bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinic and Home-Based Exercise with Blood Flow Restriction Resolves Thigh Muscle Atrophy after Anterior Cruciate Ligament Reconstruction with the Bone-Patellar Tendon-Bone Autograft: A Case Report
Authors: Solie Braidy S. , Eggleston Garrett G. , Schwery Nicole A. , Doney Christopher P. , Kiely Michael T. , Larson Christopher M.
Published: June 2023

Anterior cruciate ligament reconstruction (ACLR) results in thigh muscle atrophy. Of the various interventions proposed to mitigate thigh muscle atrophy, exercise with blood flow restriction (BFR) appears safe and effective. Some literature suggests daily exposure to exercise with BFR may be indicated during the early phase of ACLR rehabilitation; this case report outlines the methodology utilized to prescribe clinic- and home-based BFR within an outpatient rehabilitation program. A 15-year-old male soccer player suffered a left knee injury involving the anterior cruciate ligament and both menisci. He underwent ACLR and completed exercise with BFR as part of his clinic- and home-based rehabilitation program, which included practical blood flow restriction during home-based rehabilitation. After 16 weeks of rehabilitation, surgical limb thigh girth values were objectively larger than the non-surgical limb (surgical, 52.25 cm; non-surgical 50 cm), as well as the multi-frequency bioelectrical impedance analysis of his lower-extremity lean body mass (surgical limb, 10.37 kg; non-surgical limb, 10.02 kg). The findings of this case report suggest that the inclusion of clinic- and home-based BFR within an outpatient rehabilitation program may be indicated to resolve thigh muscle atrophy early after ACLR.
Generic Substitutions and Therapeutic Interchanges in Hospital Pharmacies: A Qualitative Study from Western Saudi Arabia
Authors: Alsufyani Manar Hassan , Alghoribi Manayer Hammad , Bin Salman Thekra Omar , Alrabie Asma Fayez , Alotaibi Ibtihal Saud , Kharbosh Abdullah Mosa , Alsheikh Mona Yaser , Alshahrani Ali Mofleh , Fathelrahman Ahmed Ibrahim
Published: June 2023

Background: The aim of the present study was to understand hospital pharmacists’ views and practices regarding generic substitution and therapeutic interchange. Method: This was a qualitative study involving pharmacists from three Western Saudi governorates: Taif, Makkah, and Jeddah. It included respondents from the Ministry of Health (MoH), military and private hospitals. Pharmacists were selected using a convenient sampling technique and data were collected using a structured face-to-face interview. Results: Fifty-seven pharmacists agreed to participate in this study. In MoH and private hospitals, generic substitution is a pharmacist-initiated act, while therapeutic interchange requires physician approval. Medication unavailability, side effects, patient characteristics, outcomes, and economic status justified most substitution decisions. In military hospitals, both types of substitutions are controlled by an auto-switch policy and physicians should be informed. In all hospitals, there are policies regulating substitution. Medications eligible for interchange mentioned by pharmacists from different hospitals were comparable to some extent. Pharmacists from the private sector considered substitution a supportive economic measure for both hospitals and patients. Most pharmacists highlighted that patient convenience and physician approval are the most challenging situations in substitution practice. Conclusions: An enhanced understanding of substitution and knowledge about medications included in the hospital formulary will be valuable support to the implementation of substitution practice which responds to the patients’ needs to improve their outcomes.
Anomaly Detection in Endemic Disease Surveillance Data Using Machine Learning Techniques
Authors: Eze Peter U. , Geard Nicholas , Mueller Ivo , Chades Iadine
Published: June 2023

Disease surveillance is used to monitor ongoing control activities, detect early outbreaks, and inform intervention priorities and policies. However, data from disease surveillance that could be used to support real-time decisionmaking remain largely underutilised. Using the Brazilian Amazon malaria surveillance dataset as a case study, in this paper we explore the potential for unsupervised anomaly detection machine learning techniques to discover signals of epidemiological interest. We found that our models were able to provide an early indication of outbreak onset, outbreak peaks, and change points in the proportion of positive malaria cases. Specifically, the sustained rise in malaria in the Brazilian Amazon in 2016 was flagged by several models. We found that no single model detected all anomalies across all health regions. Because of this, we provide the minimum number of machine learning models top-k models) to maximise the number of anomalies detected across different health regions. We discovered that the top three models that maximise the coverage of the number and types of anomalies detected across the thirteen health regions are principal component analysis, stochastic outlier selection, and the minimum covariance determinant. Anomaly detection is a potentially valuable approach to discovering patterns of epidemiological importance when confronted with a large volume of data across space and time. Our exploratory approach can be replicated for other diseases and locations to inform monitoring, timely interventions, and actions towards the goal of controlling endemic disease.
Enhancing Anna Apples’ Productivity, Physico-Chemical Properties, and Marketability Using Sprays of Naphthalene Acetic Acid and Inhibitors of Ethylene for Alleviating Abiotic Stresses
Authors: Abdel-Sattar Mahmoud , Al-Obeed Rashid S. , Lisek Anna , Eshra Dalia H.
Published: June 2023

