Blood Purif. 2022 Mar 11:1-9. doi: 10.1159/000521886. Online ahead of print.

ABSTRACT

INTRODUCTION: Expanded hemodialysis (HD using a medium cut-off dialyzer [HD + MCO]) provides comparable or better removal of various uremic toxins, particularly large middle-molecule uremic toxins, than post-dilution online hemodiafiltration (olHDF). Uremic toxin-removing effectiveness between HD + MCO and mixed-dilution olHDF, one of the currently most efficient olHDF modalities, has not been assessed.

METHOD: This randomized controlled trial was conducted in 14 prevalent thrice-a-week HD patients with blood flow rate above 400 mL/min. The patients were randomized into two sequences of 2-week treatment periods of HD + MCO and later mixed-dilution olHDF or vice versa. The reduction ratio (RR) values of small-molecule as well as middle-molecule uremic toxins and protein-bound uremic toxins were measured at baseline and at the end of the treatment.

RESULTS: When compared with mixed-dilution olHDF, HD + MCO provided slightly lower β2M RR, but the value was still higher than 75%; showed similar κFLC RR, IS RR, and URR; and yielded significantly higher RR values of α1M (p < 0.001) and λFLC (p < 0.001). Despite higher albumin loss in HD + MCO, the serum albumin levels at the end of the study were comparable between both groups.

CONCLUSION: Expanded HD (HD + MCO) provided similar effectiveness in removing various uremic toxins and could exhibit greater removal of large middle-molecule uremic toxins, such as α1M and λFLC. Expanded HD can be used as an effective alternative option for mixed-dilution olHDF.

PMID:35279655 | DOI:10.1159/000521886

J Arthroplasty. 2022 Feb 18:S0883-5403(22)00188-7. doi: 10.1016/j.arth.2022.02.037. Online ahead of print.

ABSTRACT

BACKGROUND: The purpose of this study is to determine whether pharmacogenetic testing could be used to effectively customize postoperative pain medicine following total joint replacement.

METHODS: Buccal swabs were collected preoperatively from 107 patients. Pharmacogenetic testing was performed for genetic variants on a panel of 16 genes, including CYP2D6, CYP2C9, OPRM1, and CYP1A2, which affect the pharmacodynamics and pharmacokinetics of non-steroidal anti-inflammatory drugs and many opioids. Patients were randomized to a control group or custom group and blinded to their group. The control group was prescribed oxycodone, tramadol, and celecoxib for postoperative pain management. If any of those were not normally metabolized, they were not prescribed to the patients in the custom group, who were given an alternative drug (hydromorphone for narcotics, meloxicam for non-steroidal anti-inflammatory drugs). Patients recorded their pain level (0-10 numeric scale) and all medications taken daily for the first 10 days following surgery. Medication was converted to milligram morphine equivalents (MMEs).

RESULTS: Genetic variations to medications in our standard postoperative pain management protocol occurred in 24 of the 107 patients (22.4%). The 10-day MME consumed by patients in the control group with genetic variants was 162.6 mg. Patients with variants who had custom postoperative medication consumed only 86.7 MME in the same timeframe (P = .126). The control group demonstrated a higher 10-day average pain level of 4.2 vs the custom group pain level of only 3.1 (P < .05).

CONCLUSION: With custom postoperative pain prescriptions based on pharmacogenetic testing, patients were able to achieve lower pain levels while reducing the consumption of pain medication.

PMID:35279338 | DOI:10.1016/j.arth.2022.02.037

Am J Health Syst Pharm. 2022 Mar 12:zxac065. doi: 10.1093/ajhp/zxac065. Online ahead of print.

ABSTRACT

In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PMID:35279024 | DOI:10.1093/ajhp/zxac065

Biostatistics. 2022 Mar 12:kxac010. doi: 10.1093/biostatistics/kxac010. Online ahead of print.

