bluuebunny/crossref_metadata_2025 huggingface dataset:
Relevance of Dietary Supplement Use in Gastrointestinal-Cancer-Associated Cachexia
Authors: Yoon Saunjoo L. , Grundmann Oliver
Published: July 2023

Cancer cachexia is a multi-organ syndrome with unintentional weight loss, sarcopenia, and systemic inflammation. Gastrointestinal (GI) cancer patients are more susceptible to cachexia development due to impaired nutrient absorption and digestion. Given the widespread availability and relatively low cost of dietary supplements, we examined the evidence and effects of fish oil (omega-3 fatty acids), melatonin, probiotics, and green tea for managing symptoms of GI cancer cachexia. A literature review of four specific supplements was conducted using PubMed, Google Scholar, and CINAHL without a date restriction. Of 4621 available literature references, 26 articles were eligible for review. Fish oil decreased C-reactive protein and maintained CD4+ cell count, while melatonin indicated inconsistent findings on managing cachexia, but was well-tolerated. Probiotics decreased serum pro-inflammatory biomarkers and increased the tolerability of chemotherapy by reducing side effects. Green tea preparations and extracts showed a decreased risk of developing various cancers and did not impact tumor growth, survival, or adverse effects. Among these four supplements, probiotics are most promising for further research in preventing systemic inflammation and maintaining adequate absorption of nutrients to prevent the progression of cancer cachexia. Supplements may benefit treatment outcomes in cancer cachexia without side effects while supporting nutritional and therapeutic needs.
Vitamin D Deficiency in COVID-19 Patients and Role of Calcifediol Supplementation
Authors: Mingiano Christian , Picchioni Tommaso , Cavati Guido , Pirrotta Filippo , Calabrese Marco , Nuti Ranuccio , Gonnelli Stefano , Fortini Alberto , Frediani Bruno , Gennari Luigi , Merlotti Daniela
Published: July 2023

Hypovitaminosis D has been associated with worse outcome in respiratory tract infections, with conflicting opinions regarding its role in Coronavirus-19 disease (COVID-19). Our study aimed to evaluate the possible relationship between 25-OH vitamin D (25OHD) values and the following conditions in patients hospitalized for COVID-19: prognosis, mortality, invasive (IV) and non-invasive (NIV) mechanical ventilation, and orotracheal intubation (OTI). A further objective was the analysis of a possible positive effect of supplementation with calcifediol on COVID-19 severity and prognosis. We analyzed 288 patients hospitalized at the San Giovanni di Dio Hospital in Florence and the Santa Maria alle Scotte Hospital in Siena, from November 2020 to February 2021. The 25OHD levels correlated positively with the partial pressure of oxygen and FiO2 (PaO2/FiO2) ratio (r = 0.17; p < 0.05). Furthermore, when we analyzed the patients according to the type of respiratory support, we found that 25OHD levels were markedly reduced in patients who underwent non-invasive ventilation and orotracheal intubation (OTI). The evaluation of the length of hospitalization in our population evidenced a longer duration of hospitalization in patients with severe 25OHD deficiency (<10 ng/mL). Moreover, we found a statistically significant difference in the mortality rate between patients who had 25OHD levels below 10 ng/mL and those with levels above this threshold in the total population (50.8% vs. 25.5%, p = 0.005), as well as between patients with 25OHD levels below 20 ng/mL and those with levels above that threshold (38.4% vs. 24.6%, p = 0.04). Moreover, COVID-19 patients supplemented with calcifediol presented a significantly reduced length of hospitalization (p < 0.05). Interestingly, when we analyzed the possible effects of calcifediol on mortality rate in patients with COVID-19, we found that the percentage of deaths was significantly higher in patients who did not receive any supplementation than in those who were treated with calcifediol (p < 0.05) In conclusion, we have demonstrated with our study the best prognosis of COVID-19 patients with adequate vitamin D levels and patients treated with calcifediol supplementation.
The Association of Carbohydrate Antigen (CA) 19-9 Levels and Low Skeletal Muscle Mass in Healthy Adults
Authors: Lee Jae Hyun , Kim Dong-Kun , Lee Mi-Yeon , Lim Han-Sol , Kwon Min-Jung , Lee Yong-Taek , Yoon Kyung Jae , Park Chul-Hyun
Published: July 2023

Carbohydrate antigen 19-9 (CA 19-9) is a commonly used tumor marker for pancreatic cancer. However, CA 19-9 can be overexpressed in several benign inflammatory diseases. We investigated the relationship between high CA 19-9 level and low muscle mass (LMM) in healthy adults without cancer. Participants who underwent evaluation of muscle mass and CA 19-9 were included. Exclusion criteria were any malignancy, cardiovascular disease, tuberculosis, and chronic lung/liver disease. Participants were classified into “normal”, “mild LMM”, and “severe LMM” groups based on the skeletal muscle mass index. Multivariable logistic regression analyses were conducted to assess the association of high CA 19-9 with muscle mass status. A total of 263,061 adults were included. The mean age and SMI were 41.03 years and 7.13 kg/m2. After adjustments for various confounders, high CA 19-9 was independently associated with mild LMM (adjusted odds ratio, 1.677 [95% confidence interval, 1.533–1.834]) and severe LMM (2.651 [2.126–3.306]) compared to the normal group. Furthermore, the association between high CA 19-9 and severe LMM was stronger in men than in women. Elevated CA 19-9 levels were independently associated with a higher prevalence of LMM in healthy adults without cancer. Therefore, increased CA 19-9 could be utilized as a novel biomarker for sarcopenia.
Effects of Menaquinone-7 on the Bone Health of Growing Rats under Calcium Restriction: New Insights from Microbiome-Metabolomics
Authors: Yuan Ya , Szeto Ignatius Man-Yau , Li Na , Yang Hua , Zhou Yunzheng , Liu Biao , He Fang , Zhang Lishi , Duan Sufang , Chen Jinyao
Published: July 2023

