs that are involved in the development of multiple sclerosis. The analysis of the selected miRNAs showed a negative correlation of SIRT1 with miR-132 and miR-34a and of BDNF with 132-3p in PBMCs, which suggests that the miRNAs we selected may regulate the expression level of the studied genes. Full article

Background: Allogeneic stem cell transplantation (aSCT) is a common treatment for a variety of hematological diseases. Advances in transplantation practices have led to an increasing number of long-term aSCT survivors, but data about health status and late complications are sparse. This analysis focusses on kidney function and urological complications in this population. Methods: This study is a prospective unicentric non-interventional trial. Before starting the study, we obtained the approval of the local ethics review board. Furthermore, the study was registered at WHO Clinical Trial Registry. The study protocol is available via UTN. Results: We were able to include 33 patients with a mean age of 60.5 years (SD 11.1). The median survival time following allogeneic stem cell transplantation was 9.0 years (IQR 8.5–13.0). Five patients (15.2%) had BKPyV viruria with mean 218.3 (SD 674.2) copies/mL. BKPyV viruria was significantly linked to pre-existing chronic kidney failure (p = 0.019), creatine > 100 µmol/L (p < 0.001), and cystatin c > 1.11 mg/L (p = 0.021), respectively. We were not able to identify a single risk factor for BKPyV viruria in univariate or multivariate Cox regression. Conclusions: BKPyV-associated nephropathy might be one reason for impaired kidney function in long-term survivors of aSCT. Full article

Autophagy, which literally means “eat yourself”, is more than just a lysosomal degradation pathway. It is a well-known regulator of cellular metabolism and a mechanism implicated in tumor initiation/progression and therapeutic resistance in many cancers. However, whether autophagy acts as a tumor suppressor or promoter is still a matter of debate. In acute myeloid leukemia (AML), it is now proven that autophagy supports cell proliferation in vitro and leukemic progression in vivo. Mitophagy, the specific degradation of mitochondria through autophagy, was recently shown to be required for leukemic stem cell functions and survival, highlighting the prominent role of this selective autophagy in leukemia initiation and progression. Moreover, autophagy in AML sustains fatty acid oxidation through lipophagy to support mitochondrial oxidative phosphorylation (OxPHOS), a hallmark of chemotherapy-resistant cells. Nevertheless, in the context of therapy, in AML, as well as in other cancers, autophagy could be either cytoprotective or cytotoxic, depending on the drugs used. This review summarizes the recent findings that mechanistically show how autophagy favors leukemic transformation of normal hematopoietic stem cells, as well as AML progression and also recapitulates its ambivalent role in resistance to chemotherapies and targeted therapies. Full article

Local ecological knowledge (LEK), including but not limited to the use of wild food plants, plays a large role in sustainable natural resource management schemes, primarily due to the synergy between plants and people. There are calls for the study of LEK in culturally diverse areas due to a loss of knowledge, the active practice of utilizing wild plants in various parts of the world, and a decline in biodiversity. An ethnobotanical study in a border region of Latvia, characterised by diverse natural landscapes and people with deep spiritual attachments to nature, provided an opportunity for such insight, as well as the context to analyse wild food plant usages among different sociocultural groups, allowing us to explore the differences among these groups. Semi-structured interviews were carried out as part of a wider ethnobotanical field study to obtain information about wild food plants and their uses. The list of wild food plant uses, derived from 72 interviews, revealed a high level of homogenisation (in regards to knowledge) among the study groups, and that many local uses of wild food plants are still actively practiced. People did not gather plants as a recreational activity but rather as a source of diet diversification. The results provide evidence of the importance of safeguarding ecological and cultural diversity due to high local community dependency on natural resources. Full article