ABSTRACT

Pharmacogenomic experiments allow for the systematic testing of drugs, at varying dosage concentrations, to study how genomic markers correlate with cell sensitivity to treatment. The first step in the analysis is to quantify the response of cell lines to variable dosage concentrations of the drugs being tested. The signal to noise in these measurements can be low due to biological and experimental variability. However, the increasing availability of pharmacogenomic studies provides replicated data sets that can be leveraged to gain power. To do this, we formulate a hierarchical mixture model to estimate the drug-specific mixture distributions for estimating cell sensitivity and for assessing drug effect type as either broad or targeted effect. We use this formulation to propose a unified approach that can yield posterior probability of a cell being susceptible to a drug conditional on being a targeted effect or relative effect sizes conditioned on the cell being broad. We demonstrate the usefulness of our approach via case studies. First, we assess pairwise agreements for cell lines/drugs within the intersection of two data sets and confirm the moderate pairwise agreement between many publicly available pharmacogenomic data sets. We then present an analysis that identifies sensitivity to the drug crizotinib for cells harboring EML4-ALK or NPM1-ALK gene fusions, as well as significantly down-regulated cell-matrix pathways associated with crizotinib sensitivity.

PMID:35277956 | DOI:10.1093/biostatistics/kxac010

Sci Rep. 2022 Mar 11;12(1):4266. doi: 10.1038/s41598-022-07997-5.

ABSTRACT

In this largest to-date genetic analysis of anti-drug antibody (ADA) response to a therapeutic monoclonal antibody (MAb), genome-wide association was performed for five measures of ADA status among 8844 individuals randomized to bococizumab, which targets PCSK9 for LDL-C lowering and cardiovascular protection. Index associations prioritized specific amino acid substitutions at the DRB1 and DQB1 MHC class II genes rather than canonical haplotypes. Two clusters of missense variants at DRB1 were associated with general ADA measures (residues 9, 11, 13; and 96, 112, 120, 180) and a third cluster of missense variants in DQB1 was associated with ADA measures including neutralizing antibody (NAb) titers (residues 66, 67, 71, 74, 75). The structural disposition of the missense substitutions implicates peptide antigen binding and CD4 effector function, mechanisms that are potentially generalizable to other therapeutic mAbs.Clinicaltrials.gov: NCT01968954, NCT01968967, NCT01968980, NCT01975376, NCT01975389, NCT02100514.

PMID:35277540 | DOI:10.1038/s41598-022-07997-5

Clin Chim Acta. 2022 Mar 9;530:87-93. doi: 10.1016/j.cca.2022.03.007. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Retrospective analysis of hair testing data provides insights in drugs abuse patterns and improves results interpretation. Cases from subjects undergoing driving fitness assessment (2010-2020) were examined to evidence patterns in methamphetamine (MA) abuse.

MATERIALS AND METHODS: All cases with positive MA (≥0.025 ng/mg) were included (n = 585). Data available were gender, age, MA and A (amphetamine) in hair (h), hair color/treatment, length of proximal hair. Cases with Ah/MAh ≤ 0.35 (n = 469) were arbitrarily selected to remove as many combined A, MA users. ANOVA was performed to detect Ah/MAh predictors.

RESULTS: No predictors affected Ah/MAh. A bimodal frequency distribution was observed. We clustered cases in two groups (1, Ah/MAh 0.025-0.070; 2, Ah/MAh 0.071-0.120) and performed logistic regression. Only gender exhibited significant difference across groups (p = 0.0080). Odds ratio for females falling into group 2 was 2.86 times higher (CI97.5 1.34-6.44).

CONCLUSION: Literature data support the hypothesis that the two Ah/MAh groups represent different phenotypes of the CYP2D6-mediated MA N-demethylation. Whether gender plays a role in such difference could not be confirmed. However, these results provide further suggestion of an association of gender and pharmacogenomics with MA disposition, requiring these factors to be considered in future research.

PMID:35276222 | DOI:10.1016/j.cca.2022.03.007

Drug Metab Pers Ther. 2022 Mar 11. doi: 10.1515/dmpt-2021-0219. Online ahead of print.