In order to improve the resistance of apples to stresses (abiotic stresses) during hot and dry summers to enhance their productivity and marketability, Anna apple trees were treated with aminoethoxyvinylglycine (AVG), 1-methlcyclopropene (1-MCP), and naphthalene acetic acid (NAA), alone, or in combination, in two successive seasons. All treatments significantly increased the yield per tree, the average fruit volume, fruit diameter, and fruit weight compared to the control (growing under hot and dry summers without any treatments). All treatments significantly reduced the apple size, total soluble solid (TSS) content, anthocyanin content, carotenoid content, total sugar solids, and sugar percentage, and they led to fruit softening, loss of fruit weight, firmness, breakdown percentage, as well as a decreased polyphenol oxidase and peroxidase activity at one-week post-harvest (except for 20-ppm NAA) in comparison with the control. Trees treated with 320-ppm 1-MCP + 250-ppm AVG exhibited maximum yield per tree, fruit firmness, and no-reducing sugars or starch. On the other hand, the 20-ppm NAA produced the maximum TSS content, total sugars, with a reduced sugar percentage, carotenoid and anthocyanin fruit content, and (TSS)/acidity ratio. The application of 320-ppm 1-MCP + 250-ppm AVG effectively delayed the harvest for 14 days compared to the control. Our results show that the sprays of NAA and inhibitors of ethylene had a significant effect on the productivity and marketability of Anna apples under abiotic stresses.
A Review of the Relationship between Socioeconomic Status Change and Health
Authors: Barakat Caroline , Konstantinidis Theodore
Published: June 2023

Objectives: This review aimed to identify and synthesize the existing literature on the effects of socioeconomic status (SES) changes on health. Methods: A review was conducted using Medline, Cochrane library, and CINAHL (Cumulative Index to Nursing and Allied Health Literature). All longitudinal or cross-sectional studies that examined links between changes to SES across different time periods and measured health outcomes were included. Screening was conducted using select inclusion and exclusion criteria in order of title, abstract, and full text. Two independent reviewers assessed the quality of the full text articles using the Downs and Black checklist. Results: Our literature search led to 2719 peer reviewed articles, 2639 of which were title screened after duplicates were removed. A total of 117 abstracts and 12 full text articles were screened. Overall, findings from 11 articles form the basis of this review. Eight different types of measures of changes to SES were identified. These include education, occupation, economic security, income sufficiency, home ownership, car ownership, health insurance, and marital status. Assessed outcomes included measures related to physical health, cardiovascular disease, mental health, and oral health. A large proportion of studies found that an SES change impacts health. Evidence suggests that those with consistently high SES have the best health outcomes, followed by those who report their SES change from low to high (upward social mobility). Evidence on the relative health effects for those who report their SES change from high to low (downward social mobility) compared to those who report consistently low SES is inconsistent. Conclusion: Current evidence suggests that an SES change has an impact on an individual’s health. More research on the effects of SES changes on health outcomes in adulthood is needed and can inform various areas of health research including health resiliency and development. Future studies should focus on individual SES indicators and their effects on health outcomes at multiple points throughout life.
Coexistence of Anaemia and Stunting among Children Aged 6–59 Months in Ethiopia: Findings from the Nationally Representative Cross-Sectional Study
Authors: Sahiledengle Biniyam , Mwanri Lillian , Petrucka Pammla , Agho Kingsley Emwinyore
Published: June 2023

Introduction: Stunting and anaemia, two severe public health problems, affect a significant number of children under the age of five. To date, the burden of and predictive factors for coexisting forms of stunting and anaemia in childhood have not been well documented in Ethiopia, where both the conditions are endemic. The primary aims of the present study were to: (i) determine the prevalence of co-morbid anaemia and stunting (CAS); (ii) and identify factors associated with these co-morbid conditions among children aged 6–59 months in Ethiopia. Methods: The study was based on data from the Ethiopian Demographic and Health Survey (EDHS 2005–2016). The EDHS was a cross-sectional study that used a two-stage stratified cluster sampling technique to select households. A total weighted sample of 21,172 children aged 6–59 months was included in the current study (EDHS-2005 (n = 3898), EDHS-2011 (n = 8943), and EDHS-2016 (n = 8332)). Children with height-for-age z-scores (HAZ) less than −2 SD were classified as stunted. Anaemia status was measured by haemoglobin level with readings below 11.0 g/deciliter (g/dL) categorized as anaemic. A multilevel mixed-effects logistic regression model was used to identify the factors associated with CAS. The findings from the models were reported as adjusted odds ratios (AOR) with 95% confidence intervals (CIs). Results: Almost half of the children were males (51.1%) and the majority were from rural areas (89.2%). The prevalence of CAS was 24.4% [95% CI: (23.8–24.9)]. Multivariate analyses revealed that children aged 12–23 months, 24–35 months, and 36–59 months, and children perceived by their mothers to be smaller than normal at birth had higher odds of CAS. The odds of CAS were significantly higher among children born to anaemic mothers [AOR: 1.25, 95% CI: (1.11–1.41)], mothers with very short stature [AOR: 2.04, 95% CI: (1.44–2.91)], children from households which practiced open defecation [AOR: 1.57, 95% CI: (1.27–1.92)], children born to mothers without education [AOR: 3.66, 95% CI: (1.85–7.22)], and those who reside in rural areas [AOR: 1.41, 95% CI: (1.10, 1.82)]. Male children had 19% lower odds of having CAS compared to female children [AOR: 0.81, 95% CI: (0.73–0.91)]. Children born to mothers who had normal body mass index (BMI) [AOR: 0.82, 95%CI: (0.73–0.92)] reported lower odds of CAS. Conclusions: One in four preschool-age children in Ethiopia had co-morbid anaemia and stunting, which is a significant public health problem. Future interventions to reduce CAS in Ethiopia should target those children perceived to be small at birth, anaemic mothers, and mothers with short stature.
Depressive and Anxiety Disorders in Patients with Inflammatory Bowel Diseases: Are There Any Gender Differences?
Authors: Fracas Elia , Costantino Andrea , Vecchi Maurizio , Buoli Massimiliano
Published: June 2023

