bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety of Combined Targeted and Helixor® Viscum album L. Therapy in Breast and Gynecological Cancer Patients, a Real-World Data Study
Authors: Schad Friedemann , Thronicke Anja
Published: February 2023

Background: Newer personalized medicines including targeted therapies such as PARP inhibitors and CDK 4/6 inhibitors have been shown to improve the survival of breast and gynaecological cancer patients. However, efficacy outcomes may be ham5pered by treatment discontinuation due to targeted therapy-related adverse drug reactions or resistance. Studies have suggested that add-on mistletoe (Viscum album L., VA) improves the quality of life and ameliorates the cytotoxic side effects of standard oncological therapy in cancer patients. The primary objective of this real-world data study was to determine the safety profile of targeted therapy in combination with add-on Helixor® VA therapy compared to targeted therapy alone in breast and gynecological cancer patients. Methods: The present study is a real-world data observational cohort study utilizing demographic and treatment data from the accredited national Network Oncology (NO) registry. The study has received ethics approval. The safety profile of targeted therapies with or without Helixor® VA therapy and safety—associated variables were evaluated by univariate and adjusted multivariable regression analyses. Results: All stages of breast and gynecological cancer patients (n = 242) were on average 54.5 ± 14.2 years old. One hundred and sixty patients (66.1%) were in the control (CTRL, targeted therapy) and 82 patients (33.9%) were in the combinational (COMB, targeted plus Helixor® VA therapy) group. The addition of Helixor® VA did not hamper the safety profile (χ2 = 0.107, p-value = 0.99) of targeted therapy. Furthermore, no adverse events and a trend towards an improved targeted therapy adherence were observed in the COMB group. Conclusions: The present study is the first of its kind showing the applicability of Helixor® VA in combination with targeted therapies. The results indicate that add-on Helixor® VA does not negatively alter the safety profile of targeted therapies in breast and gynaecological cancer patients.
Effect of Health Insurance Uptake on Hesitancy toward COVID-19 Vaccines in Nigeria: A Recursive Bivariate Probit and Decomposition Estimation
Authors: Oyekale Abayomi Samuel
Published: February 2023

Moral hazard remains one of the major challenges of health insurance administration. This paper recursively analyzed the effect of health insurance on the willingness to take COVID-19 vaccines in Nigeria. The data comprised 1892 unvaccinated respondents in the 2021/2022 National Longitudinal Phone Survey (NLPS). The data were analyzed with Coban’s recursive probit regression and decomposition approaches. The results revealed that 5.87% were health insured, and 7.93% were willing to take COVID-19 vaccines. Health insurance uptake significantly increased (p < 0.05) with an adult being the decision-maker on vaccination, requiring family planning, and urban residence, while it reduced with loss of jobs and residence in the southeast and southwest zones. In addition, health insurance significantly (p < 0.01) increased the willingness to take COVID-19 vaccines, along with each adult, all adults, and households’ heads being the major vaccination decision-makers, loss of jobs, and support for making COVID-19 vaccines compulsory. The average treatment effects (ATEs) and average treatment effect on the treated (ATET) of health insurance were significant (p < 0.01), with positive impacts on willingness to be vaccinated. It was concluded that policy reforms to promote access to health insurance would enhance COVID-19 vaccination in Nigeria. In addition, hesitancy toward COVID-19 vaccines can be reduced by targeting adults and household heads with adequate information, while health insurance uptake should target southern states and rural areas.
Iron Deficiency among School-Aged Adolescents in Hong Kong: Prevalence, Predictors, and Effects on Health-Related Quality of Life
Authors: Cheung Yin Ting , Chan Dorothy Fung Ying , Lee Cheuk Kwong , Tsoi Wai Chiu , Lau Ching Wa , Leung Jennifer Ngar Sze , So Jason Chi Chiu , Wong Chris Lei Po , Tsang Stella Tsui Ying , Chu Yvonne Yuen Ling , Li Chi Kong
Published: February 2023

Iron deficiency (ID) is a prevalent nutritional deficiency affecting children/adolescents worldwide. We reported (1) the prevalence of ID and ID with anemia (IDA) among Chinese school-aged adolescents, (2) clinical and dietary predictors of iron status, and (3) its impact on health-related qualities of life (HRQoL). This cross-sectional study recruited 183 boys and 340 girls (mean age = 17.55) from 16 schools in Hong Kong. ID is defined as serum ferritin <15 μg/L. The participants reported their dietary habits, menstrual patterns (girls), and HRQoL using structured questionnaires. The overall prevalence of ID was 11.1%. None of the boys had ID or IDA. Among girls, the rate of ID was 17.1% and IDA was 10.9%. One-third (36.3%) reported a regular habit of skipping ≥1 meal/day. Lower ferritin was found in adolescents who skipped meals (Est = −35.1, p = 0.017). Lower ferritin is correlated with poorer school functioning (Est = 0.81, p = 0.045) and fatigue (Est = 0.92, p = 0.016). Skipping meals is associated with poorer physical (p = 0.0017) and school functioning (p = 0.027). To conclude, 1 in 10 school-aged adolescents in Hong Kong are iron-deficient. The ID rate in girls (17.1%) is similar to that in other industrialized countries (5.2–16.6%). Future work should promote awareness on the potential health consequences of poor dietary habits on ID and the well-being of adolescents.
Soluble ST2 as a New Oxidative Stress and Inflammation Marker in Metabolic Syndrome
Authors: Roy Ignacio , Jover Eva , Matilla Lara , Alvarez Virginia , Fernández-Celis Amaya , Beunza Maite , Escribano Elena , Gainza Alicia , Sádaba Rafael , López-Andrés Natalia
Published: February 2023

