Low Dose Research Articles

Retardation of myopia by atropine regimes

Myopia is a huge health problem due to its high frequency, vision losses and public health cost. According to the World Health Organization, at least 2.2 billion people have vision impairment. Although myopia can be controlled at its early and middle stages, unfortunately, no cure can be achieved so far. Among the methods to control myopia, atropine, a muscarinic receptor antagonist, is the oldest but still the most effective for retardation of myopia progression. Despite such a fact, standard protocols have not been established for clinicians to use atropine for treatment of myopia. In this article, a concise and up to date summary of myopia epidemiology and pathogenesis and summarized therapeutic effects and side effects, possible mechanisms and application methods of atropine were provided in hope for clinical doctors to effectively control this problematic disease. At present, the protocol is recommend: use higher dose (1%) of atropine intermittently to effectively slowdown myopia progression in schoolchildren for 2y, and to significantly reduce side effects of atropine by decrease of atropine frequency for 1y and inhibit myopic rebound by withdrawal of topical atropine gradually for 1y. Application of a lower dose (0.05%) atropine regime should also be considered due to its effectiveness and application at regular basis.

Chromatographic assay of recently approved co-formulation of Vonoprazan fumarate with low dose Aspirin: AGREE, Complex MoGAPI, and RGB 12-model assessments.

Two simple, valid and green chromatographic based techniques are developed in the present work for first time to simultaneously analyze the recently approved combination of Aspirin (ASP) with the novel gastro-protective agent Vonoprazan (VON). First method is an HPLC-DAD "diode array detection", where separation was successful using C18 (250 × 4.6mm) column with isocratic elution of phosphate buffer-pH 6.8 and acetonitrile in ratio of 63:37 with detection at 230nm. Second method is an HPTLC method on HPTLC silica plates using ethyl acetate: ethanol (75%): ammonia (5:5:0.05 v/v) mobile phase followed by densitometric scanning at 230nm. The methods were applied successfully for analysis of VON and ASP mixture in laboratory-prepared tablets and the methods were validated in regards to linearity, precision, accuracy and selectivity. The proposed methods are assessed for their greenness and whiteness as well using the "Analytical GREEnness Metric Approach", "Complementary Modified Green Analytical Procedure Index" and the new algorithm "RGB 12 model" (Red-Green-Blue) and proved the greenness and the sustainability of the methods in the routine assay of the newly marketed formulation.

Effects of dietary Brassica rapa L. polysaccharide on growth performance, immune and antioxidant functions and intestinal flora of yellow-feathered quail.

This study aimed to explore the impact of Brassica rapa L. polysaccharides (BRP) on the growth, immune response, antioxidant capacity, and cecal microbiota in yellow-feathered quails. A total of 250 one-day-old yellow-feathered quails, evenly divided by sex, were randomly assigned to five groups, with each group comprising ten replicates of five quails each. The control group (CON) received a basic diet, while the antibiotic control group (CTC) was fed a basic diet supplemented with chlortetracycline (0.05g/kg). BRP was administered at concentrations of 0.25g/kg (Low dose BRP, LBRP), 0.5g/kg (Medium dose BRP, MBRP), and 1g/kg (High dose BRP, HBRP). The duration of the experiment was 42 days. The results indicated that, compared to the CON group, the final body weight of quails in the MBRP group significantly increased (P < 0.05), and there was a significant difference in body weight between the LBRP group and the CTC group (P < 0.05). At 21 days of age, the average weights of the thymus and bursa of Fabricius in the MBRP group were significantly greater than those in the CON group (P < 0.05), with no significant difference observed when compared to the CTC group (P > 0.05); at 42 days of age, the average weight of the thymus in the MBRP group was significantly greater than that in the CON group (P < 0.05), with no significant difference observed compared to the CTC group (P > 0.05). At 21 days of age, the levels of IgA and IgG in the MBRP group were significantly elevated compared to the CON group (P < 0.05), with no significant difference noted compared to the CTC group (P > 0.05). Additionally, the MBRP group showed significant increases in CAT, T-SOD, and GSH-Px levels (P < 0.05) compared to the CON group; the levels of IL-1β and TNF-α were significantly reduced (P < 0.05), and the level of IL-10 was significantly elevated (P < 0.05) compared to the CON group. Furthermore, 16S rRNA sequencing revealed that BRP supplementation increased the populations of beneficial cecal bacteria such as Lactococcus, Weissella, Parabacteroides, and norank_f_Ruminococcaceae, and decreased the population of the harmful bacterium Campylobacter, indicating that BRP modulates the microbial community structure in the cecum of yellow-feathered quails. In summary, BRP enhanced the growth performance, serum immunoglobulin levels, antioxidant functions, and improved the intestinal microbiota in yellow-feathered quails.