Gender differences were identified in the frequency and clinical presentations of inflammatory bowel disease (IBD) and depressive and anxiety disorders, which are more common in IBD patients than in the general population. The present manuscript provides a critical overview of gender differences in the frequency and clinical course of mood and anxiety disorders in IBD patients, with the aim of helping clinicians provide individualized management for patients. All of the included studies found that IBD patients reported a higher frequency of depressive and anxiety disorders than the general population. These findings should encourage healthcare providers to employ validated tools to monitor the mental health of their IBD patients, such as the Patient Health Questionnaire (PHQ-9). In addition, most studies confirm that women with IBD are more likely than men to develop affective disorders and show that up to 65% of women with IBD have depressive and anxiety disorders. Women with IBD require close mental health monitoring and ultimately a multidisciplinary approach involving mental health professionals. Drug treatment in women should be individualized and medications that may affect mental health (e.g., corticosteroids) should be thoroughly reconsidered. Further data are needed to ensure individualized treatment for IBD patients in a framework of precision medicine.
Surgical Management, Prevention and Outcomes for Aneurysms of Arteriovenous Dialysis Fistulas: A Case Series Study and Review
Authors: Płoński Adam , Płoński Adam Filip , Głowiński Jerzy
Published: June 2023

The escalating population of individuals afflicted with end-stage renal disease necessitates the provision of secure and efficacious vascular access for hemodialysis, with arteriovenous fistulas representing a preferred option. Nonetheless, the creation of dialysis fistulas may entail complications, including the occurrence of fistula aneurysms that may require surgical intervention. This study included eight patients with large aneurysms of dialysis fistulas and aimed to evaluate the safety and effectiveness of classic, endovascular, or hybrid methods for fistula reconstruction or ligation, depending on the indications. Vascular interventions were performed on patients on chronic hemodialysis and on those in whom hemodialysis was discontinued due to the proper functioning of the transplanted kidney. Performed procedures were considered safe and effective. The reconstructed fistulas provided the patients with patent vascular access, allowing for continued hemodialysis. No re-aneurysmal dilatation of the reconstructed or ligated fistulas was observed. Regular monitoring of dialysis fistulas is crucial to detect complications in time. Guidelines should be established to specify the dimensions at which fistula aneurysm should be excised and whether to remove asymptomatic aneurysms at all. For patients who have undergone kidney transplantation, outlines should indicate when the fistula should be preserved and when it should be ligated.
Trending Occupational Fatalities and Injuries: An Assessment of Projected Climate Change Related Impacts in the United States since 1992
Authors: Mullins-Jaime Charmaine
Published: June 2023

Background: Some impacts of climate change that are expected to affect the American workforce are rising temperatures, greater prevalence of wildland fires, increase in Lyme disease, and exposure to insecticides. The purpose of this study was to assess how fatal and non-fatal occupational injuries due to environmental heat, forest/brush fires, Lyme disease, and exposure to insecticides have changed over time in the United States and if there were any significant relationships between national occupational injury/illness data and national temperature trends. Methods: Linear regression models assessed fatal and non-fatal injuries/illnesses since 1992 by both the frequency of incidents and the proportion of total incidents and the effects of national average temperatures. Results: There were significant increases in occupational fatalities and illnesses due to exposure to environmental heat and national average annual temperatures were predictive of heat exposure fatalities and illnesses. Conclusion: Heat exposure is an occupational hazard that must be managed carefully in the coming years. Organizations will need to take more aggressive heat exposure control measures as temperatures continue to rise and remain hotter for longer periods during the year. While not currently showing increasing trends on a national scale, the prevalence of occupational incidents due to forest/brush fires, Lyme disease, and insecticides should be monitored as the United States experiences more of the projected impacts of climate change.
Sex Differences in Sphingosine-1-Phosphate Levels Are Dependent on Ceramide Synthase 1 and Ceramidase in Lung Physiology and Tumor Conditions
Authors: Terlizzi Michela , Colarusso Chiara , Ferraro Giusy , Falanga Anna , Monti Maria Chiara , Somma Pasquale , De Rosa Ilaria , Panico Luigi , Pinto Aldo , Sorrentino Rosalinda
Published: June 2023

Sex is a biological variable that can reflect clinical outcomes in terms of quality of life, therapy effectiveness, responsiveness and/or toxicity. Sphingosine-1-phosphate (S1P) is a lipidic mediator whose activity can be influenced by sex. To evaluate whether the S1P axis underlies sex ‘instructions’ in the lung during physiological and oncological lung conditions, sphingosine and S1P were quantified in the blood of healthy (H) volunteers, lung adenocarcinoma (ADK) and squamous cell carcinoma (SCC) patients of both sexes. S1P receptors and their metabolic enzymes were evaluated in the tissues. Circulating levels of S1P were similar among H female and male subjects and female SCC patients. Instead, male and female ADK patients had lower circulating S1P levels. S1P receptor 3 (S1PR3) was physiologically expressed in the lung, but it was overexpressed in male SCC, and female and male ADK, but not in female SCC patients, who showed a significantly reduced ceramide synthase 1 (CERS1) mRNA and an overexpression of the ceramidase (ASAH1) precursor in lung tumor tissues, compared to male SCC and both male and female ADK patients. These findings highlighted sex differences in S1P rheostat in pathological conditions, but not in physiological conditions, identifying S1P as a prognostic mediator depending on lung cancer histotype.
Transcriptional and Histone Acetylation Changes Associated with CRE Elements Expose Key Factors Governing the Regulatory Circuit in the Early Stage of Huntington’s Disease Models
Authors: Arancibia-Opazo Sandra , Contreras-Riquelme J. Sebastián , Sánchez Mario , Cisternas-Olmedo Marisol , Vidal René L. , Martin Alberto J. M. , Sáez Mauricio A.
Published: June 2023