Background: Metabolic syndrome (MS) is a complex and prevalent disorder. Oxidative stress and inflammation might contribute to the progression of MS. Soluble ST2 (sST2) is an attractive and druggable molecule that sits at the interface between inflammation, oxidative stress and fibrosis. This study aims to analyze the relationship among sST2, oxidative stress, inflammation and echocardiographic parameters in MS patients. Methods: Fifty-eight patients with MS were recruited and underwent physical, laboratory and transthoracic echocardiography examinations. Commercial ELISA and appropriate colorimetric assays were used to quantify serum levels of oxidative stress and inflammation markers and sST2. Results: Circulating sST2 was increased in MS patients and was significantly correlated with the oxidative stress markers nitrotyrosine and 8-hydroxy-2′-deoxyguanosine as well as with peroxide levels. The inflammatory parameters interleukin-6, intercellular adhesion molecule-1 and myeloperoxidase were positively correlated with sST2. Noteworthy, sST2 was positively correlated with left ventricular mass, filling pressures and pulmonary arterial pressures. Conclusion: Circulating levels of sST2 are associated with oxidative stress and inflammation burden and may underlie the pathological remodeling and dysfunction of the heart in MS patients. Our results suggest that sST2 elevation precedes diastolic dysfunction, emerging as an attractive biotarget in MS.
Antidiabetic Drug Prescription Pattern in Hospitalized Older Patients with Diabetes
Authors: Ardoino Ilaria , Mandelli Sara , Baviera Marta , Rossio Raffaella , Nobili Alessandro , Mannucci Pier Mannuccio , Franchi Carlotta ,   on behalf of REPOSI Investigator
Published: February 2023

Objective: To describe the prescription pattern of antidiabetic and cardiovascular drugs in a cohort of hospitalized older patients with diabetes. Methods: Patients with diabetes aged 65 years or older hospitalized in internal medicine and/or geriatric wards throughout Italy and enrolled in the REPOSI (REgistro POliterapuie SIMI—Società Italiana di Medicina Interna) registry from 2010 to 2019 and discharged alive were included. Results: Among 1703 patients with diabetes, 1433 (84.2%) were on treatment with at least one antidiabetic drug at hospital admission, mainly prescribed as monotherapy with insulin (28.3%) or metformin (19.2%). The proportion of treated patients decreased at discharge (N = 1309, 76.9%), with a significant reduction over time. Among those prescribed, the proportion of those with insulin alone increased over time (p = 0.0066), while the proportion of those prescribed sulfonylureas decreased (p < 0.0001). Among patients receiving antidiabetic therapy at discharge, 1063 (81.2%) were also prescribed cardiovascular drugs, mainly with an antihypertensive drug alone or in combination (N = 777, 73.1%). Conclusion: The management of older patients with diabetes in a hospital setting is often sub-optimal, as shown by the increasing trend in insulin at discharge, even if an overall improvement has been highlighted by the prevalent decrease in sulfonylureas prescription.
Ecological Flow Response Analysis to a Typical Strong Hydrological Alteration River in China
Authors: Xia Rui , Sun Hao , Chen Yan , Wang Qiang , Chen Xiaofei , Hu Qiang , Wang Jing
Published: February 2023

Ecological flow is an important indicator for reflecting the stability of a watershed ecosystem. The calculation of ecological discharge under hydrological variation has become a research hot-spot. The Ganjiang River south of Poyang Lake in China was taken as an example in this study. Hydrological Alteration Diagnosis System methods were used to detect the change-points. The Distributed Time Variation Gain Model (DTVGM) was used to carry out runoff restoration. The Probability-weighted Flow Duration Curve was applied to calculate the ecological flow. The results showed that: (1) The hydrological alteration of the Waizhou Station occurred in 1991, the annual runoff increased by 10%, and the Gini coefficient (GI) increased by 0.07 after the change-point. The change in precipitation was the main driving factors. (2) The R value and NSE of the DTVGM were greater than 0.84, which represents the feasibility of the model used to restore runoff. (3) Compared to the traditional hydrological method, the proposed method can better reflect the inter-annual difference of ecological flow, flow ranges for high, normal, and low flow years are 398–3771 m3/s, 352–2160 m3/s, and 277–1657 m3/s, respectively. The calculation method of ecological flow in rivers considering hydrological variation can more scientifically reflect the impact of hydrological variation on ecological flow process, ecological flow under different human activities that can be calculated, such as dam control, water intake and water transfer, furthermore, it also provides a scientific basis for water resources planning and allocation under changing environment.
Self-Management of Subclinical Common Mental Health Disorders (Anxiety, Depression and Sleep Disorders) Using Wearable Devices
Authors: Robinson Tony , Condell Joan , Ramsey Elaine , Leavey Gerard
Published: February 2023