Insufficient calcium intake during growth is a global public health concern. The aim of this study was to investigate the effects of dietary menaquinone-7 (MK-7) on bone accrual in growing Sprague–Dawley rats under calcium restriction. Following 13 weeks of treatment, various bone quality parameters, including microarchitecture, were measured. Fecal and cecal samples were subjected to microbiome (16S rRNA gene sequencing) analyses, while metabolomics analysis of the cecum and humerus samples was analyzed based on UHPLC-Q/TOF-MS. We found that calcium deficiency diminished the richness of the microbiome and disrupted microbiome composition, accompanied by an elevation in the relative abundance of Parasutterella. Furthermore, calcium insufficiency escalated the level of isovaleric acid and modified the metabolic profiles. MK-7 supplementation significantly increased the cortical thickness, cortical bone area, and the calcium content of the femur. Apart from improving bone calcium deposition and diminishing bone resorption, the mechanisms underlying the beneficial effects of MK on bone quality also involve the modulation of the host’s metabolic pathways and the composition of gut microbiota. The gut–bone axis holds promise as an efficacious target for ameliorating calcium deficiency in children’s bone quality, and MK-7 is a promising dietary supplement from this perspective.
Dietary Pattern and Nutrients Intake on Chronic Diseases
Authors: Casas Rosa
Published: July 2023

Non-communicable diseases (NCDs) are the leading causes of mortality and morbidity worldwide, primarily affecting middle-aged men, and imposing a significant global public health burden [...]
Breastfeeding Protects from Overjet in Adolescence by Reducing Pacifier Use: A Birth Cohort Study
Authors: Feldens Carlos Alberto , Petracco Laura Boianovsky , Nascimento Gustavo G. , Li Huihua , Vítolo Márcia Regina , Peres Karen Glazer
Published: July 2023

Increased dental overjet in adolescence is a clinically relevant outcome associated with the complexity and high cost of treatment, indicating the need for prevention strategies. We investigated the long-term impact of breastfeeding and pacifier use on increased overjet (IOVJ) in permanent dentition. A prospective cohort nested in a randomized controlled trial was conducted from birth to 12 years of age (n = 214). Breastfeeding and pacifier use were recorded monthly until 12 months. Overjet was assessed at age 12 years. We employed a causal mediation analysis using parametric regression models assuming no interaction between breastfeeding and pacifier usage. We found a total protective effect of breastfeeding on IOVJ (OR 0.49; 95% CI 0.28–0.96), where 63.1% were mediated by pacifier use (OR 0.61; 95% CI 0.44–0.87). Breastfeeding directly decreased the odds of IOVJ by 20%; however, the confidence interval included the null estimate (OR 0.81; 95% CI 0.41–1.60). In conclusion, breastfeeding protects by half of the IOVJ in adolescence through reducing pacifier use. Oral and general health professionals should collaborate to support WHO breastfeeding guidelines during individual patient counseling. Guidelines for practice, policy or public information require messages that include a common risk approach to oral and general health.
Uncovering the Gut–Liver Axis Biomarkers for Predicting Metabolic Burden in Mice
Authors: Yang Guiyan , Liu Rex , Rezaei Shahbaz , Liu Xin , Wan Yu-Jui Yvonne
Published: July 2023

Western diet (WD) intake, aging, and inactivation of farnesoid X receptor (FXR) are risk factors for metabolic and chronic inflammation-related health issues ranging from metabolic dysfunction-associated steatotic liver disease (MASLD) to dementia. The progression of MASLD can be escalated when those risks are combined. Inactivation of FXR, the receptor for bile acid (BA), is cancer prone in both humans and mice. The current study used multi-omics including hepatic transcripts, liver, serum, and urine metabolites, hepatic BAs, as well as gut microbiota from mouse models to classify those risks using machine learning. A linear support vector machine with K-fold cross-validation was used for classification and feature selection. We have identified that increased urine sucrose alone achieved 91% accuracy in predicting WD intake. Hepatic lithocholic acid and serum pyruvate had 100% and 95% accuracy, respectively, to classify age. Urine metabolites (decreased creatinine and taurine as well as increased succinate) or increased gut bacteria (Dorea, Dehalobacterium, and Oscillospira) could predict FXR deactivation with greater than 90% accuracy. Human disease relevance is partly revealed using the metabolite–disease interaction network. Transcriptomics data were also compared with the human liver disease datasets. WD-reduced hepatic Cyp39a1 (cytochrome P450 family 39 subfamily a member 1) and increased Gramd1b (GRAM domain containing 1B) were also changed in human liver cancer and metabolic liver disease, respectively. Together, our data contribute to the identification of noninvasive biomarkers within the gut–liver axis to predict metabolic status.
The Implications of Taste and Olfaction in Nutrition and Health
Authors: Melis Melania , Tomassini Barbarossa Iole , Sollai Giorgia
Published: July 2023

Taste and olfaction are sensory modalities that act synergistically to orchestrate the behaviors essential for survival, such as interactions with the environment, nutrient-rich food identification, and the avoidance of noxious substances [...]
Resveratrol, a Multitasking Molecule That Improves Skeletal Muscle Health
Authors: Toniolo Luana , Concato Monica , Giacomello Emiliana
Published: July 2023