Huntington’s disease (HD) is a disorder caused by an abnormal expansion of trinucleotide CAG repeats within the huntingtin (Htt) gene. Under normal conditions, the CREB Binding Protein interacts with CREB elements and acetylates Lysine 27 of Histone 3 to direct the expression of several genes. However, mutant Htt causes depletion of CBP, which in turn induces altered histone acetylation patterns and transcriptional deregulation. Here, we have studied a differential expression analysis and H3K27ac variation in 4- and 6-week-old R6/2 mice as a model of juvenile HD. The analysis of differential gene expression and acetylation levels were integrated into Gene Regulatory Networks revealing key regulators involved in the altered transcription cascade. Our results show changes in acetylation and gene expression levels that are related to impaired neuronal development, and key regulators clearly defined in 6-week-old mice are proposed to drive the downstream regulatory cascade in HD. Here, we describe the first approach to determine the relationship among epigenetic changes in the early stages of HD. We determined the existence of changes in pre-symptomatic stages of HD as a starting point for early onset indicators of the progression of this disease.
Comparative Analysis of Water Extracts from Roselle (Hibiscus sabdariffa L.) Plants and Callus Cells: Constituents, Effects on Human Skin Cells, and Transcriptome Profiles
Authors: Cho Won Kyong , Kim Soo-Yun , Jang Sung Joo , Lee Sak , Kim Hye-In , Kim Euihyun , Lee Jeong Hun , Choi Sung Soo , Moh Sang Hyun
Published: June 2023

Roselle (Hibiscus sabdariffa L.) is a plant that has traditionally been used in various food and beverage products. Here, we investigated the potential of water extracts derived from Roselle leaves and callus cells for cosmetic and pharmaceutical purposes. We generated calluses from Roselle leaves and produced two different water extracts through heat extraction, which we named Hibiscus sabdariffa plant extract (HSPE) and Hibiscus sabdariffa callus extract (HSCE). HPLC analysis showed that the two extracts have different components, with nucleic acids and metabolites such as phenylalanine and tryptophan being the most common components in both extracts. In vitro assays demonstrated that HSCE has strong anti-melanogenic effects and functions for skin barrier and antioxidant activity. Transcriptome profiling of human skin cells treated with HSPE and HSCE showed significant differences, with HSPE having more effects on human skin cells. Up-regulated genes by HSPE function in angiogenesis, the oxidation-reduction process, and glycolysis, while up-regulated genes by HSCE encode ribosome proteins and IFI6, functioning in the healing of radiation-injured skin cells. Therefore, we suggest that the two extracts from Roselle should be applied differently for cosmetics and pharmaceutical purposes. Our findings demonstrate the potential of Roselle extracts as a natural source for skincare products.
Advances in Idiosyncratic Drug-Induced Liver Injury Issues: New Clinical and Mechanistic Analysis Due to Roussel Uclaf Causality Assessment Method Use
Authors: Teschke Rolf , Danan Gaby
Published: June 2023

Clinical and mechanistic considerations in idiosyncratic drug-induced liver injury (iDILI) remain challenging topics when they are derived from mere case narratives or iDILI cases without valid diagnosis. To overcome these issues, attempts should be made on pathogenetic aspects based on published clinical iDILI cases firmly diagnosed by the original RUCAM (Roussel Uclaf Causality Assessment Method) or the RUCAM version updated in 2016. Analysis of RUCAM-based iDILI cases allowed for evaluating immune and genetic data obtained from the serum and the liver of affected patients. For instance, strong evidence for immune reactions in the liver of patients with RUCAM-based iDILI was provided by the detection of serum anti-CYP 2E1 due to drugs like volatile anesthetics sevoflurane and desflurane, partially associated with the formation of trifluoroacetyl (TFA) halide as toxic intermediates that form protein adducts and may generate reactive oxygen species (ROS). This is accompanied by production of anti-TFA antibodies detected in the serum of these patients. Other RUCAM-based studies on serum ANA (anti-nuclear antibodies) and SMA (anti-smooth muscle antibodies) associated with AIDILI (autoimmune DILI) syn DIAIH (drug-induced autoimmune hepatitis) provide additional evidence of immunological reactions with monocytes as one of several promoting immune cells. In addition, in the blood plasma of patients, mediators like the cytokines IL-22, IL-22 binding protein (IL-22BP), IL-6, IL-10, IL 12p70, IL-17A, IL-23, IP-10, or chemokines such as CD206 and sCD163 were found in DILI due to anti-tuberculosis drugs as ascertained by the prospective updated RUCAM, which scored a high causality. RUCAM-based analysis also provided compelling evidence of genetic factors such as HLA (human leucocyte antigen) alleles contributing to initiate iDILI by a few drugs. In conclusion, analysis of published RUCAM-based iDILI cases provided firm evidence of immune and genetic processes involved in iDILI caused by specific drugs.
Cisplatin in Liver Cancer Therapy
Authors: Hamaya Sae , Oura Kyoko , Morishita Asahiro , Masaki Tsutomu
Published: June 2023