Tristetraprolin (TTP) is an mRNA binding protein suggested to have a substantial role in regulating the mRNA expression of numerous inflammatory factors, but data on TTP and its association with metabolic syndrome (MetS), a chronic low-grade inflammatory disorder, are scarce. We hypothesize that TTP may modulate MetS and its components. A total of 200 Saudi adults (aged 38.6 ± 8.3 years) were included in this cross-sectional study. Anthropometrics data were collected and fasting blood glucose taken for the assessment of glycemic, lipids and inflammatory markers using commercially available assays. The National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) criteria were used to define MetS. Results showed significantly higher levels of TTP in the MetS group than in controls [288.1 pg/mL vs. 150.9 pg/mL, p < 0.001]. Circulating TTP was significantly associated with tumor necrosis factor alpha [TNF-α, R = 0.30, p < 0.05], interleukin 1β [IL-1β, R = 0.41, p < 0.01] and C-reactive protein [CRP, R = 0.36, p < 0.01], adiponectin [R = 0.36, p < 0.05], insulin [R = 0.37, p < 0.05], and insulin resistance [HOMA-IR, R = 0.40, p < 0.05]. Receiver operating characteristics (ROC) suggest a potential use of TTP as diagnostic biomarker for MetS [AUC = 0.819, p < 0.001]. The findings suggest that TTP is associated with inflammation and glycemia, which may influence MetS. TTP is a promising diagnostic biomarker for MetS which can be confirmed in larger cohorts. Full article

Aim: To compare the failure rate, marginal bone loss, and pink esthetic for the socket-shield technique and the conventional technique for immediate dental implant placement in the esthetic zone. Material and methods: A systematic literature review and meta-analysis, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, of clinical studies that evaluated the failure rate, marginal bone loss, and pink esthetic with the socket-shield technique for immediate dental implant placement in the esthetic zone was performed. A total of 4 databases were consulted in the literature search: PubMed-MEDLINE, Scopus, Embase, and Web of Science. After eliminating duplicated articles and applying the inclusion criteria, 16 articles were selected for the qualitative and quantitative analysis. Results: Four randomized controlled trials, five prospective clinical studies, four retrospective studies, and three case series were included in the meta-analysis. The dental implant failure rate for the socket-shield technique for immediate dental implant placement was 1.37% (95% CI, 0.21–2.54%); however, no statistically significant differences between the conventional and socket-shield technique were found. The estimated mean difference in the marginal bone loss for the socket-shield technique was −0.5 mm (95% CI, −0.82 to −0.18) and statistically significant (p < 0.01), with a high heterogeneity (I² = 99%). The mean pink esthetic score was 12.27 (Q test = 4.47; p-value = 0.61; I² = 0%). The difference in pink esthetic between the conventional (n = 55) and socket-shield techniques (n = 55) for immediate dental implant placement was 1.15 (95% CI, 0.73–1.58; Q test = 8.88; p value = 0.11; I² = 44%). The follow-up time was found to be significant (beta coefficient = 0.023; R² = 85.6%; QM = 3.82; p = 0.049) for the PES for the socket-shield technique. Conclusions: Within the limitations of this systematic review with meta-analysis, the dental implant failure rate did not differ between the socket-shield technique and conventional technique for immediate implant placement in the esthetic zone. However, a lower marginal bone loss and higher pink esthetic scores were found for the socket-shield technique compared to the conventional technique. Full article

Artificial sweeteners are widely used food ingredients in beverages and drinks to lower calorie intake which in turn helps prevent lifestyle diseases such as obesity. However, as their popularity has increased, the release of artificial sweetener to the aquatic environment has also increased at a tremendous rate. Thus, our study aims to systematically explore the potential cardiovascular physiology alterations caused by eight commercial artificial sweeteners, including acesulfame-K, alitame, aspartame, sodium cyclamate, dulcin, neotame, saccharine and sucralose, at the highest environmentally relevant concentration on cardiovascular performance using zebrafish (Danio rerio) as a model system. Embryonic zebrafish were exposed to the eight artificial sweeteners at 100 ppb and their cardiovascular performance (heart rate, ejection fraction, fractional shortening, stroke volume, cardiac output, heartbeat variability, and blood flow velocity) was measured and compared. Overall, our finding supports the safety of artificial sweetener exposure. However, several finding like a significant increase in the heart rate and heart rate variability after incubation in several artificial sweeteners are noteworthy. Biomarker testing also revealed that saccharine significantly increase the dopamine level in zebrafish larvae, which is might be the reason for the cardiac physiology changes observed after saccharine exposure. Full article