Resveratrol is a natural polyphenol utilized in Chinese traditional medicine and thought to be one of the determinants of the “French Paradox”. More recently, some groups evidenced its properties as a calorie-restriction mimetic, suggesting that its action passes through the modulation of skeletal muscle metabolism. Accordingly, the number of studies reporting the beneficial effects of resveratrol on skeletal muscle form and function, in both experimental models and humans, is steadily increasing. Although studies on animal models confer to resveratrol a good potential to ameliorate skeletal muscle structure, function and performance, clinical trials still do not provide clear-cut information. Here, we first summarize the effects of resveratrol on the distinct components of the skeletal muscle, such as myofibers, the neuromuscular junction, tendons, connective sheaths and the capillary bed. Second, we review clinical trials focused on the analysis of skeletal muscle parameters. We suggest that the heterogeneity in the response to resveratrol in humans could depend on sample characteristics, treatment modalities and parameters analyzed; as well, this heterogeneity could possibly reside in the complexity of skeletal muscle physiology. A systematic programming of treatment protocols and analyses could be helpful to obtain consistent results in clinical trials involving resveratrol administration.
Prevalence, Identification and Antibiotic Resistance of Gallibacterium anatis Isolates from Chickens in Poland
Authors: Kursa Olimpia , Tomczyk Grzegorz , Sieczkowska Agata , Sawicka-Durkalec Anna
Published: July 2023

The Gram-negative bacterium Gallibacterium anatis is part of the normal avian respiratory, intestinal and reproductive tract microflora and can be transmitted horizontally and vertically. With the coexistence of other relevant factors, G. anatis becomes an opportunistic pathogen, economically damaging to the poultry industry. This bacterium’s prevalence and molecular epidemiology were investigated, and the antimicrobial treatment options for G. anatis infection in chicken flocks in Poland were assessed. Tracheal samples from 182 flocks were collected between April 2022 and March 2023. The bacterial prevalence was determined by PCR targeting the gyrB gene and 16–23S rRNA. Gallibacterium anatis was identified by matrix-assisted laser desorption/ionisation–time-of-flight mass spectrometry (MALDI-TOF) after culturing and PCR amplification. Isolates’ susceptibility to 11 antimicrobials was assessed with a disc diffusion test. Isolates were also tested for gyrB, GtxA and flfA virulence genes and blaROB, aphA, tetB and tetH antibiotic resistance genes by PCR. Forty-one flocks (22.5%) were positive through PCR. Antibiotic resistance was most frequently observed against tilmicosin, tylosin, enrofloxacin, amoxicillin, tetracycline and doxycycline. Multiple resistance to at least eight antibiotics occurred in 20% of isolates and to at least four in 100%. The occurrence of gyrB was noted in 100%, GtxA was detected in 89%, and flfA was found in 14% of positive samples. The tetB gene was present in 61.0% of positive samples, tetH was in 36.0%, aphA was in 16.7%, and blaROB was in 5.6%. Significant differences were found in G. anatis isolates related to the presence of the virulence genes GtxA and gyrB and the presence of resistance genes (p < 0.05) associated with resistance to tetracyclines, β-lactams and aminoglycosides. The continued rise in the resistance of G. anatis to a broadening range of antibiotics is a major problem for the poultry industry worldwide, as well as for public health. The findings of this study may expand the knowledge of the pathogenicity of G. anatis in poultry.
Detection of Human Herpesviruses in Sera and Saliva of Asymptomatic HIV-Infected Individuals Using Multiplex RT-PCR DNA Microarray
Authors: Sufiawati Irna , Harmiyati Rahmi , Nur’aeny Nanan , Indrati Agnes Rengga , Lesmana Ronny , Wisaksana Rudi , Amalia Riezki
Published: July 2023

Human herpesviruses (HHVs) are frequently linked to an increased risk of acquiring human immunodeficiency virus (HIV), and vice versa. This study aimed to detect human herpesvirus (HHV) members in the sera and saliva of asymptomatic HIV-infected individuals. Paired saliva and serum samples were obtained from 30 asymptomatic HIV-infected individuals. HHVs were detected with a multiplex reverse transcription-polymerase chain reaction (RT-PCR) DNA microarray Clart®Entherpex kit. A total of 30 subjects were enrolled: 23 (76.67%) men and 7 (23.33%) women. The present study showed that at least one or more HHV members were detected in the saliva and sera of all (100%) of the subjects. In the saliva, we detected herpes simplex virus 1 (HSV-1) 6.67%, herpes simplex virus 2 (HSV-2) 6.67%, Epstein–Barr virus (EBV) 86.67%, cytomegalovirus (CMV) 63.33%, HHV-6 (40%), and HHV-7 (83.33%). In the sera, HSV-2 (20%), EBV (30%), CMV (40%), HHV-6 (0%), and HHV-7 (76.67%) were found, but not HSV-1. VZV and HHV-8 were not detected in either the saliva or sera. EBV and HHV6 were significantly more prevalent in the saliva than they were in the sera of asymptomatic HIV-infected individuals (p < 0.05). However, no significant differences were found in the prevalence of HSV-1, EBV, CMV, HHV-6, and HHV-7 in the saliva and sera of asymptomatic HIV-infected individuals (p > 0.05). In conclusion, the multiplex RT-PCR DNA microarray can serve as a valuable diagnostic tool that can be used as a screening tool or a first-line test for HHVs infections.
Detection and Quantification of Nocardia crassostreae, an Emerging Pathogen, in Mytilus galloprovincialis in the Mediterranean Sea Using Droplet Digital PCR
Authors: Cutarelli Anna , Carella Francesca , De Falco Francesca , Cuccaro Bianca , Di Nocera Fabio , Nava Donatella , De Vico Gionata , Roperto Sante
Published: July 2023