Rationale: Common mental health disorders (CMD) (anxiety, depression, and sleep disorders) are among the leading causes of disease burden globally. The economic burden associated with such disorders is estimated at $2.4 trillion as of 2010 and is expected to reach $16 trillion by 2030. The UK has observed a 21-fold increase in the economic burden associated with CMD over the past decade. The recent COVID-19 pandemic was a catalyst for adopting technologies for mental health support and services, thereby increasing the reception of personal health data and wearables. Wearables hold considerable promise to empower users concerning the management of subclinical common mental health disorders. However, there are significant challenges to adopting wearables as a tool for the self-management of the symptoms of common mental health disorders. Aims: This review aims to evaluate the potential utility of wearables for the self-management of sub-clinical anxiety and depressive mental health disorders. Furthermore, we seek to understand the potential of wearables to reduce the burden on the healthcare system. Methodology: a systematic review of research papers was conducted, focusing on wearable devices for the self-management of CMD released between 2018–2022, focusing primarily on mental health management using technology. Results: We screened 445 papers and analysed the reports from 12 wearable devices concerning their device type, year, biometrics used, and machine learning algorithm deployed. Electrodermal activity (EDA/GSR/SC/Skin Temperature), physical activity, and heart rate (HR) are the most common biometrics with nine, six and six reference counts, respectively. Additionally, while smartwatches have greater penetration and integration within the marketplace, fitness trackers have the most significant public value benefit of £513.9 M, likely due to greater retention.
Maize Productivity and Household Welfare Impacts of Mobile Money Usage in Tanzania
Authors: Kilombele Happiness , Feleke Shiferaw , Abdoulaye Tahirou , Cole Steven , Sekabira Haruna , Manyong Victor
Published: February 2023

This study examined the determinants and impacts of mobile money (MM) usage on maize productivity and poverty likelihood (i.e., the probability of a household falling below the international poverty line at USD 1.9 per capita per day) in the Mbeya Region, Tanzania. The analysis was conducted using the endogenous switching regression (ESR) model on data from a random sample of 1310 households selected from seven districts in the region. Results of the ESR estimation show that MM usage is strongly and positively associated with the education level of the household head, asset ownership, credit access, input access, and social networks. MM usage is also significantly associated with increased maize productivity and a reduced poverty likelihood. Farmers who chose to use MM services increased their maize productivity by about 124 kg/acre and reduced their poverty likelihood by nearly 25 percentage points, as measured by the progress out of poverty index. These findings call for a targeted approach to reaching and supporting MM usage among households with constrained access to formal financial services to increase maize productivity and reduce poverty likelihood.
Geospatial Modeling of Health, Socioeconomic, Demographic, and Environmental Factors with COVID-19 Incidence Rate in Arkansas, US
Authors: He Yaqian , Seminara Paul J. , Huang Xiao , Yang Di , Fang Fang , Song Chao
Published: February 2023

The COVID-19 pandemic has posed numerous challenges to human society. Previous studies explored multiple factors in virus transmission. Yet, their impacts on COVID-19 are not universal and vary across geographical regions. In this study, we thoroughly quantified the spatiotemporal associations of 49 health, socioeconomic, demographic, and environmental factors with COVID-19 at the county level in Arkansas, US. To identify the associations, we applied the ordinary least squares (OLS) linear regression, spatial lag model (SLM), spatial error model (SEM), and multiscale geographically weighted regression (MGWR) model. To reveal how such associations change across different COVID-19 times, we conducted the analyses for each season (i.e., spring, summer, fall, and winter) from 2020 to 2021. We demonstrate that there are different driving factors along with different COVID-19 variants, and their magnitudes change spatiotemporally. However, our results identify that adult obesity has a positive association with the COVID-19 incidence rate over entire Arkansas, thus confirming that people with obesity are vulnerable to COVID-19. Humidity consistently negatively affects COVID-19 across all seasons, denoting that increasing humidity could reduce the risk of COVID-19 infection. In addition, diabetes shows roles in the spread of both early COVID-19 variants and Delta, while humidity plays roles in the spread of Delta and Omicron. Our study highlights the complexity of how multifactor affect COVID-19 in different seasons and counties in Arkansas. These findings are useful for informing local health planning (e.g., vaccine rollout, mask regulation, and testing/tracing) for the residents in Arkansas.
Age-Related Changes in Neurons and Satellite Glial Cells in Mouse Dorsal Root Ganglia
Authors: Hanani Menachem , Spray David C. , Huang Tian-Ying
Published: February 2023

The effects of aging on the nervous system are well documented. However, most previous studies on this topic were performed on the central nervous system. The present study was carried out on the dorsal root ganglia (DRGs) of mice, and focused on age-related changes in DRG neurons and satellite glial cells (SGCs). Intracellular electrodes were used for dye injection to examine the gap junction-mediated coupling between neurons and SGCs, and for intracellular electrical recordings from the neurons. Tactile sensitivity was assessed with von Frey hairs. We found that 3-23% of DRG neurons were dye-coupled to SGCs surrounding neighboring neurons in 8–24-month (Mo)-old mice, whereas in young adult (3 Mo) mice, the figure was 0%. The threshold current for firing an action potential in sensory neurons was significantly lower in DRGs from 12 Mo mice compared with those from 3 Mo mice. The percentage of neurons with spontaneous subthreshold membrane potential oscillation was greater by two-fold in 12 Mo mice. The withdrawal threshold was lower by 22% in 12 Mo mice compared with 3 Mo ones. These results show that in the aged mice, a proportion of DRG neurons is coupled to SGCs, and that the membrane excitability of the DRG neurons increases with age. We propose that augmented neuron–SGC communications via gap junctions are caused by low-grade inflammation associated with aging, and this may contribute to pain behavior.
PTCHD1 Binds Cholesterol but Not Sonic Hedgehog, Suggesting a Distinct Cellular Function
Authors: Hiltunen Mimmu K. , Timmis Alex J. , Thomsen Maren , Gkotsi Danai S. , Iwaï Hideo , Ribeiro Orquidea M. , Goldman Adrian , Riobo-Del Galdo Natalia A.
Published: February 2023