ABSTRACT

OBJECTIVES: The fluoropyrimidine derivatives 5-Fluorouracil and Capecitabine are widely used for the treatment of solid tumors. Fluoropyrimidine metabolism involves a cascade of different enzymes, including MTHFR enzyme. MTHFR c.665C>T polymorphism, leading to decreased MTHFR activity, is a potential pharmacogenomic marker for fluoropyrimidine drug response. The aim of the present study was to analyze the association of MTHFR c.665C>T polymorphism with fluoropyrimidine response in terms of therapy induced adverse events (AEs), requirement of dose reduction and delayed drug administration or therapy discontinuation.

METHODS: The study group consisted of 313 fluoropyrimidine-treated cancer patients. PCR-RFLP was used to analyze MTHFR c.665C>T polymorphism.

RESULTS: In female patients, MTHFR c.665 CT and TT genotypes were associated with dose reduction (p=0.029). In gender stratification, regression analysis adjusted for age of disease onset, body surface area and AE incidence, showed that MTHFR CT and TT genotypes increased both need for fluoropyrimidine dose reduction (OR 5.050, 95% CI 1.346-18.948, p=0.016) and percentage of dose reduction (β=3.318, 95% C.I. 1.056-5.580, p=0.004) in female patients. Such differences were not present in male patients. No other associations were found.

CONCLUSIONS: MTHFR c.665C>T polymorphism was associated with fluoropyrimidine dose reduction in female cancer patients. This gender*MTHFR interaction merits further investigation.

PMID:35272420 | DOI:10.1515/dmpt-2021-0219

Biomed Pharmacother. 2022 Feb 25;148:112753. doi: 10.1016/j.biopha.2022.112753. Online ahead of print.

ABSTRACT

COVID-19 is a lethal disease caused by the pandemic SARS-CoV-2, which continues to be a public health threat. COVID-19 is principally a respiratory disease and is often associated with sputum retention and cytokine storm, for which there are limited therapeutic options. In this regard, we evaluated the use of BromAc®, a combination of Bromelain and Acetylcysteine (NAC). Both drugs present mucolytic effect and have been studied to treat COVID-19. Therefore, we sought to examine the mucolytic and anti-inflammatory effect of BromAc® in tracheal aspirate samples from critically ill COVID-19 patients requiring mechanical ventilation.

METHOD: Tracheal aspirate samples from COVID-19 patients were collected following next of kin consent and mucolysis, rheometry and cytokine analysis using Luminex kit was performed.

RESULTS: BromAc® displayed a robust mucolytic effect in a dose dependent manner on COVID-19 sputum ex vivo. BromAc® showed anti-inflammatory activity, reducing the action of cytokine storm, chemokines including MIP-1alpha, CXCL8, MIP-1b, MCP-1 and IP-10, and regulatory cytokines IL-5, IL-10, IL-13 IL-1Ra and total reduction for IL-9 compared to NAC alone and control. BromAc® acted on IL-6, demonstrating a reduction in G-CSF and VEGF-D at concentrations of 125 and 250 µg.

CONCLUSION: These results indicate robust mucolytic and anti-inflammatory effect of BromAc® ex vivo in tracheal aspirates from critically ill COVID-19 patients, indicating its potential to be further assessed as pharmacological treatment for COVID-19.

PMID:35272139 | DOI:10.1016/j.biopha.2022.112753

Int J Mol Sci. 2022 Mar 4;23(5):2819. doi: 10.3390/ijms23052819.

ABSTRACT

Non-invasive prenatal testing (NIPT) is based on the detection and characterization of circulating cell-free fetal DNA (ccffDNA) in maternal plasma and aims to identify genetic abnormalities. At present, commercial NIPT kits can detect only aneuploidies, small deletions and insertions and some paternally inherited single-gene point mutations causing genetic diseases, but not maternally inherited ones. In this work, we have developed two NIPT assays, based on the innovative and sensitive droplet digital PCR (ddPCR) technology, to identify the two most common β thalassemia mutations in the Mediterranean area (β+IVSI-110 and β039), maternally and/or paternally inherited, by fetal genotyping. The assays were optimized in terms of amplification efficiency and hybridization specificity, using mixtures of two genomic DNAs with different genotypes and percentages to simulate fetal and maternal circulating cell-free DNA (ccfDNA) at various gestational weeks. The two ddPCR assays were then applied to determine the fetal genotype from 52 maternal plasma samples at different gestational ages. The diagnostic outcomes were confirmed for all the samples by DNA sequencing. In the case of mutations inherited from the mother or from both parents, a precise dosage of normal and mutated alleles was required to determine the fetal genotype. In particular, we identified two diagnostic ranges for allelic ratio values statistically distinct and not overlapping, allowing correct fetal genotype determinations for almost all the analyzed samples. In conclusion, we have developed a simple and sensitive diagnostic tool, based on ddPCR, for the NIPT of β+IVSI-110 and β039 mutations paternally and, for the first time, maternally inherited, a tool, which may be applied to other single point mutations causing monogenic diseases.