Combined therapy with pirfenidone and nintedanib counteracts fibrotic silicosis in mice.

Pneumoconiosis, especially silicosis, is a prevalent occupational disease with substantial global economic implications and lacks a definitive cure. Both pneumoconiosis and idiopathic pulmonary fibrosis (IPF) are interstitial lung diseases, which share many common physiological characteristics. Because pirfenidone and nintedanib are approved to treat IPF, their potential efficacy as antifibrotic agents in advanced silicosis deserves further exploration. Thus, we aimed to evaluate the individual and combined effects of pirfenidone and nintedanib in treating advanced silicosis mice and elucidate the underlying mechanisms of their therapeutic actions via multiomics. We administered monotherapy or combined therapy of pirfenidone and nintedanib, with low and high doses, in silicosis established after 6weeks and evaluated lung function, inflammatory responses and fibrotic status. Additionally, we employed transcriptomic and metabolomic analyses to uncover the mechanisms underlying different therapeutic strategies. Both pirfenidone and nintedanib were effective in treating advanced silicosis, with superior outcomes observed in combination therapy. Transcriptomic and metabolomic analyses revealed that pirfenidone and nintedanib primarily exerted their therapeutic effects by modulating immune responses, signalling cascades and metabolic processes involving lipids, nucleotides and carbohydrates. Furthermore, we experimentally validated both monotherapy and combined therapy yielded therapeutic benefits through two common signalling pathways: steroid biosynthesis and purine metabolism. In conclusion, pirfenidone and nintedanib, either individually or in combination, demonstrate substantial potential in advanced silicosis. Furthermore, combined therapy outperformed monotherapy, even at low doses. These therapeutic benefits are attributed to their influence on diverse signalling pathways and metabolic processes.

New Pharmacological Insight into Etanercept and Pregabalin in Allodynia and Nociception: Behavioral Studies in a Murine Neuropathic Pain Model

Background/Objectives: Neuropathic pain is challenging to treat, often resistant to current therapies, and associated with significant side effects. Pregabalin, an anticonvulsant that modulates calcium channels, is effective but can impair mental and motor functions, especially in older patients. To improve patient outcomes, reducing the doses of pregabalin and combining it with other drugs targeting different neuropathic pain mechanisms may be beneficial. TNF-α blockers such as etanercept have shown potential in addressing neuropathic pain by affecting sodium channels, synaptic transmission, and neuroinflammation. This study evaluates the efficacy and safety of combining low doses of etanercept and pregabalin in allodynia and nociceptive tests. Materials and Methods: Male C57/BL6 mice underwent chronic constriction injury (CCI) of the sciatic nerve to induce neuropathic pain. They were divided into seven groups: sham control, CCI control, low and high doses of pregabalin, low and high doses of etanercept, and a combination of low doses of both drugs. Behavioral tests, including von Frey, hot-plate, and rotarod tests, were used to assess pain responses and motor activity. Results: The results indicated that a high dose of pregabalin significantly reduced mechanical allodynia and thermal hyperalgesia but impaired motor function. Conversely, low doses of etanercept alone had no significant effect. However, the combination of low doses of etanercept (20 mg/kg) and pregabalin (5 mg/kg) effectively alleviated pain without compromising locomotor activity. Conclusions: These results suggest a novel therapeutic strategy for neuropathic pain, enhancing analgesic efficacy while minimizing adverse effects.

Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis.