Deleterious mutations in the X-linked Patched domain-containing 1 (PTCHD1) gene may account for up to 1% of autism cases. Despite this, the PTCHD1 protein remains poorly understood. Structural similarities to Patched family proteins point to a role in sterol transport, but this hypothesis has not been verified experimentally. Additionally, PTCHD1 has been suggested to be involved in Hedgehog signalling, but thus far, the experimental results have been conflicting. To enable a variety of biochemical and structural experiments, we developed a method for expressing PTCHD1 in Spodoptera frugiperda cells, solubilising it in glycol-diosgenin, and purifying it to homogeneity. In vitro and in silico experiments show that PTCHD1 function is not interchangeable with Patched 1 (PTCH1) in canonical Hedgehog signalling, since it does not repress Smoothened in Ptch1−/− mouse embryonic fibroblasts and does not bind Sonic Hedgehog. However, we found that PTCHD1 binds cholesterol similarly to PTCH1. Furthermore, we identified 13 PTCHD1-specific protein interactors through co-immunoprecipitation and demonstrated a link to cell stress responses and RNA stress granule formation. Thus, our results support the notion that despite structural similarities to other Patched family proteins, PTCHD1 may have a distinct cellular function.
Pyruvate Kinase M2: A New Biomarker for the Early Detection of Diabetes-Induced Nephropathy
Authors: Park Yeon Su , Han Joo Hee , Park Jae Hyeon , Choi Ji Soo , Kim Seung Hyeon , Kim Hyung Sik
Published: February 2023

Diabetic nephropathy (DN) is a common complication of diabetes. DN progresses to end-stage renal disease, which has a high mortality rate. Current research is focused on identifying non-invasive potential biomarkers in the early stage of DN. We previously indicated that pyruvate kinase M2 (PKM2) is excreted in the urine of rats after cisplatin-induced acute kidney injury (AKI). However, it has not been reported whether PKM2 can be used as a biomarker to diagnose DN. Therefore, we try to compare whether the protein PKM2 can be detected in the urine samples from diabetic patients as shown in the results of DN models. In this study, high-fat diet (HFD)-induced Zucker diabetic fatty (ZDF) rats were used for DN phenotyping. After 19 weeks of receiving a HFD, the DN model’s blood glucose, blood urea nitrogen, and serum creatinine levels were significantly increased; severe tubular and glomerular damages were also noted. The following protein-based biomarkers were increased in the urine of these models: kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and PKM2. PKM2 had the earliest detection rate. In the urine samples of patients, PKM2 protein was highly detected in the urine of diabetic patients but was not excreted in the urine of normal subjects. Therefore, PKM2 was selected as the new biomarker for the early diagnosis of DN. Our results reflect current knowledge on the role of PKM2 in DN.
Application of Antisense Conjugates for the Treatment of Myotonic Dystrophy Type 1
Authors: Stoodley Jessica , Vallejo-Bedia Francisco , Seone-Miraz David , Debasa-Mouce Manuel , Wood Matthew J. A. , Varela Miguel A.
Published: February 2023

Myotonic dystrophy type 1 (DM1) is one of the most common muscular dystrophies and can be potentially treated with antisense therapy decreasing mutant DMPK, targeting miRNAs or their binding sites or via a blocking mechanism for MBNL1 displacement from the repeats. Unconjugated antisense molecules are able to correct the disease phenotype in mouse models, but they show poor muscle penetration upon systemic delivery in DM1 patients. In order to overcome this challenge, research has focused on the improvement of the therapeutic window and biodistribution of antisense therapy using bioconjugation to lipids, cell penetrating peptides or antibodies. Antisense conjugates are able to induce the long-lasting correction of DM1 pathology at both molecular and functional levels and also efficiently penetrate hard-to-reach tissues such as cardiac muscle. Delivery to the CNS at clinically relevant levels remains challenging and the use of alternative administration routes may be necessary to ameliorate some of the symptoms experienced by DM1 patients. With several antisense therapies currently in clinical trials, the outlook for achieving a clinically approved treatment for patients has never looked more promising.
Microenvironmental Impact on InP/ZnS-Based Quantum Dots in In Vitro Models and in Living Cells: Spectrally- and Time-Resolved Luminescence Analysis
Authors: Litvinov Ilia , Salova Anna , Aksenov Nikolay , Kornilova Elena , Belyaeva Tatiana
Published: February 2023

Quantum dots (QDs) have attracted great attention as tools for theranostics that combine the possibility of simultaneous biological target visualization and medicine delivery. Here, we address whether core/shell InP/ZnS QDs (InP-QDs) may be an alternative to toxic Cd-based QDs. We analyze InP-QD photophysical characteristics in cell culture medium, salt solutions, and directly in the cells. It was demonstrated that InP-QDs were internalized into endolysosomes in HeLa and A549 cells with dynamics similar to Cd-based QDs of the same design, but the two cell lines accumulated them with different efficiencies. InP-QDs were reliably detected in the endosomes despite their low quantum yields. Cell culture medium efficiently decreased the InP-QD photoluminescence lifetime by 50%, acidic pH (4.0) had a moderate effect (20–25% reduction), and quenching by salt solutions typical of intra-endosomal medium composition resulted in a decrease of about 10–15%. The single-vesicle fluorescence-lifetime imaging microscopy analysis of QDs inside and outside the cells shows that the scatter between endosomes in the same cell can be significant, which indicates the complex impact of the abovementioned factors on the state of InP-QDs. The PI test and MTT test demonstrate that InP-QDs are toxic for both cell lines at concentrations higher than 20 nM. Possible reasons for InP-QD toxicity are discussed.
A Comprehensive Review of mRNA Vaccines
Authors: Gote Vrinda , Bolla Pradeep Kumar , Kommineni Nagavendra , Butreddy Arun , Nukala Pavan Kumar , Palakurthi Sushesh Srivatsa , Khan Wahid
Published: February 2023