PMID:35269962 | DOI:10.3390/ijms23052819

Int J Mol Sci. 2022 Feb 28;23(5):2720. doi: 10.3390/ijms23052720.

ABSTRACT

Uterine fibroids (UFs) are monoclonal, benign tumors that contain abnormal smooth muscle cells and the accumulation of extracellular matrix (ECM). Although benign, UFs are a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor. Many risk factors are involved in the pathogenesis of UFs via genetic and epigenetic mechanisms. The latter involving DNA methylation and demethylation reactions provide specific DNA methylation patterns that regulate gene expression. Active DNA demethylation reactions mediated by ten-eleven translocation proteins (TETs) and elevated levels of 5-hydroxymethylcytosine have been suggested to be involved in UF formation. This review paper summarizes the main findings regarding the function of TET enzymes and their activity dysregulation that may trigger the development of UFs. Understanding the role that epigenetics plays in the pathogenesis of UFs may possibly lead to a new type of pharmacological fertility-sparing treatment method.

PMID:35269864 | DOI:10.3390/ijms23052720

Molecules. 2022 Mar 4;27(5):1691. doi: 10.3390/molecules27051691.

ABSTRACT

The fresh fruits of Prunus spinosa L., a wild plum species, are traditionally used for dietary purposes and medicinal applications in disorders related to inflammation and oxidative stress. This study aimed to investigate the phytochemical composition of the fruits in the function of fractionated extraction and evaluate the biological potential of the extracts as functional products in two models of human immune cells ex vivo. Fifty-seven phenolic components were identified in the extracts by UHPLC-PDA-ESI-MS3, including twenty-eight new for the analysed fruits. Fractionation enabled the enrichment of polyphenols in the extracts up to 126.5 mg gallic acid equivalents/g dw total contents, 91.3 mg/g phenolic acids (caffeoyl-, coumaroyl-, and feruloylquinic acids), 41.1 mg/g flavonoids (mostly quercetin mono-, di- and triglycosides), 44.5 mg/g condensed proanthocyanidins, and 9.2 mg/g anthocyanins (cyanidin and peonidin glycosides). The hydroalcoholic extract and phenolic-enriched fractions of the fruits revealed significant ability to modulate pro-oxidant, pro-inflammatory, and anti-inflammatory functions of human neutrophils and peripheral blood mononuclear cells (PBMCs): they strongly downregulated the release of reactive oxygen species, TNF-α, and neutrophils elastase, upregulated the secretion of IL-10, and slightly inhibited the production of IL-8 and IL-6 in the cells stimulated by fMLP, fMLP+cytochalasin B, and LPS, depending on the test. Correlation studies and experiments on the pure compounds indicated a significant contribution of polyphenols to these effects. Moreover, cellular safety was confirmed for the extracts by flow cytometry in a wide range of concentrations. The results support the traditional use of fresh blackthorn fruits in inflammatory disorders and indicate extracts that are most promising for functional applications.

PMID:35268792 | DOI:10.3390/molecules27051691

Cancers (Basel). 2022 Mar 5;14(5):1343. doi: 10.3390/cancers14051343.