Nocardia crassostreae is a novel pathogen responsible for infections in oysters (Crassostrea gigas) and mussels (Mytilus galloprovincialis). N. crassostreae is also responsible for nocardiosis both in immunocompetent and immunocompromised patients. We investigated N. crassostreae DNA in mussels grown in marine sites of the Mediterranean Sea in the Campania Region. We examined 185 mussel pooled samples by droplet digital PCR (ddPCR) and real-time quantitative PCR (qPCR), each pool composed of 10 mussels and 149 individual mussels. ddPCR detected N. crassostreae DNA in 48 mussel pooled samples and in 23 individual mussel samples. qPCR detected N. crassostreae DNA in six pooled samples and six individual mussel samples. The two molecular assays for the detection of N. crassostreae DNA showed significant differences both in the pooled and in individual samples. Our study demonstrated that ddPCR outperformed real-time qPCR for N. crassostreae DNA detection, thus confirming that ddPCR technology can identify the pathogens in many infectious diseases with high sensitivity and specificity. Furthermore, in individual mussels showing histological lesions due to N. crassostreae, the lowest copy number/microliter detected by ddPCR of this pathogen was 0.3, which suggests that this dose could be enough to cause infections of N. crassostreae in mussels.
Exploring Factors Influencing Changes in Incidence and Severity of Multisystem Inflammatory Syndrome in Children
Authors: Castaldo Pasquale , d’Alanno Gabriele , Biserni Giovanni Battista , Moratti Mattia , Conti Francesca , Fabi Marianna , Lanari Marcello
Published: July 2023

Multisystem inflammatory syndrome (MIS-C) is a rare condition associated with COVID-19 affecting children, characterized by severe and aberrant systemic inflammation leading to nonspecific symptoms, such as gastrointestinal, cardiac, respiratory, hematological, and neurological disorders. In the last year, we have experienced a progressive reduction in the incidence and severity of MIS-C, reflecting the worldwide trend. Thus, starting from the overall trend in the disease in different continents, we reviewed the literature, hypothesizing the potential influencing factors contributing to the reduction in cases and the severity of MIS-C, particularly the vaccination campaign, the spread of different SARS-CoV-2 variants (VOCs), and the changes in human immunological response. The decrease in the severity of MIS-C and its incidence seem to be related to a combination of different factors rather than a single cause. Maturation of an immunological memory to SARS-CoV-2 over time, the implication of mutations of key amino acids of S protein in VOCs, and the overall immune response elicited by vaccination over the loss of neutralization of vaccines to VOCs seem to play an important role in this change.
Dynamics of Infections in Cattle and Rhipicephalus microplus: A Preliminary Study
Authors: Piloto-Sardiñas Elianne , Foucault-Simonin Angélique , Wu-Chuang Alejandra , Mateos-Hernández Lourdes , Marrero-Perera Roxana , Abuin-Denis Lianet , Roblejo-Arias Lisset , Díaz-Corona Cristian , Zając Zbigniew , Kulisz Joanna , Woźniak Aneta , Moutailler Sara , Corona-González Belkis , Cabezas-Cruz Alejandro
Published: July 2023

Tick-borne pathogens (TBPs) pose a significant threat to livestock, including bovine species. This study aimed to investigate TBPs in cattle and ticks across four sampling points, utilizing real-time microfluidic PCR. The results revealed that Rhipicephalus microplus ticks were found infesting all animals. Among the detected TBPs in cattle, Anaplasma marginale was the most frequently identified, often as a single infection, although mixed infections involving Rickettsia felis, uncharacterized Rickettsia sp., and Anaplasma sp. were also observed. In ticks, A. marginale was predominant, along with R. felis, Rickettsia sp., and Ehrlichia sp. It is noteworthy that although A. marginale consistently infected all cattle during various sampling times, this pathogen was not detected in all ticks. This suggests a complex dynamic of pathogen acquisition by ticks. A phylogenetic analysis focused on the identification of Anaplasma species using amplified 16S rDNA gene fragments revealed the presence of A. marginale and Anaplasma platys strains in bovines. These findings underscore the presence of multiple TBPs in both cattle and ticks, with A. marginale being the most prevalent. Understanding the dynamics and phylogenetics of TBPs is crucial for developing effective control strategies to mitigate tick-borne diseases in livestock.
Cannabis-Based Medicine for Neuropathic Pain and Spasticity—A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial
Authors: Hansen Julie Schjødtz , Gustavsen Stefan , Roshanisefat Homayoun , Kant Matthias , Biering-Sørensen Fin , Andersen Claus , Olsson Anna , Chow Helene Højsgaard , Asgari Nasrin , Hansen Julie Richter , Nielsen Helle Hvilsted , Hansen Rikke Middelhede , Petersen Thor , Oturai Annette Bang , Sellebjerg Finn , Sædder Eva Aggerholm , Kasch Helge , Rasmussen Peter Vestergaard , Finnerup Nanna Brix , Svendsen Kristina Bacher
Published: July 2023