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and is often diagnosed at an unresectable advanced stage. Systemic chemotherapy as well as transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) are used to treat advanced HCC. TACE and HAIC have long been the standard of care for patients with unresectable HCC but are limited to the treatment of intrahepatic lesions. Systemic chemotherapy with doxorubicin or chemohormonal therapy with tamoxifen have also been considered, but neither has demonstrated survival benefits. In the treatment of unresectable advanced HCC, cisplatin is administered transhepatic arterially for local treatment. Subsequently, for cisplatin-refractory cases due to drug resistance, a shift to systemic therapy with a different mechanism of action is expected to produce new antitumor effects. Cisplatin is also used for the treatment of liver tumors other than HCC. This review summarizes the action and resistance mechanism of cisplatin and describes the treatment of the major hepatobiliary cancers for which cisplatin is used as an anticancer agent, with a focus on HCC.
Osteocytes Exposed to Titanium Particles Inhibit Osteoblastic Cell Differentiation via Connexin 43
Authors: Chai Hao , Huang Qun , Jiao Zixue , Wang Shendong , Sun Chunguang , Geng Dechun , Xu Wei
Published: June 2023

Periprosthetic osteolysis (PPO) induced by wear particles is the most severe complication of total joint replacement; however, the mechanism behind PPO remains elusive. Previous studies have shown that osteocytes play important roles in wear-particle-induced osteolysis. In this study, we investigated the effects of connexin 43 (Cx43) on the regulation of osteocyte-to-osteoblast differentiation. We established an in vivo murine model of calvarial osteolysis induced by titanium (Ti) particles. The osteolysis characteristic and osteogenesis markers in the osteocyte-selective Cx43 (CKO)-deficient and wild-type (WT) mice were observed. The calvarial osteolysis induced by Ti particles was partially attenuated in CKO mice. The expression of β-catenin and osteogenesis markers increased significantly in CKO mice. In vitro, the osteocytic cell line MLO-Y4 was treated with Ti particles. The co-culturing of MLO-Y4 cells with MC3T3-E1 osteoblastic cells was used to observe the effects of Ti-treated osteocytes on osteoblast differentiation. When Cx43 of MLO-Y4 cells was silenced or overexpressed, β-catenin was detected. Additionally, co-immunoprecipitation detection of Cx43 and β-catenin binding in MLO-Y4 cells and MC3T3-E1 cells was performed. Finally, β-catenin expression in MC3T3-E1 cells and osteoblast differentiation were evaluated after 18α-glycyrrhetinic acid (18α-GA) was used to block the intercellular communication of Cx43 between MLO-Y4 and MC3T3-E1 cells. Ti particles increased Cx43 expression and decreased β-catenin expression in MLO-Y4 cells. The silencing of Cx43 increased the β-catenin expression, and the over-expression of Cx43 decreased the β-catenin expression. In the co-culture model, Ti treatment of MLO-Y4 cells inhibited the osteoblastic differentiation of MC3T3-E1 cells and Cx43 silencing in MLO-Y4 cells attenuated the inhibitory effects on osteoblastic differentiation. With Cx43 silencing in the MLO-Y4 cells, the MC3T3-E1 cells, co-cultured alongside MLO-Y4, displayed decreased Cx43 expression, increased β-catenin expression, activation of Runx2, and promotion of osteoblastic differentiation in vitro co-culture. Finally, Cx43 expression was found to be negatively correlated to the activity of the Wnt signaling pathway, mostly through the Cx43 binding of β-catenin from its translocation to the nucleus. The results of our study suggest that Ti particles increased Cx43 expression in osteocytes and that osteocytes may participate in the regulation of osteoblast function via the Cx43 during PPO.
Diverse Sphingolipid Profiles in Rectal and Colon Cancer
Authors: Markowski Adam R. , Błachnio-Zabielska Agnieszka U. , Pogodzińska Karolina , Markowska Anna J. , Zabielski Piotr
Published: June 2023

Colorectal cancer is a heterogenous group of neoplasms showing a variety of clinical and pathological features depending on their anatomical location. Sphingolipids are involved in the formation and progression of cancers, and their changes are an important part of the abnormalities observed during carcinogenesis. Because the course of rectal and colonic cancer differs, the aim of the study was to assess whether the sphingolipid profile is also different in tumors of these two regions. Using a combination of ultra-high-performance liquid chromatography combined with triple quadrupole mass spectrometry, differences in the amounts of cellular sphingolipids were found in colorectal cancer. Sphingosine content was higher in rectal cancer than in adjacent healthy tissue, while the content of two ceramides (C18:0-Cer and C20:0-Cer) was lower. In colon cancer, a higher content of sphingosine, sphinganine, sphingosine-1-phosphate, and two ceramides (C14:0-Cer and C24:0-Cer) was found compared to healthy tissue, but there was no decrease in the amount of any of the assessed sphingolipids. In rectal cancer, the content of sphinganine and three ceramides (C16:0-Cer, C22:0-Cer, C24:0-Cer), as well as the entire pool of ceramides, was significantly lower compared to colon cancer. The S1P/Cer ratio in rectal cancer (S1P/C18:1-Cer, S1P/C20:0-Cer, S1P/C22:0-Cer, S1P/C24:1-Cer) and in colon cancer (S1P/C18:0-Cer, S1P/C18:1-Cer, S1P/C20:0-Cer) was higher than in adjacent healthy tissue and did not differ between the two sites (rectal cancer vs. colonic cancer). It seems that the development of colorectal cancer is accompanied by complex changes in the metabolism of sphingolipids, causing not only qualitative shifts in the ceramide pool of cancer tissue but also quantitative disturbances, depending on the location of the primary tumor.
Chicken Cartilage-Derived Carbon for Efficient Xylene Removal
Authors: Dobrzyńska Joanna , Jankovská Zuzana , Matějová Lenka
Published: June 2023