mRNA vaccines have been demonstrated as a powerful alternative to traditional conventional vaccines because of their high potency, safety and efficacy, capacity for rapid clinical development, and potential for rapid, low-cost manufacturing. These vaccines have progressed from being a mere curiosity to emerging as COVID-19 pandemic vaccine front-runners. The advancements in the field of nanotechnology for developing delivery vehicles for mRNA vaccines are highly significant. In this review we have summarized each and every aspect of the mRNA vaccine. The article describes the mRNA structure, its pharmacological function of immunity induction, lipid nanoparticles (LNPs), and the upstream, downstream, and formulation process of mRNA vaccine manufacturing. Additionally, mRNA vaccines in clinical trials are also described. A deep dive into the future perspectives of mRNA vaccines, such as its freeze-drying, delivery systems, and LNPs targeting antigen-presenting cells and dendritic cells, are also summarized.
Garcinol Promotes the Formation of Slow-Twitch Muscle Fibers by Inhibiting p300-Dependent Acetylation of PGC-1α
Authors: Yao Weilei , Guo Baoyin , Jin Taimin , Bao Zhengxi , Wang Tongxin , Wen Shu , Huang Feiruo
Published: February 2023

The conversion of skeletal muscle fiber from fast-twitch to slow-twitch is crucial for sustained contractile and stretchable events, energy homeostasis, and anti-fatigue ability. The purpose of our study was to explore the mechanism and effects of garcinol on the regulation of skeletal muscle fiber type transformation. Forty 21-day-old male C57/BL6J mice (n = 10/diet) were fed a control diet or a control diet plus garcinol at 100 mg/kg (Low Gar), 300 mg/kg (Mid Gar), or 500 mg/kg (High Gar) for 12 weeks. The tibialis anterior (TA) and soleus muscles were collected for protein and immunoprecipitation analyses. Dietary garcinol significantly downregulated (p < 0.05) fast myosin heavy chain (MyHC) expression and upregulated (p < 0.05) slow MyHC expression in the TA and soleus muscles. Garcinol significantly increased (p < 0.05) the activity of peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) and markedly decreased (p < 0.05) the acetylation of PGC-1α. In vitro and in vivo experiments showed that garcinol decreased (p < 0.05) lactate dehydrogenase activity and increased (p < 0.05) the activities of malate dehydrogenase and succinic dehydrogenase. In addition, the results of C2C12 myotubes showed that garcinol treatment increased (p < 0.05) the transformation of glycolytic muscle fiber to oxidative muscle fiber by 45.9%. Garcinol treatment and p300 interference reduced (p < 0.05) the expression of fast MyHC but increased (p < 0.05) the expression of slow MyHC in vitro. Moreover, the acetylation of PGC-1α was significantly decreased (p < 0.05). Garcinol promotes the transformation of skeletal muscle fibers from the fast-glycolytic type to the slow-oxidative type through the p300/PGC-1α signaling pathway in C2C12 myotubes.
Health Benefits of Coffee Consumption for Cancer and Other Diseases and Mechanisms of Action
Authors: Safe Stephen , Kothari Jainish , Hailemariam Amanuel , Upadhyay Srijana , Davidson Laurie A. , Chapkin Robert S.
Published: February 2023

Coffee is one of the most widely consumed beverages worldwide, and epidemiology studies associate higher coffee consumption with decreased rates of mortality and decreased rates of neurological and metabolic diseases, including Parkinson’s disease and type 2 diabetes. In addition, there is also evidence that higher coffee consumption is associated with lower rates of colon and rectal cancer, as well as breast, endometrial, and other cancers, although for some of these cancers, the results are conflicting. These studies reflect the chemopreventive effects of coffee; there is also evidence that coffee consumption may be therapeutic for some forms of breast and colon cancer, and this needs to be further investigated. The mechanisms associated with the chemopreventive or chemotherapeutic effects of over 1000 individual compounds in roasted coffee are complex and may vary with different diseases. Some of these mechanisms may be related to nuclear factor erythroid 2 (Nrf2)-regulated pathways that target oxidative stress or pathways that induce reactive oxygen species to kill diseased cells (primarily therapeutic). There is evidence for the involvement of receptors which include the aryl hydrocarbon receptor (AhR) and orphan nuclear receptor 4A1 (NR4A1), as well as contributions from epigenetic pathways and the gut microbiome. Further elucidation of the mechanisms will facilitate the potential future clinical applications of coffee extracts for treating cancer and other inflammatory diseases.
Giant Fern Genomes Show Complex Evolution Patterns: A Comparative Analysis in Two Species of Tmesipteris (Psilotaceae)
Authors: Fernández Pol , Leitch Ilia J. , Leitch Andrew R. , Hidalgo Oriane , Christenhusz Maarten J. M. , Pokorny Lisa , Pellicer Jaume
Published: February 2023