The retinoic acid receptor-related orphan receptor γt (RORγt) is a key regulator of Th17 cells, associated with autoimmune diseases, making it a significant drug target. Herein, we designed and synthesized 1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline derivatives, improving upon GSK2981278 to enhance bioavailability. Of which, D4 exhibited superior bioavailability (F = 48.1 and 32.9% in mice and rats, respectively) compared to GSK2981278 (F = 6.2 and 4.1%, respectively), and effectively treated psoriasis in mice at lower doses. Moreover, for the first time, we report the efficacies of a RORγt inverse agonist in mouse models of rheumatoid arthritis. (R)-D4, the eutomer of D4, matched or exceeded GSK2981278's therapeutic effects at lower doses, with no adverse effects observed after 2 weeks of administration. These results position (R)-D4 as a promising and orally bioavailable candidate for Th17-mediated autoimmune disease treatment.

The Variability of the Cervicothoracic Inflection Point: A Cohort Analysis of the Multi-Ethnic Asymptomatic Normative Study (MEANS).

Cross-sectional Cohort Study. To determine the cervicothoracic inflection point in an asymptomatic, adult population. The cervicothoracic inflection point (CTIP) is an important sagittal marker to understand for patients with cervical deformities. We aimed to identify the CTIP and understand the relationship to other sagittal alignment markers. 468 adult asymptomatic volunteers (18-80years) from 5 countries (United States, France, Japan, Singapore, Tunisia). All volunteers underwent standing full body, low dose stereo radiographs. The CTIP was identified by measuring the cervical sagittal angle (CSA) and thoracic kyphosis maximum angle (TKMax), using the end vertebra concept. The CTIP was defined as the vertebra or disc between the lower end vertebra of the CSA and upper end vertebra of TKMax. A correlation matrix was utilized to identify the relationship between the CTIP and spinopelvic sagittal parameters of interest. The most common CTIP value was the T1 vertebra. CTIPs ranged from C5 to T4, respectively. CTIP showed a weak positive correlation to age (r = 0.10, P = 0.03) and negative correlation to BMI (r = -0.11, P = 0.04). Additionally, CTIP had a minor positive correlation with OC2-CL, C7 slope, T1 slope, T1PA, T1-T12TK, and T4-T12TK, all statistically significant. Linear regression demonstrated increased cervical lordosis and increased TK was associated with more caudal CTIP segments. CTIP segments ranged from C5 to T4, with the most common segment being T1. Understanding the relationship of the CTIP to other sagittal variables is critical to patients with CD.

Evaluation of ethanolic extract of Piper methysticum leaves on anxiolytic activity of mice

The ethanol extract of Piper methysticum, commonly known as kava, has shown promising results in reducing anxiety. Studies suggest it may have anxiolytic effects, potentially offering a natural alternative to conventional anxiety treatments. The ethanolic extract of Piper methysticum can increase the duration of action. It can also increase the time spent in open arm, entry in open arm (in elevated plus model) as well as increase the time spent in light field (in Light Dark field) thus we can conclude that it can also possesses Anxiolytic action. The ethanolic extract of Piper methysticum possesses an anxiolytic like activity without sedative side effect. The corticosterone level in mice is increased when they got anxiety. So when the plasma corticosterone level of mice is checked in control group its turn out to be 10.28±0.52. It gets decreased with increase in doses. When treated with low dose of Aqueous extract is 7.28±1.44 is less effective than low dose of Ethanolic extract that is 6.22±1.28. Same as that high dose of extract shows the corticosterone level was 6.24±2.28 which was also less effective than high dose of ethanolic extract which was 5.52±0.32. Most effectively stress was decreased when treated with the Standard drug (Alprazolam) which shows plasma corticosterone level was 1.24±0.36. The mice of Piper methysticum extract (300 &amp;600 mg/kg/ p.o.) treated group showed significantly (p&lt;0.05) increased in body water intake as compared to the control group. Results showed that synthesized extract is very effective for the treatment of anxiety. Keywords: Piper methysticum; anxiolytic activity; Anthraquinones; Light Dark model

Porcine Airway Organoid-Derived Well-Differentiated Epithelial Cultures as a Tool for the Characterization of Swine Influenza a Virus Strains