Patients with multiple sclerosis (MS) and spinal cord injury (SCI) commonly sustain central neuropathic pain (NP) and spasticity. Despite a lack of consistent evidence, cannabis-based medicine (CBM) has been suggested as a supplement treatment. We aimed to investigate the effect of CBM on NP and spasticity in patients with MS or SCI. We performed a randomized, double-blinded, placebo-controlled trial in Denmark. Patients aged ≥18 years with NP (intensity >3, ≤9 on a numerical rating scale (NRS0-10) and/or spasticity (>3 on NRS0-10) were randomized to treatment consisting of either delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), a combination of THC&CBD in maximum doses of 22.5 mg, 45 mg and 22.5/45 mg per day, respectively, or placebo. A baseline registration was performed before randomization. Treatment duration was six weeks followed by a one-week phaseout. Primary endpoints were the intensity of patient-reported NP and/or spasticity. Between February 2019 and December 2021, 134 patients were randomized (MS n = 119, SCI n = 15), where 32 were assigned to THC, 31 to CBD, 31 to THC&CBD, and 40 to placebo. No significant difference was found for: mean pain intensity (THC 0.42 (−0.54–1.38), CBD 0.45 (−0.47–1.38) and THC&CBD 0.16 (−0.75–1.08)), mean spasticity intensity (THC 0.24 (−0.67–1.45), CBD 0.46 (−0.74–1.65), and THC&CBD 0.10 (−1.18–1.39), secondary outcomes (patient global impression of change and quality of life), or any tertiary outcomes. We aimed to include 448 patients in the trial; however, due to COVID-19 and recruitment challenges, fewer were included. Nevertheless, in this four-arm parallel trial, no effect was found between placebo and active treatment with THC or CBD alone or in combination on NP or spasticity in patients with either MS or SCI. The trial was registered with the EU Clinical Trials Register EudraCT (2018-002315-98).
Parenteral Ready-to-Use Fixed-Dose Combinations Including NSAIDs with Paracetamol or Metamizole for Multimodal Analgesia—Approved Products and Challenges
Authors: Silva Fernando , Costa Gustavo , Veiga Francisco , Cardoso Catarina , Paiva-Santos Ana Cláudia
Published: July 2023

The combination of non-steroidal anti-inflammatory drugs (NSAIDs) with non-opioid analgesics is common in clinical practice for the treatment of acute painful conditions like post-operative and post-traumatic pain. Despite the satisfactory results achieved by oral analgesics, parenteral analgesia remains a key tool in the treatment of painful conditions when the enteral routes of administration are inconvenient. Parenteral ready-to-use fixed-dose combinations of non-opioid analgesics combinations, including NSAIDs and paracetamol or metamizole, could play a central role in the treatment of painful conditions by combining the advantages of multimodal and parenteral analgesia in a single formulation. Surprisingly, only in 2020, a parenteral ready-to-use fixed-dose combination of ibuprofen/paracetamol was launched to the market. This review aims to investigate the current availability of combinations of NSAIDs with paracetamol or metamizole in both European and American markets, and how the combination of such drugs could play a central role in a multimodal analgesia strategy. Also, we explored how the parenteral formulations of NSAIDs, paracetamol, and metamizole could serve as starting elements for the development of new parenteral ready-to-use fixed-dose combinations. We concluded that, despite the well-recognized utility of combining NSAIDs with paracetamol or metamizole, several randomized clinical trial studies demonstrate no clear advantages concerning their efficacy and safety. Future clinical trials specifically designed to assess the efficacy and safety of pre-formulated fixed-dose combinations are required to generate solid evidence about their clinical advantages.
Nanoparticle-Mediated Therapy with miR-198 Sensitizes Pancreatic Cancer to Gemcitabine Treatment through Downregulation of VCP-Mediated Autophagy
Authors: Marin-Muller Christian , Li Dali , Lü Jian-Ming , Liang Zhengdong , Vega-Martínez Osvaldo , Crawford Sue E. , Estes Mary K. , Fisher William E. , Chen Changyi , Yao Qizhi
Published: July 2023

Pancreatic ductal adenocarcinoma (PDAC) remains an extremely aggressive disease characterized by rapidly acquired multi-drug resistance, including to first-line chemotherapeutic agent gemcitabine. Autophagy is a process that is often exploited by cancer and is one of several intrinsic factors associated with resistance to gemcitabine. We have previously found that miR-198 acts as a tumor suppressor in PDAC through the targeting of factors including Valosin-containing protein (VCP). VCP has been reported to play an important role in autophagic flux. In this study, we investigated whether the repression of VCP through miR-198 administration disrupts the autophagy process and sensitizes PDAC cells to gemcitabine treatment in vitro. Moreover, we used LGA-PEI (LPNP) nanoparticles to effectively administer miR-198 to tumors in vivo, inducing tumor sensitization to gemcitabine and leading to a significant reduction in tumor burden and metastases and a concomitant downregulation of VCP expression and autophagy maturation. Our results indicate a potential therapeutic strategy for targeting gemcitabine resistant PDAC and establishes the use of LPNPs for effective therapeutic delivery of nucleic acids in vitro and in vivo.
Design of Protegrin-1 Analogs with Improved Antibacterial Selectivity
Authors: Bolosov Ilia A. , Panteleev Pavel V. , Sychev Sergei V. , Khokhlova Veronika A. , Safronova Victoria N. , Toropygin Ilia Yu. , Kombarova Tatiana I. , Korobova Olga V. , Pereskokova Eugenia S. , Borzilov Alexander I. , Ovchinnikova Tatiana V. , Balandin Sergey V.
Published: July 2023

Protegrin-1 (PG-1) is a cationic β-hairpin pore-forming antimicrobial peptide having a membranolytic mechanism of action. It possesses in vitro a potent antimicrobial activity against a panel of clinically relevant MDR ESKAPE pathogens. However, its extremely high hemolytic activity and cytotoxicity toward mammalian cells prevent the further development of the protegrin-based antibiotic for systemic administration. In this study, we rationally modulated the PG-1 charge and hydrophobicity by substituting selected residues in the central β-sheet region of PG-1 to design its analogs, which retain a high antimicrobial activity but have a reduced toxicity toward mammalian cells. In this work, eight PG-1 analogs with single amino acid substitutions and five analogs with double substitutions were obtained. These analogs were produced as thioredoxin fusions in Escherichia coli. It was shown that a significant reduction in hemolytic activity without any loss of antimicrobial activity could be achieved by a single amino acid substitution, V16R in the C-terminal β-strand, which is responsible for the PG-1 oligomerization. As the result, a selective analog with a ≥30-fold improved therapeutic index was obtained. FTIR spectroscopy analysis of analog, [V16R], revealed that the peptide is unable to form oligomeric structures in a membrane-mimicking environment, in contrast to wild-type PG-1. Analog [V16R] showed a reasonable efficacy in septicemia infection mice model as a systemic antibiotic and could be considered as a promising lead for further drug design.
Neurodegenerative Proteinopathies Induced by Environmental Pollutants: Heat Shock Proteins and Proteasome as Promising Therapeutic Tools
Authors: Moyano Paula , Sola Emma , Naval María Victoria , Guerra-Menéndez Lucia , Fernández Maria De la Cabeza , del Pino Javier
Published: July 2023