Giant genomes are rare across the plant kingdom and their study has focused almost exclusively on angiosperms and gymnosperms. The scarce genetic data that are available for ferns, however, indicate differences in their genome organization and a lower dynamism compared to other plant groups. Tmesipteris is a small genus of mainly epiphytic ferns that occur in Oceania and several Pacific Islands. So far, only two species with giant genomes have been reported in the genus, T. tannensis (1C = 73.19 Gbp) and T. obliqua (1C = 147.29 Gbp). Low-coverage genome skimming sequence data were generated in these two species and analyzed using the RepeatExplorer2 pipeline to identify and quantify the repetitive DNA fraction of these genomes. We found that both species share a similar genomic composition, with high repeat diversity compared to taxa with small (1C < 10 Gbp) genomes. We also found that, in general, characterized repetitive elements have relatively high heterogeneity scores, indicating ancient diverging evolutionary trajectories. Our results suggest that a whole genome multiplication event, accumulation of repetitive elements, and recent activation of those repeats have all played a role in shaping these genomes. It will be informative to compare these data in the future with data from the giant genome of the angiosperm Paris japonica, to determine if the structures observed here are an emergent property of massive genomic inflation or derived from lineage specific processes.
Biallelic Variants in TULP1 Are Associated with Heterogeneous Phenotypes of Retinal Dystrophy
Authors: Bodenbender Jan-Philipp , Marino Valerio , Bethge Leon , Stingl Katarina , Haack Tobias B. , Biskup Saskia , Kohl Susanne , Kühlewein Laura , Dell’Orco Daniele , Weisschuh Nicole
Published: February 2023

Biallelic pathogenic variants in TULP1 are mostly associated with severe rod-driven inherited retinal degeneration. In this study, we analyzed clinical heterogeneity in 17 patients and characterized the underlying biallelic variants in TULP1. All patients underwent thorough ophthalmological examinations. Minigene assays and structural analyses were performed to assess the consequences of splice variants and missense variants. Three patients were diagnosed with Leber congenital amaurosis, nine with early onset retinitis pigmentosa, two with retinitis pigmentosa with an onset in adulthood, one with cone dystrophy, and two with cone-rod dystrophy. Seventeen different alleles were identified, namely eight missense variants, six nonsense variants, one in-frame deletion variant, and two splice site variants. For the latter two, minigene assays revealed aberrant transcripts containing frameshifts and premature termination codons. Structural analysis and molecular modeling suggested different degrees of structural destabilization for the missense variants. In conclusion, we report the largest cohort of patients with TULP1-associated IRD published to date. Most of the patients exhibited rod-driven disease, yet a fraction of the patients exhibited cone-driven disease. Our data support the hypothesis that TULP1 variants do not fold properly and thus trigger unfolded protein response, resulting in photoreceptor death.
Experimental Models of In Vitro Blood–Brain Barrier for CNS Drug Delivery: An Evolutionary Perspective
Authors: Chaulagain Bivek , Gothwal Avinash , Lamptey Richard Nii Lante , Trivedi Riddhi , Mahanta Arun Kumar , Layek Buddhadev , Singh Jagdish
Published: February 2023

Central nervous system (CNS) disorders represent one of the leading causes of global health burden. Nonetheless, new therapies approved against these disorders are among the lowest compared to their counterparts. The absence of reliable and efficient in vitro blood–brain barrier (BBB) models resembling in vivo barrier properties stands out as a significant roadblock in developing successful therapy for CNS disorders. Therefore, advancement in the creation of robust and sensitive in vitro BBB models for drug screening might allow us to expedite neurological drug development. This review discusses the major in vitro BBB models developed as of now for exploring the barrier properties of the cerebral vasculature. Our main focus is describing existing in vitro models, including the 2D transwell models covering both single-layer and co-culture models, 3D organoid models, and microfluidic models with their construction, permeability measurement, applications, and limitations. Although microfluidic models are better at recapitulating the in vivo properties of BBB than other models, significant gaps still exist for their use in predicting the performance of neurotherapeutics. However, this comprehensive account of in vitro BBB models can be useful for researchers to create improved models in the future.
Moderating Gut Microbiome/Mitochondrial Axis in Oxazolone Induced Ulcerative Colitis: The Evolving Role of β-Glucan and/or, Aldose Reductase Inhibitor, Fidarestat
Authors: El-Deeb Omnia Safwat , Elesawy Rasha Osama , Eltokhy Amira K. , Al-Shenawy Hanan Alsaeid , Ghanem Heba Bassiony , Rizk Fatma H. , Barhoma Ramez AE , Shalaby Rania H. , Abdelsattar Amal M. , Mashal Shaimaa S. , Eshra Kareman Ahmed , El-Sharaby Radwa Mahmoud , Ali Dina Adam , Ibrahim Rowida Raafat
Published: February 2023

A mechanistic understanding of the dynamic interactions between the mitochondria and the gut microbiome is thought to offer innovative explanations for many diseases and thus provide innovative management approaches, especially in GIT-related autoimmune diseases, such as ulcerative colitis (UC). β-Glucans, important components of many nutritious diets, including oats and mushrooms, have been shown to exhibit a variety of biological anti-inflammatory and immune-modulating actions. Our research study sought to provide insight into the function of β-glucan and/or fidarestat in modifying the microbiome/mitochondrial gut axis in the treatment of UC. A total of 50 Wistar albino male rats were grouped into five groups: control, UC, β-Glucan, Fidarestat, and combined treatment groups. All the groups were tested for the presence of free fatty acid receptors 2 and 3 (FFAR-2 and -3) and mitochondrial transcription factor A (TFAM) mRNA gene expressions. The reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP content were found. The trimethylamine N-oxide (TMAO) and short-chain fatty acid (SCFA) levels were also examined. Nuclear factor kappa β (NF-kβ), nuclear factor (erythroid-2)-related factor 2 (Nrf2) DNA binding activity, and peroxisome proliferator-activated receptor gamma co-activator-1 (PGC-1) were identified using the ELISA method. We observed a substantial increase FFAR-2, -3, and TFAM mRNA expression after the therapy. Similar increases were seen in the ATP levels, MMP, SCFA, PGC-1, and Nrf2 DNA binding activity. The levels of ROS, TMAO, and NF-kβ, on the other hand, significantly decreased. Using β-glucan and fidarestat together had unique therapeutic benefits in treating UC by focusing on the microbiota/mitochondrial axis, opening up a new avenue for a potential treatment for such a complex, multidimensional illness.
Synthesis of 1,4-Dialkoxynaphthalene-Based Imidazolium Salts and Their Cytotoxicity in Cancer Cell Lines
Authors: Lee Haena , Jeon Yejin , Moon Hyejin , Lee Eunjoo H. , Lee Tae Hoon , Kim Hakwon
Published: February 2023