Swine influenza A viruses (IAVsw) are important causes of disease in pigs but also constitute a public health risk. IAVsw strains show remarkable differences in pathogenicity. We aimed to generate airway organoids from the porcine lower respiratory tract and use these to establish well-differentiated airway epithelial cell (WD-AEC) cultures grown at an air–liquid interface (ALI) for in vitro screening of IAVsw strain virulence. Epithelial cells were isolated from bronchus tissue of juvenile pigs, and airway organoids were cultured in an extracellular matrix in a culture medium containing human growth factors. Single-cell suspensions of these 3D organoids were seeded on Transwell filters and differentiated at ALI to form a pseudostratified epithelium containing ciliated cells, mucus-producing cells and tight junctions. Inoculation with a low dose of IAVsw in a low volume inoculum resulted in virus replication without requiring the addition of trypsin, and was quantified by the detection of viral genome loads in apical washes. Interestingly, inoculation of an H3N2 strain known to cause severe disease in pigs induced a greater reduction in trans-epithelial resistance and more damage to tight junctions than H1N2 or H1N1 strains associated with mild disease in pigs. We conclude that the porcine WD-AEC model is useful in assessing the virulence of IAVsw strains.

Effect of soy protein isolate supplementation on the estradiol biosynthesis pathway in a female rat model

Background Soy protein isolate (SPI) has gained popularity as an alternative to animal proteins. Soy consumption may have a link to rising serum estrogen in humans. This concern is attributed to phytoestrogens, specifically isoflavones present in soy protein, acting as estrogen substitutes and modulators. Objective The objective of this research was to assess the influence of SPI supplementation on estradiol hormone levels and the expression of genes associated with estrogen synthesis in female rats. Materials and methods Female Wistar rats (n=18) were evenly divided into three groups: group 1 (normal control) received oral administration of a saline vehicle. Group 2 (low dose) received 450 mg/kg body weight of SPI for 30 days. Group 3 (high dose) received 900 mg/kg body weight of SPI for 30 days. All administrations were conducted intragastrically. Results and conclusion The results of our study indicate that there was a significant increase in the levels of estradiol hormone in groups receiving low and high doses of SPI when compared with the control group. There was an upregulation in the messenger ribonucleic acid expression of the Cyp19 gene in low-dose and high-dose groups. Moreover, the low-dose group showed upregulation in the expression of the HSD3B gene. These genes are involved in the biosynthesis pathway of estrogen hormone in females. Therefore, the use of SPI should be cautious because it contains phytoestrogens (isoflavones), which have structural similarities to endogenous female estrogen and may cause hormonal disturbance in females.

Comparison of High and Low Dose Calcium Supplementation in Prevention of Hypertensive Disorders of Pregnancy

Calcium supplementation during pregnancy may prevent high blood pressure and preterm labour. Out of 500 women, 480 completed the study. At hospital enrolment, the average systolic blood pressure (SBP) was similar between the two groups (116.10 mm Hg vs. 115.01 mm Hg; P = 0.215), as was the average diastolic blood pressure (DBP) (72.74 mm Hg vs. 72.12 mm Hg; P = 0.301). No significant increase in blood pressure was observed in the majority of pregnant women in either group until delivery. Only 2.5% of women in the low-dose group (LDG - group I) and 1.88% in the high-dose group (HDG - group II) developed pre-eclampsia by the end of the study, with no significant association between different calcium dosages and the occurrence of pre-eclampsia (P = 0.503). Regarding maternal complications, 0.63% of women in the group I and 0.21% in the group II experienced major complications during pregnancy or postpartum, but this was not statistically significant (P = 0.623). Among the 480 women, 475 had term labor, and only 5 had preterm deliveries (before 36 weeks of gestation). No maternal deaths were reported.Our study concluded that calcium supplementation, whether in low or high dose, provides significant benefit for pregnant women. The findings demonstrate a notable advantage in preventing pregnancy-induced hypertension (PIH), preterm labor, premature births, and related complications. Therefore, calcium supplementation is highly effective in preventing PIH, which in turn helps prevent pre-eclampsia and eclampsia. As both low and high dose Calcium are effective in preventing PE and Eclampsia, it may be recommended that low dose calcium supplementation may be helpful in prevention of HDP and have favourable feto-maternal outcome in a low resource setting like ours. Keywords: Hypertensive disorders of pregnancy (HDP), Blood Pressure, Pre-eclampsia, Calcium.