Environmental pollutants’ (EPs) amount and diversity have increased in recent years due to anthropogenic activity. Several neurodegenerative diseases (NDs) are theorized to be related to EPs, as their incidence has increased in a similar way to human EPs exposure and they reproduce the main ND hallmarks. EPs induce several neurotoxic effects, including accumulation and gradual deposition of misfolded toxic proteins, producing neuronal malfunction and cell death. Cells possess different mechanisms to eliminate these toxic proteins, including heat shock proteins (HSPs) and the proteasome system. The accumulation and deleterious effects of toxic proteins are induced through HSPs and disruption of proteasome proteins’ homeostatic function by exposure to EPs. A therapeutic approach has been proposed to reduce accumulation of toxic proteins through treatment with recombinant HSPs/proteasome or the use of compounds that increase their expression or activity. Our aim is to review the current literature on NDs related to EP exposure and their relationship with the disruption of the proteasome system and HSPs, as well as to discuss the toxic effects of dysfunction of HSPs and proteasome and the contradictory effects described in the literature. Lastly, we cover the therapeutic use of developed drugs and recombinant proteasome/HSPs to eliminate toxic proteins and prevent/treat EP-induced neurodegeneration.
Ways to Assess and Regulate the Performance of a Bi-Mechanism-Induced Borneol-Based In Situ Forming Matrix
Authors: Lertsuphotvanit Nutdanai , Sirirak Jitnapa , Tamdee Poomipat , Tuntarawongsa Sarun , Phaechamud Thawatchai , Chantadee Takron
Published: July 2023

As an alternative to the traditional polymeric-based system, it is now possible to use an in situ forming system that is based on small molecules. Borneol was used as matrix formation in this study. While triacetin was incorporated into the formulation for prolonging the drug release. The objective of this study is to understand the initial period of the solvent exchange mechanism at the molecular level, which would provide a basis for explaining the matrix formation and drug release phenomena. The evaluation of basic physical properties, matrix formation, in vitro drug release, and molecular dynamics (MD) simulation of borneol-based in situ forming matrixes (ISM) was conducted in this study. The proportion of triacetin was found to determine the increase in density and viscosity. The density value was found to be related to viscosity which could be used for the purpose of prediction. Slow self-assembly of ISM upon the addition of triacetin was associated with higher viscosity and lower surface tension. This phenomenon enabled the regulation of solvent exchange and led to sustaining the drug release. In MD simulation using AMBER Tools, the free movement of the drug and the rapid approach to equilibrium of both solvent and water molecule in a solvent exchange mechanism in borneol-free ISM was observed, supporting that sustained release would not occur. Water infiltration was slowed down and NMP movement was restricted by the addition of borneol and triacetin. In addition, the increased proportion of triacetin promoted the diminished down of all substances’ movement because of the viscosity. The diffusion constant of relevant molecules decreased with the addition of borneol and/or triacetin. Although the addition of triacetin tended to slow down the solvent exchange and molecular movement from computation modelling results, it may not guarantee to imply the best drug release control. The Low triacetin-incorporated (5%) borneol-based ISM showed the highest ability to sustain the drug release due to its self-assembly and has proper solvent exchange. MD simulation addressed the details of the mechanism at the beginning of the process. Therefore, both MD and classical methods contribute to a clearer understanding of solvent exchange from the molecular to macroscopic level and from the first nanosecond of the formulation contact with water to the 10-day of drug release. These would be beneficial for subsequent research and development efforts in small molecule-based in situ forming systems.
In Vitro and In Vivo Efficacy of Topical Dosage Forms Containing Self-Nanoemulsifying Drug Delivery System Loaded with Curcumin
Authors: Frei Gréta , Haimhoffer Ádám , Csapó Enikő , Bodnár Krisztina , Vasvári Gábor , Nemes Dániel , Lekli István , Gyöngyösi Alexandra , Bácskay Ildikó , Fehér Pálma , Józsa Liza
Published: July 2023

The external use of curcumin is rare, although it can be a valuable active ingredient in the treatment of certain inflammatory diseases. The aim of our experimental work was to formulate topical dosage forms containing curcumin for the treatment of atopic dermatitis. Curcumin has extremely poor solubility and bioavailability, so we have tried to increase it with the usage of self-emulsifying drug delivery systems. Creams and gels were formulated using penetration-enhancing surfactants and gelling agents. The release of the drug from the vehicle and its penetration through the membrane were determined using a Franz diffusion cell. An MTT cytotoxicity and in vitro antioxidant assays were performed on HaCaT cell line. The in vivo anti-inflammatory effect of the preparations was tested by measuring rat paw edema. In addition, we examined the degree of inflammation induced by UV radiation after pretreatment with the cream and the gel on rats. For the gels containing SNEDDS, the highest penetration was measured after half an hour, while for the cream, it took one hour to reach the maximum concentration. The gel containing Pemulen TR-1 showed the highest drug release. It was determined that the curcumin-containing preparations can be safely applied on the skin and have antioxidant effects. The animal experiments have proven the effectiveness of curcumin-containing topical preparations.
Biosynthetic Melanin/Ce6-Based Photothermal and Sonodynamic Therapies Significantly Improved the Anti-Tumor Efficacy
Authors: Yang Yuping , He Yaling , Zhou Meijun , Fu Meijun , Li Xinxin , Liu Hongmei , Yan Fei
Published: July 2023