ABSTRACT

Metformin and 2-deoxy-D-glucose (2DG) exhibit multiple metabolic and immunomodulatory anti-cancer effects, such as suppressed proliferation or PD-L1 expression. Their combination or 2DG alone induce triple-negative breast cancer (TNBC) cell detachment, but their effects on mitochondria, crucial for anchorage-independent growth and metastasis formation, have not yet been evaluated. In the present study, we explored the effects of metformin, 2DG and their combination (metformin + 2DG) on TNBC cell mitochondria in vitro. Metformin + 2DG increased mitochondrial mass in TNBC cells. This was associated with an increased size but not number of morphologically normal mitochondria and driven by the induction of mitochondrial biogenesis rather than suppressed mitophagy. 2DG and metformin + 2DG strongly induced the unfolded protein response by inhibiting protein N-glycosylation. Together with adequate energy stress, this was one of the possible triggers of mitochondrial enlargement. Suppressed N-glycosylation by 2DG or metformin + 2DG also caused PD-L1 deglycosylation and reduced surface expression in MDA-MB-231 cells. PD-L1 was increased in low glucose and normalized by both drugs. 2DG and metformin + 2DG reduced PD-1 expression in Jurkat cells beyond the effects on activation, while cytokine secretion was mostly preserved. Despite increasing mitochondrial mass in TNBC cells, metformin and 2DG could therefore potentially be used as an adjunct therapy to improve anti-tumor immunity in TNBC.

PMID:35267651 | DOI:10.3390/cancers14051343

Cancers (Basel). 2022 Feb 23;14(5):1131. doi: 10.3390/cancers14051131.

ABSTRACT

While over ten-thousand phase I studies are published in oncology, fewer than 1% of these studies stratify patients based on genetic variants that influence pharmacology. Pharmacogenetics-based patient stratification can improve the success of clinical trials by identifying responsive patients who have less potential to develop toxicity; however, the scientific limits imposed by phase I study designs reduce the potential for these studies to make conclusions. We compiled all phase I studies in oncology with pharmacogenetics endpoints (n = 84), evaluating toxicity (n = 42), response or PFS (n = 32), and pharmacokinetics (n = 40). Most of these studies focus on a limited number of agent classes: Topoisomerase inhibitors, antimetabolites, and anti-angiogenesis agents. Eight genotype-directed phase I studies were identified. Phase I studies consist of homogeneous populations with a variety of comorbidities, prior therapies, racial backgrounds, and other factors that confound statistical analysis of pharmacogenetics. Taken together, phase I studies analyzed herein treated small numbers of patients (median, 95% CI = 28, 24-31), evaluated few variants that are known to change phenotype, and provided little justification of pharmacogenetics hypotheses. Future studies should account for these factors during study design to optimize the success of phase I studies and to answer important scientific questions.

PMID:35267440 | DOI:10.3390/cancers14051131

J Infect Dis. 2022 Mar 10:jiac091. doi: 10.1093/infdis/jiac091. Online ahead of print.

ABSTRACT

BACKGROUND: Excessive complement activation has been implicated in the pathogenesis of COVID-19, but the mechanisms leading to this response remain unclear.

METHODS: We measured plasma levels of key complement markers, SARS-CoV-2 RNA and antibodies against SARS-CoV-2 and common cold coronaviruses (CCC) in hospitalized patients with COVID-19 of moderate (n=18) and critical severity (n=37), and healthy control subjects (n=10).

RESULTS: We confirmed that complement activation is systemically increased in COVID-19 patients and is associated with a worse disease outcome. We showed that plasma levels of C1q and circulating immune complexes (CIC) were markedly increased in severe COVID-19 patients and correlated with higher IgG titers, greater complement activation and higher disease severity score. Additional analyses showed that the classical pathway was the main arm responsible for augmented complement activation in severe patients. In addition, we demonstrated that a rapid IgG response to SARS-CoV-2 and an anamnestic IgG response to the nucleoprotein of the CCC were strongly correlated with CIC levels, complement activation, and disease severity.

CONCLUSIONS: These findings indicate that early, non-neutralizing IgG responses may play a key role in complement overactivation in severe COVID-19. Our work underscores the urgent need to develop therapeutic strategies to modify complement overactivation in COVID-19 patients.