Effects of a Saccharomyces cerevisiae-Derived Postbiotic in Adult Labrador Retrievers Undergoing Exercise and Transport Stress

Postbiotics are emerging as potential functional ingredients for companion animal diets. This study aimed to determine if a Saccharomyces cerevisiae-based postbiotic can alter cytokine and stress responses to exercise and transport stress in adult Labrador Retrievers. Dogs received 15 g ground corn germ (Control, n = 12), 7.5 g postbiotic (Low, n = 12), or 15 g postbiotic (High, n = 12), daily for 63 days. Exercise was twice weekly for 7 weeks, and a single transport per dog occurred in week 8. Fecal inflammatory biomarkers, serum chemistries, and complete blood counts were assessed at the beginning and end of the study. Serum cytokines were quantified before and 18–20 h after the first and last exercise runs. Gait analysis was assessed before and 24 h after the first and final runs. Saliva cortisol was measured before and after transportation. Treatment did not affect blood chemistries, gait, fecal biomarkers, or saliva cortisol (p ≥ 0.19). Eosinophils increased slightly in Controls (p = 0.01), though remained below 0.80 × 109 cells/L. Most cytokines were unaffected by treatment (p ≥ 0.15), but there were minor changes in circulating monocyte chemoattractant protein-1 (p = 0.01) and IL-8 over time at the initial run (p = 0.03) and IL-10 in males (p = 0.02) in the Low dose dogs. The High dose decreased Blautia (p = 0.04) slightly and tended to decrease Fusobacterium abundances (p = 0.07). The Low dose tended to increase Clostridium hiranonis (p = 0.07) slightly. The tested S. cerevisiae postbiotic produced small changes in immune function and gut microbial species in dogs.

Management of venous aneurysms and the vascular surgical treatment options : Selection of representative case constellations illustrating experiences at acenter for vascular surgery

Venous aneurysms are arare entity in vascular surgery, which are mostly described in individual case series and meta-analyses generated from them. The treatment concepts are diverse and surgical treatment is highlighted due to the risk of thrombosis and pulmonary embolism. There is still an ongoing debate regarding the postoperative necessity and duration of anticoagulation. Case series of aconsecutive patient cohort with venous aneurysms from the last 18years in acenter of (highly specialized care) vascular surgery including i)own experiences obtained in daily vascular surgical practice and ii)aselected and current literature search of relevant references on possible and, in particular, established diagnosis-specific therapeutic concepts. Between 2005 and 2023, atotal of 11cases of venous aneurysms were reported in patients aged 30-84years (mean: 52.5, median: 50), with 1 patient requiring surgery for a recurrence after 2years. The gender ratio was 7:3 (m:f) and the popliteal vein was the most frequently affected anatomical region with 36.4%, followed by the internal jugular vein and axillary/subclavian vein each with 18.2%. Aneurysms of the inferior vena cava, the common iliac vein and the cubital vein occurred only once. Surgical treatment of the aneurysms was performed in 9cases. The surgical methods used were i)tangential resection of the aneurysm wall and continuous purse-string suture, ii)resection of the aneurysm and interposition of an 8‑mm GORE-TEX® vascular graft prosthesis (Gore, Putzbrunn, Germany), iii)ligation of the aneurysm and iv)ligation with subsequent resection of the aneurysm. The rarity of venous aneurysms should be a reason to register these cases centrally (possibly, nationwide diagnosis-related register). Surgical treatment is usually unproblematic and associated with few complications. The risk of pulmonary embolism appears to be significantly increased in venous aneurysms of the extremities, pelvic veins and inferior vena cava, while venous aneurysms of the head and neck are significantly less prone to this. Perioperative and postoperative anticoagulation has been adapted to the development of specific anticoagulants and novel drugs, in favor of treatment with direct oral anticoagulants (DOAC). In personal experience, immediate postoperative heparin perfusion (low dose) and subsequent therapeutic bridging with low-molecular-weight heparin before switching to an anticoagulant for outpatient clinic-based care appears to safeguard the perioperative phase with respect to keeping the surgery-related complication rate (e.g., thrombosis, bleeding) low.