In this study, we designed and synthesized novel 1,4-dialkoxynaphthalene-2-alkyl imidazolium salt (IMS) derivatives containing both 1,4-dialkoxynaphthalene and imidazole, which are well known as pharmacophores. The cytotoxicities of these newly synthesized IMS derivatives were investigated in order to explore the possibility of using them to develop anticancer drugs. It was found that some of the new IMS derivatives showed good cytotoxic activities. In addition, an initial, qualitative structure–activity relationship is presented on the basis of observations of activity changes corresponding to structural changes.
Betaine- and L-Carnitine-Based Ionic Liquids as Solubilising and Stabilising Agents for the Formulation of Antimicrobial Eye Drops Containing Diacerein
Authors: Grassiri Brunella , Mezzetta Andrea , Maisetta Giuseppantionio , Migone Chiara , Fabiano Angela , Esin Semih , Guazzelli Lorenzo , Zambito Ylenia , Batoni Giovanna , Piras Anna Maria
Published: February 2023

The therapeutic efficacy of topically administered drugs, however powerful, is largely affected by their bioavailability and, thus, ultimately, on their aqueous solubility and stability. The aim of this study was to evaluate the use of ionic liquids (ILs) as functional excipients to solubilise, stabilise, and prolong the ocular residence time of diacerein (DIA) in eye drop formulations. DIA is a poorly soluble and unstable anthraquinone prodrug, rapidly hydrolysed to rhein (Rhe), for the treatment of osteoarthritis. DIA has recently been evaluated as an antimicrobial agent for bacterial keratitis. Two ILs based on natural zwitterionic compounds were investigated: L-carnitine C6 alkyl ester bromide (Carn6), and betaine C6 alkyl ester bromide (Bet6). The stabilising, solubilising, and mucoadhesive properties of ILs were investigated, as well as their cytotoxicity to the murine fibroblast BALB/3T3 clone A31 cell line. Two IL–DIA-based eye drop formulations were prepared, and their efficacy against both Staphylococcus aureus and Pseudomonas aeruginosa was determined. Finally, the eye drops were administered in vivo on New Zealand albino rabbits, testing their tolerability as well as their elimination and degradation kinetics. Both Bet6 and Carn6 have good potential as functional excipients, showing solubilising, stabilising, mucoadhesive, and antimicrobial properties; their in vitro cytotoxicity and in vivo ocular tolerability pave the way for their future use in ophthalmic applications.
From the Allergic Cascade to the Epithelium-Driven Disease: The Long Road of Bronchial Asthma
Authors: Domingo Christian , Mirapeix Rosa M.
Published: February 2023

In medicine, much of the progress made is due to the emergence of new drugs [...]
CD123 a Therapeutic Target for Acute Myeloid Leukemia and Blastic Plasmocytoid Dendritic Neoplasm
Authors: Pelosi Elvira , Castelli Germana , Testa Ugo
Published: February 2023

In spite of consistent progress at the level of basic research and of clinical treatment, acute myeloid leukemia (AML) still represents an unmet clinical need for adult and pediatric patients. To improve the outcomes of these patients, it is necessary to identify new therapeutic targets. IL3RA (CD123, alpha subunit of the interleukin 3 receptor) is a cell membrane protein overexpressed in several hematologic malignancies, including AML blastic plasmocytoid dendritic cell neoplasms (BPDCN). Given the higher expression of CD123 on leukemic cells compared to normal hematopoietic cells and its low/absent expression on normal hematopoietic stem cells, it appears as a suitable and attractive target for therapy. Various drugs targeting CD123 have been developed and evaluated at clinical level: interleukin-3 conjugated with diphtheria toxin; naked neutralizing anti-CD123 antibodies; drug–antibody conjugates; bispecific antibodies targeting both CD123 and CD3; and chimeric antigen receptor (CAR) T cells engineered to target CD123. Some of these agents have shown promising results at the clinical level, including tagraxofusp (CD123 conjugated with diphtheria toxin) for the treatment of BPDCN and IMGN632 (anti-CD123 drug-conjugate), and flotetuzumab (bispecific anti-CD123 and anti-CD3 monoclonal antibody) for the treatment of AML. However, the therapeutic efficacy of CD123-targeting treatments is still unsatisfactory and must be improved through new therapeutic strategies and combined treatments with other antileukemic drugs.
Mechanobiology of the Human Intervertebral Disc: Systematic Review of the Literature and Future Perspectives
Authors: Ruffilli Alberto , Viroli Giovanni , Neri Simona , Traversari Matteo , Barile Francesca , Manzetti Marco , Assirelli Elisa , Ialuna Marco , Vita Fabio , Faldini Cesare
Published: February 2023