PMID:35267024 | DOI:10.1093/infdis/jiac091

Clin Transl Sci. 2022 Mar 10. doi: 10.1111/cts.13266. Online ahead of print.

ABSTRACT

PDE4B (phosphodiesterase-4B) has an important role in cancer and in pharmacology of some disorders, such as inflammatory diseases. Remarkably in Native Americans, PDE4B variants are associated with acute lymphoblastic leukemia (ALL) relapse, as this gene modulates sensitivity of glucocorticoids used in ALL chemotherapy. PDE4B allele rs6683977.G, associated with genomic regions of Native American origin in US-Hispanics (admixed between Native Americans, Europeans and Africans), increases ALL relapse risk, contributing to an association between Native American ancestry and ALL relapse that disappeared with an extra-phase of chemotherapy. This result insinuates that indigenous populations along the Americas may have high frequencies of rs6683977.G, but this has never been corroborated. We studied ancestry and PDE4B diversity in 951 healthy individuals from 9 Latin American populations. In non-admixed Native American populations rs6683977.G has frequencies >90%, is in linkage disequilibrium with other ALL relapse associated and regulatory variants in PDE4B-intron-7, conforming haplotypes showing their highest worldwide frequencies in Native Americans (>0.82). Our findings inform the discussion on the pertinence of an extra-phase of chemotherapy in Native American populations, and exemplifies how knowledge generated in US-Hispanics is relevant for their even more neglected and vulnerable Native American ancestors along the American continent.

PMID:35266293 | DOI:10.1111/cts.13266

Front Nutr. 2022 Feb 21;9:772243. doi: 10.3389/fnut.2022.772243. eCollection 2022.

ABSTRACT

Type 2 diabetes mellitus (T2DM) is a heterogeneous metabolic disorder of multifactorial etiology that includes genetic and dietary influences. By addressing the latter, medical nutrition therapy (MNT) contributes to the management of T2DM or pre-diabetes toward achieving glycaemic control and improved insulin sensitivity. However, the clinical outcomes of MNT vary and may further benefit from personalized nutritional plans that take into consideration genetic variations associated with individual responses to macronutrients. The aim of the present series of n-of-1 trials was to assess the effects of genetically-guided vs. conventional MNT on patients with pre-diabetes or T2DM. A quasi-experimental, cross-over design was adopted in three Caucasian adult men with either diagnosis. Complete diet, bioclinical and anthropometric assessment was performed and a conventional MNT, based on the clinical practice guidelines was applied for 8 weeks. After a week of "wash-out," a precision MNT was prescribed for an additional 8-week period, based on the genetic characteristics of each patient. Outcomes of interest included changes in body weight (BW), fasting plasma glucose (FPG), and blood pressure (BP). Collectively, the trials indicated improvements in BW, FPG, BP, and glycosylated hemoglobin (HbA1c) following the genetically-guided precision MNT intervention. Moreover, both patients with pre-diabetes experienced remission of the condition. We conclude that improved BW loss and glycemic control can be achieved in patients with pre-diabetes/T2DM, by coupling MNT to their genetic makeup, guiding optimal diet, macronutrient composition, exercise and oral nutrient supplementation in a personalized manner.

PMID:35265654 | PMC:PMC8899711 | DOI:10.3389/fnut.2022.772243

Blood Cancer J. 2022 Mar 9;12(3):39. doi: 10.1038/s41408-022-00636-2.