Objective: Chronic renal antibody-mediated rejection (ABMR) is a common cause of allograft failure, but an effective therapy is not available. Extracorporeal photopheresis (ECP) has been proven successful in chronic lung and heart rejection, and graft versus host disease. The aim of this study was to evaluate the effectiveness of ECP in chronic ABMR patients. Patients and Methods: We investigated ECP treatment in 14 patients with biopsy-proven chronic ABMR and stage 2–3 chronic renal failure. The primary aim was to e valuate the eGFR lowering after 1 year of ECP therapy. The ECP responders (R) showed eGFR reduction greater than 20% vs the basal levels. We also evaluated the effectiveness of ECP on proteinuria, anti-HLA antibodies (HLAab), interleukin 6 (IL-6) serum levels, and CD3, CD4, CD8, CD19, NK, Treg and T helper 17 (Th17) circulating cells. Results: Three patients dropped out of the study. The R patients were eight (72.7%) out of the 11 remaining patients. Because ECP was not associated with any adverse reaction, the R patients continued such treatment for up to 3 years, showing a persisting eGFR stabilization. Twenty four hour proteinuria did not increase in the R patients over the follow-up when compared to the non-responder patients (NR). In the R patients, the HLAab levels were reduced and completely cleared in six out of eight patients when compared with the NR patients. The NR HLAab levels also increased after the discontinuation of the ECP. The ECP in the R patients showed a decrease in CD3, CD4, CD8, CD19, and NK circulating cells. The ECP treatment in the R patients also induced Tregs and Th17 cell increases, and a decrease of the IL-6 serum levels. Conclusions: ECP abates the HLAab titer and renal failure progression in patients with chronic renal ABMR, modulating the immune cellular and humoral responses. Full article

The main characteristic of the pathophysiology of β-thalassemia is reduced β-globin chain production. The inevitable imbalance in the α/β-globin ratio and α-globin accumulation lead to oxidative stress in the erythroid lineage, apoptosis, and ineffective erythropoiesis. The result is compensatory hematopoietic expansion and impaired hepcidin production that causes increased intestinal iron absorption and progressive iron overload. Chronic hemolysis and red blood cell transfusions also contribute to iron tissue deposition. A better understanding of the underlying mechanisms led to the detection of new curative or “disease-modifying” therapeutic options. Substantial evolvement has been made in allogeneic hematopoietic stem cell transplantation with current clinical trials investigating new condition regimens as well as different donors and stem cell source options. Gene therapy has also moved forward, and phase 2 clinical trials with the use of β-globin insertion techniques have recently been successfully completed leading to approval for use in transfusion-dependent patients. Genetic and epigenetic manipulation of the γ- or β-globin gene have entered the clinical trial setting. Agents such as TGF-β ligand traps and pyruvate kinase activators, which reduce the ineffective erythropoiesis, have been tested in clinical trials with favorable results. One TGF-β ligand trap, luspatercept, has been approved for use in adults with transfusion-dependent β-thalassemia. The induction of HbF with the phosphodiesterase 9 inhibitor IMR-687, which increase cyclic guanosine monophosphate, is currently being tested. Another therapeutic approach is to target the dysregulation of iron homeostasis, using, for example, hepcidin agonists (inhibitors of TMPRSS6 and minihepcidins) or ferroportin inhibitors (VIT-2763). This review provides an update on the novel therapeutic options that are presently in development at the clinical level in β-thalassemia. Full article

The ongoing coronavirus disease 2019 (COVID-19) crisis has led to a new socioeconomic reality with the acquisition of novel habits. Measures imposed by governments and health authorities such as confinement and lockdown have had important consequences, including mental health problems, economic crisis, and social isolation. Combined with newly acquired habits such as hand washing, sanitization, and face masks, these have all directly and indirectly led to reduced immunity. Such effects on the immune system not only impact the epidemiological profile with respect to COVID-19 and other infectious diseases but also limit the efficacy of the ongoing anti-COVID-19 vaccination campaign. Therefore, there is a need to review these approaches and optimize measures towards better population immunity, which is much needed during such an epidemic. Full article

The heavy metal cadmium (Cd), as one of the major environmentally toxic pollutants, has serious impacts on the growth, development, and physiological functions of plants and animals, leading to deterioration of environmental quality and threats to human health. Research on how plants absorb and transport Cd, as well as its enrichment and detoxification mechanisms, is of great significance to the development of phytoremediation technologies for ecological and environmental management. This article summarises the research progress on the enrichment of heavy metal cadmium in plants in recent years, including the uptake, transport, and accumulation of Cd in plants. The role of plant roots, compartmentalisation, chelation, antioxidation, stress, and osmotic adjustment in the process of plant Cd enrichment are discussed. Finally, problems are proposed to provide a more comprehensive theoretical basis for the further application of phytoremediation technology in the field of heavy metal pollution. Full article