Chicken cartilage was used for the first time as a raw material for the microwave-assisted synthesis of biochar and activated carbon. Various microwave absorbers, i.e., commercial active carbon, scrap tyres, silicon carbide, and chicken bone-derived biochar, as well as various microwave powers, were tested for their effect on the rate of pyrolysis and the type of products formed. Biochars synthesised under 400 W in the presence of scrap tyres and chicken bone-derived biochar were activated with KOH and K2CO3 with detergent to produce activated carbon with a highly developed porous structure that would be able to effectively adsorb xylene vapours. All carbons were thoroughly characterised (infrared spectroscopy, X-ray fluorescence spectrometry, nitrogen adsorption/desorption, Raman spectroscopy, proximate and ultimate analysis) and tested as xylene sorbents in dynamic systems. It was found that the activation causes an increase of up to 1042 m2·g−1 in the specific surface area, which ensures the sorption capacity of xylene about 300 mg·g−1. Studies of the composition of biogas emitted during pyrolysis revealed that particularly valuable gaseous products are formed when pyrolysis is carried out in the presence of silicon carbide as a microwave absorber.
Regulatory Cues in Pulmonary Fibrosis—With Emphasis on the AIM2 Inflammasome
Authors: Tseng Yu-Hsin , Chen I-Chen , Li Wan-Chun , Hsu Jong-Hau
Published: June 2023

Pulmonary fibrosis (PF) is a chronic lung disorder characterized by the presence of scarred and thickened lung tissues. Although the Food and Drug Administration approved two antifibrotic drugs, pirfenidone, and nintedanib, that are currently utilized for treating idiopathic PF (IPF), the clinical therapeutic efficacy remains unsatisfactory. It is crucial to develop new drugs or treatment schemes that combine pirfenidone or nintedanib to achieve more effective outcomes for PF patients. Understanding the complex mechanisms underlying PF could potentially facilitate drug discovery. Previous studies have found that the activation of inflammasomes, including nucleotide-binding and oligomerization domain (NOD)-like receptor protein (NLRP)1, NLRP3, NOD-like receptor C4, and absent in melanoma (AIM)2, contributes to lung inflammation and fibrosis. This article aims to summarize the cellular and molecular regulatory cues that contribute to PF with a particular emphasis on the role of AIM2 inflammasome in mediating pathophysiologic events during PF development. The insights gained from this research may pave the way for the development of more effective strategies for the prevention and treatment of PF.
Bypass of Abasic Site–Peptide Cross-Links by Human Repair and Translesion DNA Polymerases
Authors: Yudkina Anna V. , Barmatov Alexander E. , Bulgakov Nikita A. , Boldinova Elizaveta O. , Shilkin Evgeniy S. , Makarova Alena V. , Zharkov Dmitry O.
Published: June 2023

DNA–protein cross-links remain the least-studied type of DNA damage. Recently, their repair was shown to involve proteolysis; however, the fate of the peptide remnant attached to DNA is unclear. Particularly, peptide cross-links could interfere with DNA polymerases. Apurinuic/apyrimidinic (AP) sites, abundant and spontaneously arising DNA lesions, readily form cross-links with proteins. Their degradation products (AP site–peptide cross-links, APPXLs) are non-instructive and should be even more problematic for polymerases. Here, we address the ability of human DNA polymerases involved in DNA repair and translesion synthesis (POLβ, POLλ, POLη, POLκ and PrimPOL) to carry out synthesis on templates containing AP sites cross-linked to the N-terminus of a 10-mer peptide (APPXL-I) or to an internal lysine of a 23-mer peptide (APPXL-Y). Generally, APPXLs strongly blocked processive DNA synthesis. The blocking properties of APPXL-I were comparable with those of an AP site, while APPXL-Y constituted a much stronger obstruction. POLη and POLκ demonstrated the highest bypass ability. DNA polymerases mostly used dNTP-stabilized template misalignment to incorporate nucleotides when encountering an APPXL. We conclude that APPXLs are likely highly cytotoxic and mutagenic intermediates of AP site–protein cross-link repair and must be quickly eliminated before replication.
Identification of a Gene Signature Predicting (Nano)Particle-Induced Adverse Lung Outcome in Rats
Authors: Valentino Sarah Amandine , Seidel Carole , Lorcin Mylène , Sébillaud Sylvie , Wolff Henrik , Grossmann Stéphane , Viton Stéphane , Nunge Hervé , Saarimäki Laura Aliisa , Greco Dario , Cosnier Frédéric , Gaté Laurent
Published: June 2023