Photothermal therapy (PTT) and sonodynamic therapy (SDT) are becoming promising therapeutic modalities against various tumors in recent years. However, the single therapeutic modality with SDT or PTT makes it difficult to achieve a satisfactory anti-tumor outcome due to their own inherent limitations, such as poor tissue penetration for the near-infrared (NIR) laser and the limited cytotoxic reactive oxygen species (ROS) generated from conventional sonosensitizers irradiated by ultrasound (US). Here, we successfully biosynthesized melanin with a controllable particle size with genetically engineered bacteria harboring a heat-inducible gene circuit. The biosynthetic melanin with 8 nm size and chlorin e6 (Ce6) was further encapsulated into liposomes and obtained SDT/PTT dual-functional liposomes (designated as MC@Lip). The resulting MC@Lip had an approximately 100 nm particle size, with 74.71% ± 0.54% of encapsulation efficiency for melanin and 94.52% ± 0.78% for Ce6. MC@Lip exhibited efficient 1O2 production and photothermal conversion capability upon receiving irradiation by US and NIR laser, producing significantly enhanced anti-tumor efficacy in vitro and in vivo. Especially, US and NIR laser irradiation of tumors received with MC@Lip lead to complete tumor regression in all tested tumor-bearing mice, indicating the great advantage of the combined use of SDT and PTT. More importantly, MC@Lip possessed good photoacoustic (PA) and fluorescence dual-modal imaging performance, making it possible to treat tumors under imaging guidance. Our study provides a novel approach to synthesize a melanin nanoparticle with controllable size and develops a promising combined SDT/PTT strategy to treat tumors.
Exploring the Impact of an Innovative Peer Role-Play Simulation to Cultivate Student Pharmacists’ Motivational Interviewing Skills
Authors: Denvir Paul , Briceland Laurie L.
Published: July 2023

Effective patient-centered communication is a foundational skill for student pharmacists, with recent decades broadening the scope of professional responsibilities to include an increased emphasis on empathic communication and motivational interviewing (MI) as tools to support patients’ therapeutic adherence. Role-play is a potentially effective pedagogical approach to cultivate these skills, although previous research has identified common shortcomings that can hinder its educational value, particularly in peer role-play with relatively inexperienced learners. The purpose of this study is to describe and provide initial assessment data for an innovative approach to peer role-play that incorporates pedagogical principles to address these common shortcomings. Using a mixed-methods study design that includes instructor-graded rubrics and inductive thematic analysis of student reflections, our findings indicate that students successfully demonstrated a range of important competencies through this experience and perceived it to be both challenging and highly beneficial for their personal and professional development. Among the MI principles and techniques practiced, students performed especially well on expressing empathy and frequently reflected on its importance for future patient care and clinical collaborations. Our findings also suggest that peer engagement through team activities and partnered role-play provides a felicitous context to explore empathic communication together.
MsDjB4, a HSP40 Chaperone in Alfalfa (Medicago sativa L.), Improves Alfalfa Hairy Root Tolerance to Aluminum Stress
Authors: Liu Siyan , Mo Xin , Sun Linjie , Gao Li , Su Liantai , An Yuan , Zhou Peng
Published: July 2023

The toxicity of aluminum (Al) in acidic soils poses a significant limitation to crop productivity. In this study, we found a notable increase in DnaJ (HSP40) expression in the roots of Al-tolerant alfalfa (WL-525HQ), which we named MsDjB4. Transient conversion assays of tobacco leaf epidermal cells showed that MsDjB4 was targeted to the membrane system including Endoplasmic Reticulum (ER), Golgi, and plasma membrane. We overexpressed (MsDjB4-OE) and suppressed (MsDjB4-RNAi) MsDjB4 in alfalfa hairy roots and found that MsDjB4-OE lines exhibited significantly better tolerance to Al stress compared to wild-type and RNAi hairy roots. Specifically, MsDjB4-OE lines had longer root length, more lateral roots, and lower Al content compared to wild-type and RNAi lines. Furthermore, MsDjB4-OE lines showed lower levels of lipid peroxidation and ROS, as well as higher activity of antioxidant enzymes SOD, CAT, and POD compared to wild-type and RNAi lines under Al stress. Moreover, MsDjB4-OE lines had higher soluble protein content compared to wild-type and RNAi lines after Al treatment. These findings provide evidence that MsDjB4 contributes to the improved tolerance of alfalfa to Al stress by facilitating protein synthesis and enhancing antioxidant capacity.
Overexpression of OsPIN9 Impairs Chilling Tolerance via Disturbing ROS Homeostasis in Rice
Authors: Ouyang Qiqi , Zhang Yanwen , Yang Xiaoyi , Yang Chong , Hou Dianyun , Liu Hao , Xu Huawei
Published: July 2023