Male mice lacking HuR in skeletal muscle (HuR^m−/−) have been shown to have decreased gastrocnemius lipid oxidation and increased adiposity and insulin resistance. The same consequences have not been documented in female HuR^m−/− mice. Here we examine this sexually dimorphic phenotype. HuR^m−/− mice have an increased fat mass to lean mass ratio (FM/LM) relative to controls where food intake is similar. Increased body weight for male mice correlates with increased blood glucose during glucose tolerance tests (GTT), suggesting increased fat mass in male HuR^m−/− mice as a driver of decreased glucose clearance. However, HuR^m−/− female mice show decreased blood glucose levels during GTT relative to controls. HuR^m−/− mice display decreased palmitate oxidation in skeletal muscle relative to controls. This difference is more robust for male HuR^m−/− mice and more exaggerated for both sexes at high dietary fat. A high-fat diet stimulates expression of Pgc1α in HuR^m−/− male skeletal muscle, but not in females. However, the lipid oxidation Pparα pathway remains decreased in HuR^m−/− male mice relative to controls regardless of diet. This pathway is only decreased in female HuR^m−/− mice fed high fat diet. A decreased capacity for lipid oxidation in skeletal muscle in the absence of HuR may thus be linked to decreased glucose clearance in male but not female mice. Full article

Alzheimer’s disease (AD) is a detrimental brain disorder characterized by a gradual cognitive decline and neuronal deterioration. To date, the treatments available are effective only in the early stage of the disease. The AD etiology has not been completely revealed, and investigating new pathological mechanisms is essential for developing effective and safe drugs. The recreational and pharmacological properties of marijuana are known for centuries, but only recently the scientific community started to investigate the potential use of cannabinoids in AD therapy—sometimes with contradictory outcomes. Since the endocannabinoid system (ECS) is highly expressed in the hippocampus and cortex, cannabis use/abuse has often been associated with memory and learning dysfunction in vulnerable individuals. However, the latest findings in AD rodent models have shown promising effects of cannabinoids in reducing amyloid plaque deposition and stimulating hippocampal neurogenesis. Beneficial effects on several dementia-related symptoms have also been reported in clinical trials after cannabinoid treatments. Accordingly, future studies should address identifying the correct therapeutic dosage and timing of treatment from the perspective of using cannabinoids in AD therapy. The present paper aims to summarize the potential and limitations of cannabinoids as therapeutics for AD, focusing on recent pre-clinical and clinical evidence. Full article

Vasodilators are an important class in the management of hypertension and related cardiovascular disorders. In this regard, the chloroform fraction of Hypericum revolutum (HR) has been reported to produce vasodilating activity in phenylephrine-precontracted aortae. The current work aims to identify the active metabolites in the chloroform fraction of HR and illustrate the possible mechanism of action. The vasodilation activities were investigated using the isolated artery technique. NO vascular release was assessed by utilizing the NO-sensitive fluorescent probe DAF-FM. Free radical scavenging capacity was assessed utilizing DPPH. Chemical investigation of this fraction yielded two new compounds, revolutin (1) and hyperevolutin C (2), along with three known metabolites, β-sitosterol (3), euxanthone (4), and 2,3,4-tirmethoxy xanthone (5). Compounds 1, 2, 3, and 5 showed significant vasodilation activities that were blocked by either endothelial denudation or L-NAME (nitric oxide synthase inhibitor), pointing towards a role of endothelial nitric oxide in their activities. In confirmation of this role, compounds 1–3 showed a significant release of NO from isolated vessels, as indicated by DAF-FM. On the other hand, only compound 5 showed free radical scavenging activities, as indicated by DPPH. In conclusion, isolated compounds 1, 2, 3, and 5 produce vasodilation activities that are dependent on endothelial nitric oxide release. Full article