Nanoparticles are extensively used in industrial products or as food additives. However, despite their contribution to improving our quality of life, concerns have been raised regarding their potential impact on occupational and public health. To speed up research assessing nanoparticle-related hazards, this study was undertaken to identify early markers of harmful effects on the lungs. Female Sprague Dawley rats were either exposed to crystalline silica DQ-12 with instillation, or to titanium dioxide P25, carbon black Printex-90, or multi-walled carbon nanotube Mitsui-7 with nose-only inhalation. Tissues were collected at three post-exposure time points to assess short- and long-term effects. All particles induced lung inflammation. Histopathological and biochemical analyses revealed phospholipid accumulation, lipoproteinosis, and interstitial thickening with collagen deposition after exposure to DQ-12. Exposure to the highest dose of Printex-90 and Mitsui-7, but not P25, induced some phospholipid accumulation. Comparable histopathological changes were observed following exposure to P25, Printex-90, and Mitsui-7. Comparison of overall gene expression profiles identified 15 potential early markers of adverse lung outcomes induced by spherical particles. With Mitsui-7, a distinct gene expression signature was observed, suggesting that carbon nanotubes trigger different toxicity mechanisms to spherical particles.
TRIM21 Promotes Rabies Virus Production by Degrading IRF7 through Ubiquitination
Authors: Zhang Boyue , Cai Ting , He Hongling , Huang Xuezhe , Chen Guie , Lai Yanqin , Luo Yongwen , Huang Shile , Luo Jun , Guo Xiaofeng
Published: June 2023

Rabies, a highly fatal zoonotic disease, is a significant global public health threat. Currently, the pathogenic mechanism of rabies has not been fully elucidated, and no effective treatment for rabies is available. Increasing evidence shows that the tripartite-motif protein (TRIM) family of proteins participates in the host’s regulation of viral replication. Studies have demonstrated the upregulated expression of tripartite-motif protein 21 (TRIM21) in the brain tissue of mice infected with the rabies virus. Related studies have shown that TRIM21 knockdown inhibits RABV replication, while overexpression of TRIM21 exerted the opposite effect. Knockdown of interferon-alpha and interferon-beta modulates the inhibition of RABV replication caused by TRIM21 knockdown and promotes the replication of the virus. Furthermore, our previous study revealed that TRIM21 regulates the secretion of type I interferon during RABV infection by targeting interferon regulatory factor 7 (IRF7). IRF7 knockdown reduced the inhibition of RABV replication caused by the knockdown of TRIM21 and promoted viral replication. TRIM21 regulates RABV replication via the IRF7-IFN axis. Our study identified TRIM21 as a novel host factor required by RABV for replication. Thus, TRIM21 is a potential target for rabies treatment or management.
Untangling Macropore Formation and Current Facilitation in P2X7
Authors: Cevoli Federico , Arnould Benoit , Peralta Francisco Andrés , Grutter Thomas
Published: June 2023

Macropore formation and current facilitation are intriguing phenomena associated with ATP-gated P2X7 receptors (P2X7). Macropores are large pores formed in the cell membrane that allow the passage of large molecules. The precise mechanisms underlying macropore formation remain poorly understood, but recent evidence suggests two alternative pathways: a direct entry through the P2X7 pore itself, and an indirect pathway triggered by P2X7 activation involving additional proteins, such as TMEM16F channel/scramblase. On the other hand, current facilitation refers to the progressive increase in current amplitude and activation kinetics observed with prolonged or repetitive exposure to ATP. Various mechanisms, including the activation of chloride channels and intrinsic properties of P2X7, have been proposed to explain this phenomenon. In this comprehensive review, we present an in-depth overview of P2X7 current facilitation and macropore formation, highlighting new findings and proposing mechanistic models that may offer fresh insights into these untangled processes.
Loss of IP3R-BKCa Coupling Is Involved in Vascular Remodeling in Spontaneously Hypertensive Rats
Authors: Niloy Sayeman Islam , Shen Yue , Guo Lirong , O’Rourke Stephen T. , Sun Chengwen
Published: June 2023

Mechanisms by which BKCa (large-conductance calcium-sensitive potassium) channels are involved in vascular remodeling in hypertension are not fully understood. Vascular smooth muscle cell (VSMC) proliferation and vascular morphology were compared between hypertensive and normotensive rats. BKCa channel activity, protein expression, and interaction with IP3R (inositol 1,4,5-trisphosphate receptor) were examined using patch clamp, Western blot analysis, and coimmunoprecipitation. On inside-out patches of VSMCs, the Ca2+-sensitivity and voltage-dependence of BKCa channels were similar between hypertensive and normotensive rats. In whole-cell patch clamp configuration, treatment of cells with the IP3R agonist, Adenophostin A (AdA), significantly increased BKCa channel currents in VSMCs of both strains of rats, suggesting IP3R-BKCa coupling; however, the AdA-induced increases in BKCa currents were attenuated in VSMCs of hypertensive rats, indicating possible IP3R-BKCa decoupling, causing BKCa dysfunction. Co-immunoprecipitation and Western blot analysis demonstrated that BKCa and IP3R proteins were associated together in VSMCs; however, the association of BKCa and IP3R proteins was dramatically reduced in VSMCs of hypertensive rats. Genetic disruption of IP3R-BKCa coupling using junctophilin-2 shRNA dramatically augmented Ang II-induced proliferation in VSMCs of normotensive rats. Subcutaneous infusion of NS1619, a BKCa opener, to reverse BKCa dysfunction caused by IP3R-BKCa decoupling significantly attenuated vascular hypertrophy in hypertensive rats. In summary, the data from this study demonstrate that loss of IP3R-BKCa coupling in VSMCs induces BKCa channel dysfunction, enhances VSMC proliferation, and thus, may contribute to vascular hypertrophy in hypertension.
Chemokine Heteromers and Their Impact on Cellular Function—A Conceptual Framework
Authors: Blanchet Xavier , Weber Christian , von Hundelshausen Philipp
Published: June 2023