ABSTRACT

Multiple myeloma, the second-most common hematopoietic malignancy in the United States, still remains an incurable disease with dose-limiting toxicities and resistance to primary drugs like proteasome inhibitors (PIs) and Immunomodulatory drugs (IMiDs).We have created a computational pipeline that uses pharmacogenomics data-driven optimization-regularization/greedy algorithm to predict novel drugs ("secDrugs") against drug-resistant myeloma. Next, we used single-cell RNA sequencing (scRNAseq) as a screening tool to predict top combination candidates based on the enrichment of target genes. For in vitro validation of secDrugs, we used a panel of human myeloma cell lines representing drug-sensitive, innate/refractory, and acquired/relapsed PI- and IMiD resistance. Next, we performed single-cell proteomics (CyTOF or Cytometry time of flight) in patient-derived bone marrow cells (ex vivo), genome-wide transcriptome analysis (bulk RNA sequencing), and functional assays like CRISPR-based gene editing to explore molecular pathways underlying secDrug efficacy and drug synergy. Finally, we developed a universally applicable R-software package for predicting novel secondary therapies in chemotherapy-resistant cancers that outputs a list of the top drug combination candidates with rank and confidence scores.Thus, using 17AAG (HSP90 inhibitor) + FK866 (NAMPT inhibitor) as proof of principle secDrugs, we established a novel pipeline to introduce several new therapeutic options for the management of PI and IMiD-resistant myeloma.

PMID:35264575 | DOI:10.1038/s41408-022-00636-2

Am J Med. 2022 Mar 6:S0002-9343(22)00149-8. doi: 10.1016/j.amjmed.2022.02.008. Online ahead of print.

NO ABSTRACT

PMID:35263634 | DOI:10.1016/j.amjmed.2022.02.008

PLoS One. 2022 Mar 9;17(3):e0264987. doi: 10.1371/journal.pone.0264987. eCollection 2022.

ABSTRACT

Bryophyllum pinnatum (Lam.) Oken (BP) is a plant that is used worldwide to treat inflammation, infections, anxiety, restlessness, and sleep disorders. While it is known that BP leaves are rich in flavonoids, the extent of the beneficial and toxic effects of its crude extracts remains unclear. Although some neurobehavioral studies using leaf extracts have been conducted, none has examined the effects of water-extracted leaf samples. The zebrafish is a powerful animal model used to gain insights into the efficacy and toxicity profiles of this plant due to its high fecundity, external development, and ease of performing behavioral assays. In this study, we performed behavioral testing after acute exposure to different concentrations of aqueous extract from leaves of B. pinnatum (LABP) on larval zebrafish, investigating light/dark preference, thigmotaxis, and locomotor activity parameters under both normal and stressed conditions. LABP demonstrated dose-and time-dependent biphasic effects on larval behavior. Acute exposure (25 min) to 500 mg/L LABP resulted in decreased locomotor activity. Exposure to 300 mg/L LABP during the sleep cycle decreased dark avoidance and thigmotaxis while increasing swimming velocity. After sleep deprivation, the group treated with 100 mg/L LABP showed decreased dark avoidance and increased velocity. After a heating stressor, the 30 mg/L and 300 mg/L LABP-treated groups showed decreased dark avoidance. These results suggest both anxiolytic and psychoactive effects of LABP in a dose-dependent manner in a larval zebrafish model. These findings provide a better understanding of the mechanisms underlying relevant behavioral effects, consequently supporting the safe and effective use of LABP for the treatment of mood disorders.

PMID:35263358 | DOI:10.1371/journal.pone.0264987

Biogerontology. 2022 Mar 9. doi: 10.1007/s10522-022-09958-x. Online ahead of print.

ABSTRACT

Molecular causes of aging and longevity interventions have witnessed an upsurge in the last decade. The resurgent interests in the application of small molecules as potential geroprotectors and/or pharmacogenomics point to nicotinamide adenine dinucleotide (NAD) and its precursors, nicotinamide riboside, nicotinamide mononucleotide, nicotinamide, and nicotinic acid as potentially intriguing molecules. Upon supplementation, these compounds have shown to ameliorate aging related conditions and possibly prevent death in model organisms. Besides being a molecule essential in all living cells, our understanding of the mechanism of NAD metabolism and its regulation remain incomplete owing to its omnipresent nature. Here we discuss recent advances and techniques in the study of chronological lifespan (CLS) and replicative lifespan (RLS) in the model unicellular organism Saccharomyces cerevisiae. We then follow with the mechanism and biology of NAD precursors and their roles in aging and longevity. Finally, we review potential biotechnological applications through engineering of microbial lifespan, and laid perspective on the promising candidature of alternative redox compounds for extending lifespan.

PMID:35260986 | DOI:10.1007/s10522-022-09958-x