Background: The present study attempted to investigate the therapeutic effect and duration of low intensity extracorporeal shock wave therapy (LiESWT) on overactive bladder (OAB) symptoms, including social activity and the quality of life (QoL). Methods: In this prospective, randomized, single-blinded clinical trial, 65 participants with OAB symptom were randomly divided into receive LiESWT (0.25 mJ/mm², 3000 pulses, 3 pulses/second) once a week for 8 weeks, or an identical sham LiESWT treatment without the energy transmission. We analyzed the difference in overactive bladder symptom score (OABSS) and 3-day urinary diary as the primary end. The secondary endpoint consisted of the change in uroflowmetry, post-voided residual (PVR) urine, and validated standardized questionnaires at the baseline (W0), 4-week (W4) and 8-week (W8) of LiESWT, and 1-month (F1), 3-month (F3) and 6-month (F6) follow-up after LiESWT. Results: 8-week LiESWT could significantly decrease urinary frequency, nocturia, urgency, and PVR volume, but meaningfully increase functional bladder capacity, average voided volume and maximal flow rate (Qmax) as compared with the W0 in the LiESWT group. In addition, the scores calculated from questionnaires were meaningfully reduced at W4, W8, F1, F3, and F6 in the LiESWT group. Conclusions: Our results revealed that the therapeutic efficacy of LiESWT could improve voided volume and ameliorate OAB symptoms, such as urgency, frequency, nocturia, and urinary incontinence, and lasted up to 6 month of follow-up. Moreover, LiESWT treatment brought statistically significant and clinically meaningful improvements in social activity and QoL of patients. These findings suggested that LiESWT could serve as an alternative non-invasive therapy for OAB patients. Full article

The development of robust skeletal muscle models has been challenging due to the partial recapitulation of human physiology and architecture. Reliable and innovative 3D skeletal muscle models recently described offer an alternative that more accurately captures the in vivo environment but require an abundant cell source. Direct reprogramming or transdifferentiation has been considered as an alternative. Recent reports have provided evidence for significant improvements in the efficiency of derivation of human skeletal myotubes from human fibroblasts. Herein we aimed at improving the transdifferentiation process of human fibroblasts (tHFs), in addition to the differentiation of murine skeletal myoblasts (C2C12), and the differentiation of primary human skeletal myoblasts (HSkM). Differentiating or transdifferentiating cells were exposed to single or combinations of biological ligands, including Follistatin, GDF8, FGF2, GDF11, GDF15, hGH, TMSB4X, BMP4, BMP7, IL6, and TNF-α. These were selected for their critical roles in myogenesis and regeneration. C2C12 and tHFs displayed significant differentiation deficits when exposed to FGF2, BMP4, BMP7, and TNF-α, while proliferation was significantly enhanced by FGF2. When exposed to combinations of ligands, we observed consistent deficit differentiation when TNF-α was included. Finally, our direct reprogramming technique allowed for the assembly of elongated, cross-striated, and aligned tHFs within tissue-engineered 3D skeletal muscle constructs. In conclusion, we describe an efficient system to transdifferentiate human fibroblasts into myogenic cells and a platform for the generation of tissue-engineered constructs. Future directions will involve the evaluation of the functional characteristics of these engineered tissues. Full article

Purpose: Drugs with cardiovascular protective properties (statins, acetylsalicylic acid (ASS)) were assumed to have positive effects on patients suffering from glaucoma disease. The present retrospective study aimed to investigate the influence of statins, ASS or a combination of both on the glaucoma conversion and progression rate in glaucoma suspects and glaucoma patients with a 20-year follow-up period. Methods: A retrospective analysis of 199 eyes of 120 patients (63 male, 57 female) of the Erlanger Glaucoma Registry (EGR; ClinicalTrials.gov Identifier: NCT00494923; ISSN 2191-5008, CS-2011) was performed considering systemic therapy with statins, ASS or a combination of both: 107 eyes with ocular hypertension (OHT) and 92 eyes with pre-perimetric primary open-angle glaucoma (pre-POAG). All patients received an ophthalmological examination including morphometric and functional glaucoma diagnostics. Glaucoma conversion was defined as the conversion of OHT to pre-POAG. Glaucoma progression was defined as confirmed visual field loss. Data were shown as percentages. Statistical analysis was performed by Chi-Quadrat tests. Results: 1. Glaucoma conversion/progression was observed in 46.7% of the subjects, additionally in combination with hypercholesterinemia in 76.8%. 2. Statins: 27.3% of eyes under systemic statin therapy showed a conversion/progression. Patients taking statins ≥ 10 years yielded a reduced conversion/progression rate (p = 0.028, non-significant after Bonferroni–Holm). 3. ASS: 34.7% of eyes under systemic ASS therapy showed a conversion/progression. A significantly lower conversion/progression rate was observed after ASS therapy ≥ 12 years (p = 0.017, significant after Bonferroni–Holm). 4. ASS and statins: 25.0% of eyes under combined therapy showed a conversion/progression. A significantly reduced conversion/progression rate was reached after 8 years of combined therapy (p = 0.049, non-significant after Bonferroni–Holm). Conclusions: Patients with ocular hypertension and early glaucoma seem to benefit from adjuvant cardiovascular protective therapy. However, the benefits and disadvantages of treatment with statins and/or ASS should be kept in mind. Thus, a thorough risk–benefit evaluation has to be performed for each patient individually to avoid unwanted side effects. Full article