Cinnamaldehyde ameliorates diabetes-induced biochemical impairments and AGEs macromolecules in a pre-clinical model of diabetic nephropathy.

Cinnamaldehyde, has various therapeutic potentials including glucose-lowering effect, and insulinotropic effect; however, its glycation inhibitory mechanism is not known yet. In this study, we explored the effects of cinnamaldehyde for its AGEs inhibitory mechanism in a streptozotocin-complete Freund's adjuvant (STZ-CFA) induced diabetic nephropathy (DN) rat model. Pre-clinical DN model was developed by the administration of multiple low doses of STZ-CFA in rats, mainly characterized by abnormal blood parameters and nephrotic damages. Diabetes-related systemic profile and histopathological hallmarks were evaluated using biochemical assays, microscopic imaging, immunoblot, and real-time PCR analyses, supported by cinnamaldehyde-albumin interaction assessed using STD-NMR and in silico site-directed interactions in the presence of glucose. Cinnamaldehyde-treatment significantly reversed DN hallmarks, fasting blood glucose (FBG), serum insulin, glycated hemoglobin (HbA1c), urinary microalbumin, and creatinine contrasted to non-treated DN rats and aminoguanidine, a positive reference advanced glycation end products (AGEs) inhibitor. The pathological depositions of AGEs, receptor for advanced glycation end products (RAGE), and carboxymethyl lysine (CML), and transcriptional levels of AGE-RAGE targeted immunomodulatory factors (IL1β, TNF-α, NF-κB, TGF-β) were significantly improved in cinnamaldehyde treated rats as compared to aminoguanidine. Cinnamaldehyde post-treatment improved pancreatic pathology and systemic glycemic index (0.539 ± 0.01 vs. 0.040 ± 0.001, P < 0.001) in DN rats. Subsequently, in silico profiling of cinnamaldehyde defined the competitive binding inhibition with glucose in AGE and RAGE receptors that was further confirmed by in vitro STD-NMR analysis. These findings suggest potential role of cinnamaldehyde in reversing STZ-induced diabetic nephropathic impairments; therefore, appears promising candidate for further pharmacological explorations towards diabetes-associated complications.

Dose sparing enabled by immunization with influenza vaccine using orally dissolving film.

Influenza vaccine delivered by orally dissolving film vaccine (ODFV) is a promising approach. In this study, we generated three ODFVs each comprising pulluan and trehalose with different doses of inactivated A/Puerto Rico/8/34, H1N1 virus (ODFV I, II, III) to evaluate their dose-sparing effect in mice. The ODFVs were placed on the tongues of mice to elicit immunization and after 3 immunizations at 4-week intervals, mice were challenged with a lethal dose of A/PR/8/34 to assess vaccine-induced protection. The 3 ODFVs containing 50, 250, or 750 μg of inactivated viruses elicited virus-specific antibody responses and virus neutralization in a dose-dependent manner. Dose-dependent antibody responses were also observed from the mucosal tissue samples, and also from antibody-secreting cells of the lungs and spleens. ODFV-induced cellular immunity, particularly germinal center B cells and T cells were also dose-dependent. Importantly, all 3 ODFVs evaluated in this study provided complete protection by strongly suppressing the pro-inflammatory cytokine production and lung virus titers. None of the immunized mice underwent noticeable weight loss nor succumbed to death, a phenomenon that was only observed in the infection challenge controls. These results indicated that the protection conferred by a low dose influenza vaccine formulated in ODF is comparable to that of a high-dose vaccine, thereby enabling vaccine dose sparing effect.

Short-term exposure to low doses of aflatoxin B1 aggravates nonalcoholic steatohepatitis by TLR4-mediated necroptosis.