Low back pain is an extremely common condition with severe consequences. Among its potential specific causes, degenerative disc disease (DDD) is one of the most frequently observed. Mechanobiology is an emerging science studying the interplay between mechanical stimuli and the biological behavior of cells and tissues. The aim of the presented study is to review, with a systematic approach, the existing literature regarding the mechanobiology of the human intervertebral disc (IVD), define the main pathways involved in DDD and identify novel potential therapeutic targets. The review was carried out in accordance with the Preferential Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies were included if they described biological responses of human IVD cells under mechanical stimulation or alterations of mechanical properties of the IVD determined by different gene expression. Fifteen studies were included and showed promising results confirming the mechanobiology of the human IVD as a key element in DDD. The technical advances of the last decade have allowed us to increase our understanding of this topic, enabling us to identify possible therapeutic targets to treat and to prevent DDD. Further research and technological innovations will shed light on the interactions between the mechanics and biology of the human IVD.
Vascular Endothelial Growth Factor as Molecular Target for Bronchopulmonary Dysplasia Prevention in Very Low Birth Weight Infants
Authors: Perrone Serafina , Manti Sara , Buttarelli Luca , Petrolini Chiara , Boscarino Giovanni , Filonzi Laura , Gitto Eloisa , Esposito Susanna Maria Roberta , Nonnis Marzano Francesco
Published: February 2023

Bronchopulmonary dysplasia (BPD) still represents an important burden of neonatal care. The definition of the disease is currently undergoing several revisions, and, to date, BPD is actually defined by its treatment rather than diagnostic or clinic criteria. BPD is associated with many prenatal and postnatal risk factors, such as maternal smoking, chorioamnionitis, intrauterine growth restriction (IUGR), patent ductus arteriosus (PDA), parenteral nutrition, sepsis, and mechanical ventilation. Various experimental models have shown how these factors cause distorted alveolar and vascular growth, as well as alterations in the composition and differentiation of the mesenchymal cells of a newborn’s lungs, demonstrating a multifactorial pathogenesis of the disease. In addition, inflammation and oxidative stress are the common denominators of the mechanisms that contribute to BPD development. Vascular endothelial growth factor-A (VEGFA) constitutes the most prominent and best studied candidate for vascular development. Animal models have confirmed the important regulatory roles of epithelial-expressed VEGF in lung development and function. This educational review aims to discuss the inflammatory pathways in BPD onset for preterm newborns, focusing on the role of VEGFA and providing a summary of current and emerging evidence.
A Phytoprostane from Gracilaria longissima Increases Platelet Activation, Platelet Adhesion to Leukocytes and Endothelial Cell Migration by Potential Binding to EP3 Prostaglandin Receptor
Authors: Montoro-García Silvia , Martínez-Sánchez Sara , Carmena-Bargueño Miguel , Pérez-Sánchez Horacio , Campillo María , Oger Camille , Galano Jean-Marie , Durand Thierry , Gil-Izquierdo Ángel , Gabaldón José Antonio
Published: February 2023

Plant phytoprostanes (PhytoPs) are lipid oxidative stress mediators that share structural similarities with mammal prostaglandins (PGs). They have been demonstrated to modulate inflammatory processes mediated by prostaglandins. The present study aims to test the effects of the most abundant oxylipin from Gracilaria longissima, ent-9-D1t-Phytoprostane (9-D1t-PhytoP), on platelet activation and vascular cells as well as clarify possible interactions with platelets and the endothelial EP3 receptor Platelet and monocyte activation was assessed by flow cytometry in the presence of purified 9-D1t-PhytoP. Cell migration was studied using the human Ea.hy926 cell line by performing a scratch wound healing assay. The RNA expression of inflammatory markers was evaluated by RT-PCR under inflammatory conditions. Blind docking consensus was applied to the study of the interactions of selected ligands against the EP3 receptor protein. The 9D1t-PhytoP exerts several pharmacological effects; these include prothrombotic and wound-healing properties. In endothelial cells, 9D1t-PhytP mimics the migration stimulus of PGE2. Computational analysis revealed that 9D1t-PhytP forms a stable complex with the hydrophobic pocket of the EP3 receptor by interaction with the same residues as misoprostol and prostaglandin E2 (PGE2), thus supporting its potential as an EP3 agonist. The potential to form procoagulant platelets and the higher endothelial migration rate of the 9-D1t-PhytoP, together with its capability to interact with PGE2 main target receptor in platelets suggest herein that this oxylipin could be a strong candidate for pharmaceutical research from a multitarget perspective.
Tryptophan and Substance Abuse: Mechanisms and Impact
Authors: Davidson Majid , Rashidi Niloufar , Hossain Md Kamal , Raza Ali , Nurgali Kulmira , Apostolopoulos Vasso
Published: February 2023

Addiction, the continuous misuse of addictive material, causes long-term dysfunction in the neurological system. It substantially affects the control strength of reward, memory, and motivation. Addictive substances (alcohol, marijuana, caffeine, heroin, methamphetamine (METH), and nicotine) are highly active central nervous stimulants. Addiction leads to severe health issues, including cardiovascular diseases, serious infections, and pulmonary/dental diseases. Drug dependence may result in unfavorable cognitive impairments that can continue during abstinence and negatively influence recovery performance. Although addiction is a critical global health challenge with numerous consequences and complications, currently, there are no efficient options for treating drug addiction, particularly METH. Currently, novel treatment approaches such as psychological contingency management, cognitive behavioral therapy, and motivational enhancement strategies are of great interest. Herein, we evaluate the devastating impacts of different addictive substances/drugs on users′ mental health and the role of tryptophan in alleviating unfavorable side effects. The tryptophan metabolites in the mammalian brain and their potential to treat compulsive abuse of addictive substances are investigated by assessing the functional effects of addictive substances on tryptophan. Future perspectives on developing promising modalities to treat addiction and the role of tryptophan and its metabolites to alleviate drug dependency are discussed.