The foraging and consumption of wild food plants is a long-standing tradition in many parts of the world and their importance in promoting food security has become more widely debated in recent years. The current study aimed to document, analyze, and interpret the traditional knowledge of non-cultivated vegetables among four Pathan tribes (Alisher Khel, Hadarzai, Haji Khel, and Umarzai) living in the Gadoon Valley, Swabi District, Khyber Pakhtunkhwa, NW Pakistan, and to evaluate how these practices vary among the considered tribal communities. A total of 104 informants were interviewed via a semi-structured, open-ended questionnaire and group discussions. The field survey was conducted from October 2018 to November 2020. Information about local names, growth habit, used plant parts, food/cooking details, medicinal perceptions, availability season, and market prices were collected. The field survey recorded 51 non-cultivated vegetables belonging to 24 botanical families, for which the frequently used plant parts included young leaves, stems, and flowers. The greatest number of use reports was recorded for Colocasia and the highest cultural index value was recorded for Rumex dentatus; the dominant botanical families were Asteraceae and Fabaceae (six species each). Seven species were found to be sold at local and regional markets. Cross-cultural analysis among the four considered tribes showed that the largest number of species was reported by members of the Hadarzai and Umarzai tribes, although most of the quoted wild vegetables were homogenously gathered among all considered communities, with some more idiosyncratic plant uses among the Umarzai group, who have likely been less affected by the erosion of traditional knowledge or possibly have had less access to traded cultivated vegetables. The novelty of the data was assessed by comparing it with the previously published wild food ethnobotanical literature of Pakistan, which showed fifteen new wild vegetables not yet reported in the NW of the country. The recorded food biocultural heritage should be seriously considered in future local development projects aimed at fostering environmental sustainability and food security. Full article

Imaging subject-specific heart valve, a crucial step to its design, has experimental variables that if unaccounted for, may lead to erroneous computational analysis and geometric errors of the resulting model. Preparation methods are developed to mitigate some sources of the geometric error. However, the resulting 3D geometry often does not retain the original dimensions before excision. Inverse fluid–structure interaction analysis is used to analyze the resulting geometry and to assess the valve’s closure. Based on the resulting closure, it is determined if the geometry used can yield realistic results. If full closure is not reached, the geometry is adjusted adequately until closure is observed. Full article

The present study was designed to identify and quantify the major phenolic compounds (phenolics) in the inner and outer husks, buds and bark of the Persian walnut, Juglans regia L. A comparison across six different cultivars grown in Slovenia was also carried out: ‘Fernor’, ‘Fernette’, ‘Franquette’, ‘Sava’, ‘Krka’ and ‘Rubina’. A total of 83 compounds were identified, which included 25 naphthoquinones, 15 hydroxycinnamic acids, 8 hydroxybenzoic acids, 13 flavanols, 2 flavones, 1 flavanone and 19 flavonols. For the first time, 38 phenolics in the husks, 57 phenolics in the buds and 29 phenolics in the bark were presented in J. regia within this study. Naphthoquinones were the major phenolics determined, approximately 75% of all analysed phenolics in the inner husk, 85% in the outer husk, 50% in buds and 80% in bark. The highest content of phenolics was found in the walnut buds, followed by the bark, the inner husk and the outer husk. On the basis of these high phenolic contents, walnut husks, buds and bark represented valuable by-products of the walnut tree. These data also show origin-related phenolic contents across the cultivars, and thus these phenolic profiles might serve to define the origins of different walnut cultivars. Full article