Chemoattractant cytokines or chemokines are proteins involved in numerous biological activities. Their essential role consists of the formation of gradient and (immune) cell recruitment. Chemokine biology and its related signaling system is more complex than simple ligand–receptor interactions. Beside interactions with their cognate and/or atypical chemokine receptors, and glycosaminoglycans (GAGs), chemokines form complexes with themselves as homo-oligomers, heteromers and also with other soluble effector proteins, including the atypical chemokine MIF, carbohydrate-binding proteins (galectins), damage-associated molecular patterns (DAMPs) or with chemokine-binding proteins such as evasins. Likewise, nucleic acids have been described as binding targets for the tetrameric form of CXCL4. The dynamic balance between monomeric and dimeric structures, as well as interactions with GAGs, modulate the concentrations of free chemokines available along with the nature of the gradient. Dimerization of chemokines changes the canonical monomeric fold into two main dimeric structures, namely CC- and CXC-type dimers. Recent studies highlighted that chemokine dimer formation is a frequent event that could occur under pathophysiological conditions. The structural changes dictated by chemokine dimerization confer additional biological activities, e.g., biased signaling. The present review will provide a short overview of the known functionality of chemokines together with the consequences of the interactions engaged by the chemokines with other proteins. Finally, we will present potential therapeutic tools targeting the chemokine multimeric structures that could modulate their biological functions.
ATO Increases ROS Production and Apoptosis of Cells by Enhancing Calpain-Mediated Degradation of the Cancer Survival Protein TG2
Authors: Jambrovics Károly , Póliska Szilárd , Scholtz Beáta , Uray Iván P. , Balajthy Zoltán
Published: June 2023

Transglutaminase 2 (TG2) is a critical cancer cell survival factor that activates several signalling pathways to foster drug resistance, cancer stem cell survival, metastasis, inflammation, epithelial-mesenchymal transition, and angiogenesis. All-trans retinoic acid (ATRA) and chemotherapy have been the standard treatments for acute promyelocytic leukaemia (APL), but clinical studies have shown that arsenic trioxide (ATO), alone or in combination with ATRA, can improve outcomes. ATO exerts cytotoxic effects in a variety of ways by inducing oxidative stress, genotoxicity, altered signal transduction, and/or epigenetic modification. In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukaemia cells, and that these responses were enhanced when TG2 was deleted. The combined ATRA + ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of the cellular oxidative stress response, and calpain proteolytic activity, resulting in TG2 degradation and the reduced survival of WT leukaemia cells. We further showed that the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line and primary peripheral blood mononuclear cells upon ATO treatment, thereby sensitising these cell types to apoptotic signals.
Inhibition of Ferroptosis Enables Safe Rewarming of HEK293 Cells following Cooling in University of Wisconsin Cold Storage Solution
Authors: Gartzke Lucas P. , Hendriks Koen D. W. , Hoogstra-Berends Femke , Joschko Christian P. , Strandmoe Anne-Lise , Vogelaar Pieter C. , Krenning Guido , Henning Robert H.
Published: June 2023

The prolonged cooling of cells results in cell death, in which both apoptosis and ferroptosis have been implicated. Preservation solutions such as the University of Wisconsin Cold Storage Solution (UW) encompass approaches addressing both. The use of UW improves survival and thus extends preservation limits, yet it remains unclear how exactly organ preservation solutions exert their cold protection. Thus, we explored cooling effects on lipid peroxidation and adenosine triphosphate (ATP) levels and the actions of blockers of apoptosis and ferroptosis, and of compounds enhancing mitochondrial function. Cooling and rewarming experiments were performed in a cellular transplantation model using Human Embryonic Kidney (HEK) 293 cells. Cell viability was assessed by neutral red assay. Lipid peroxidation levels were measured by Western blot against 4-Hydroxy-Nonenal (4HNE) and the determination of Malondialdehyde (MDA). ATP was measured by luciferase assay. Cooling beyond 5 h in Dulbecco’s Modified Eagle Medium (DMEM) induced complete cell death in HEK293, whereas cooling in UW preserved ~60% of the cells, with a gradual decline afterwards. Cooling-induced cell death was not precluded by inhibiting apoptosis. In contrast, the blocking of ferroptosis by Ferrostatin-1 or maintaining of mitochondrial function by the 6-chromanol SUL150 completely inhibited cell death both in DMEM- and UW-cooled cells. Cooling for 24 h in UW followed by rewarming for 15 min induced a ~50% increase in MDA, while concomitantly lowering ATP by >90%. Treatment with SUL150 of cooled and rewarmed HEK293 effectively precluded the increase in MDA and preserved normal ATP in both DMEM- and UW-cooled cells. Likewise, treatment with Ferrostatin-1 blocked the MDA increase and preserved the ATP of rewarmed UW HEK293 cells. Cooling-induced HEK293 cell death from hypothermia and/or rewarming was caused by ferroptosis rather than apoptosis. UW slowed down ferroptosis during hypothermia, but lipid peroxidation and ATP depletion rapidly ensued upon rewarming, ultimately resulting in complete cell death. Treatment throughout UW cooling with small-molecule Ferrostatin-1 or the 6-chromanol SUL150 effectively prevented ferroptosis, maintained ATP, and limited lipid peroxidation in UW-cooled cells. Counteracting ferroptosis during cooling in UW-based preservation solutions may provide a simple method to improve graft survival following cold static cooling.