The auxin efflux transporter PIN-FORMED (PIN) family is one of the major protein families that facilitates polar auxin transport in plants. Here, we report that overexpression of OsPIN9 leads to altered plant architecture and chilling tolerance in rice. The expression profile analysis indicated that OsPIN9 was gradually suppressed by chilling stress. The shoot height and adventitious root number of OsPIN9-overexpressing (OE) plants were significantly reduced at the seedling stage. The roots of OE plants were more tolerant to N-1-naphthylphthalamic acid (NPA) treatment than WT plants, indicating the disturbance of auxin homeostasis in OE lines. The chilling tolerance assay showed that the survival rate of OE plants was markedly lower than that of wild-type (WT) plants. Consistently, more dead cells, increased electrolyte leakage, and increased malondialdehyde (MDA) content were observed in OE plants compared to those in WT plants under chilling conditions. Notably, OE plants accumulated more hydrogen peroxide (H2O2) and less superoxide anion radicals (O2−) than WT plants under chilling conditions. In contrast, catalase (CAT) and superoxide dismutase (SOD) activities in OE lines decreased significantly compared to those in WT plants at the early chilling stage, implying that the impaired chilling tolerance of transgenic plants is probably attributed to the sharp induction of H2O2 and the delayed induction of antioxidant enzyme activities at this stage. In addition, several OsRboh genes, which play a crucial role in ROS production under abiotic stress, showed an obvious increase after chilling stress in OE plants compared to that in WT plants, which probably at least in part contributes to the production of ROS under chilling stress in OE plants. Together, our results reveal that OsPIN9 plays a vital role in regulating plant architecture and, more importantly, is involved in regulating rice chilling tolerance by influencing auxin and ROS homeostasis.
Assessing Genetic Variation among Strychnos spinosa Lam. Morphotypes Using Simple Sequence Repeat Markers
Authors: Mbhele Zoliswa , Zharare Godfrey Elijah , Zimudzi Clemence , Ntuli Nontuthuko Rosemary
Published: July 2023

Strychnos spinosa Lam., commonly known as green monkey orange, is a highly valued indigenous fruit tree in South Africa with potential for domestication and commercialization. However, no study has reported on the molecular diversity of Strychnos spinosa morphotypes. Therefore, this study aimed to determine genetic variation among 32 Strychnos spinosa morphotypes using simple sequence repeat (SSR) markers. Fourteen amplified SSR markers produced 159 alleles, with a mean of 5.68 per locus. The polymorphic information content (PIC) values ranged from 0.22 (Ssp_1) to 0.84 (Ssp_6). Morphotypes were clustered in a biplot based on their genetic distances. The dendrogram chiefly discriminated morphotypes according to variation of pericarp texture. The population structure had the highest delta value K = 3, thus the 32 morphotypes were divided into three subpopulations based on the Bayesian approach. The affinities produced by the population structure agreed with the genetic distance of closely related morphotypes. This study is the first to report on SSR marker development and their successful use for genetic diversity and population structure studies of Strychnos spinosa. It provides insights into the molecular characterisation of Strychnos spinosa. This can lead to breeding programs and crop improvement programs, particularly in varietal developmental programs, which can contribute to alleviating food security challenges.
Detecting the Minimum Limit on Wheat Stripe Rust in the Latent Period Using Proximal Remote Sensing Coupled with Duplex Real-Time PCR and Machine Learning
Authors: Liu Qi , Sun Tingting , Wen Xiaojie , Zeng Minghao , Chen Jing
Published: July 2023

Wheat stripe rust (WSR) is an airborne disease that causes severe damage to wheat. The rapid and early detection of WSR is essential for the prevention and control of this disease. The minimum detection limit (MDL) is one of the most important characteristics of quantitative methods that can be used to determine the scope and applicability of a measurement technique. Three wheat cultivars were inoculated with Puccinia striiformis f.sp. tritici (Pst), and a spectrometer was used to collect the canopy hyperspectral data, and the Pst content was obtained via a duplex real-time polymerase chain reaction (PCR) during the latent period, respectively. The disease index (DI) and molecular disease index (MDI) were calculated. The regression tree algorithm was used to determine the MDL of the Pst based on hyperspectral feature parameters. The logistic, IBK, and random committee algorithms were used to construct the classification model based on the MDL. The results showed that when the MDL was 0.7, IBK had the best recognition accuracy. The optimal model, which used the spectral feature R_2nd.dv ((the second derivative of the original hyperspectral value)) and the modeling ratio 2:1, had an accuracy of 91.67% on the testing set and 90.67% on the 10-fold cross-validation. Thus, during the latent period, the MDL of Pst was determined using hyperspectral technology as 0.7.
Enhancing the Adaptability of Tea Plants (Camellia sinensis L.) to High-Temperature Stress with Small Peptides and Biosurfactants
Authors: Chen Hao , Song Yujie , Li He , Zaman Shah , Fan Kai , Ding Zhaotang , Wang Yu
Published: July 2023

Tea plants are highly susceptible to the adverse effects of a high-temperature climate, which can cause reduced yield and quality and even lead to plant death in severe cases. Therefore, reducing the damage caused by high-temperature stress and maintaining the photosynthetic capacity of tea plants is a critical technical challenge. In this study, we investigated the impact of small oligopeptides (small peptides) and surfactants on the high-temperature-stress tolerance of tea plants. Our findings demonstrated that the use of small peptides and surfactants enhances the antioxidant capacity of tea plants and protects their photosynthetic system. They also induce an increase in gibberellin (GA) content and a decrease in jasmonic acid (JA), strigolactone (SL), auxin (IAA), and cytokinin (CTK) content. At the same time, small peptides regulate the metabolic pathways of diterpenoid biosynthesis. Additionally, small peptides and surfactants induce an increase in L-Carnosine and N-Glycyl-L-Leucine content and a decrease in (5-L-Glutamyl)-L-Amino Acid content, and they also regulate the metabolic pathways of Beta-Alanine metabolism, Thiamine metabolism, and Glutathione metabolism. In summary, small peptides and surfactants enhance the ability of tea plants to resist high-temperature stress.