Aflatoxin B1 (AFB1), a worldwide mycotoxin found in food and foodstuffs, is a potent hepatotoxin in humans and animals. Non-alcoholic fatty liver disease (NAFLD), a widespread disease, could progress from simple steatosis to non-alcoholic steatohepatitis (NASH), hepatic cirrhosis, and even hepatocellular carcinoma (HCC). To date, little is known concerning the relationship between AFB1 and the progression of NAFLD. The effects of low doses of AFB1 on the development of NASH and their mechanism were investigated in vivo and in vitro. The results in vivo showed that AFB1 at 20 and 40 μg/kg.bw aggravated CDAHFD-induced NASH in mice as demonstrated by increasing the serum and liver lipid accumulation, liver inflammation and injury. The results in vitro showed that AFB1 at 1.0 μM aggravated FFA-induced lipid accumulation, inflammation and cell damage in HepG2 cells. In addition, RNA-seq indicated that necroptosis, Toll like receptor signaling and TNF-α signaling showed a significant change in KEGG pathway enrichment in AFB1 at 40 μg/kg.bw. AFB1 significantly upregulated the mRNA and protein levels of TLR4, RIPK3, p-RIPK3, MLKL and p-MLKL, and increased TUNEL positive cells. Also, immunofluorescence results showed that TUNEL, TLR4, TNF-α had co-localized with RIPK3, respectively. Necroptosis inhibitor (GSK-872) attenuated the aggravating effects of AFB1 on NASH. Knockout of TLR4 inhibited necroptosis and rescued the aggravating effects of AFB1 on NASH. These data indicate that low dose of AFB1 aggravated NASH via TLR4-mediated necroptosis. This suggests that low dose of AFB1 is potentially harmful to animals and humans, as they exacerbate NASH.

Microtubule poleward flux as a target for modifying chromosome segregation errors

Cancer cells often display errors in chromosome segregation, some of which result from improper chromosome alignment at the spindle midplane. Chromosome alignment is facilitated by different rates of microtubule poleward flux between sister kinetochore fibers. However, the role of the poleward flux in supporting mitotic fidelity remains unknown. Here, we introduce the hypothesis that the finely tuned poleward flux safeguards against lagging chromosomes and micronuclei at mitotic exit by promoting chromosome alignment in metaphase. We used human untransformed RPE-1 cells depleted of KIF18A/kinesin-8 as a system with reduced mitotic fidelity, which we rescued by three mechanistically independent treatments, comprising low-dose taxol or codepletion of the spindle proteins HAUS8 or NuMA. The rescue of mitotic errors was due to shortening of the excessively long overlaps of antiparallel microtubules, serving as a platform for motor proteins that drive the flux, which in turn slowed down the overly fast flux and improved chromosome alignment. In contrast to the prevailing view, the rescue was not accompanied by reduction of overall microtubule growth rates. Instead, speckle microscopy revealed that the improved chromosome alignment in the rescue treatments was associated with slower growth and flux of kinetochore microtubules. In a similar manner, a low-dose taxol treatment rescued mitotic errors in a high-grade serous ovarian carcinoma cell line OVKATE. Collectively, our results highlight the potential of targeting microtubule poleward flux to modify chromosome instability and provide insight into the mechanism through which low doses of taxol rescue certain mitotic errors in cancer cells.

Genetic and phytochemical evaluation of M2 generation mutants of fenugreek (Trigonella foenum-graecum L.) induced by gamma rays and Ethyl Methane Sulphonate (EMS).

Fenugreek (Trigonella foenum-graecum L.) is highly esteemed for its therapeutic properties and is widely used in traditional medicine and modern pharmacology. Enhancing its genetic traits and phytochemical profile, particularly its trigonelline content, can significantly increase its medicinal and agricultural value. This study aims to investigate the effects of gamma rays and Ethyl Methane Sulphonate (EMS) as mutagenic agents on the genetic and phytochemical characteristics of the M2 generation of fenugreek, focusing on genetic diversity and desirable trait enhancement. To achieve this, various concentrations of EMS and gamma rays were administered to fenugreek seeds, and 27 traits were assessed in the resulting M2 generation. These traits were analyzed for variance, mean values, and correlations. The genetic diversity of 23 M2 offspring was investigated using nine Start Codon Targeted (SCoT) markers. The genetic diversity assessment involved Principal Coordinate Analysis (PCoA) and cluster analysis, utilizing the Dice similarity coefficients and the Unweighted Pair Group Method with Arithmetic Mean (UPGMA). A Bayesian model provided deeper insights into the genetic structure. Results revealed that lower doses of gamma rays (100Gy) and EMS (0.2%) positively impacted specific traits. In comparison, higher doses (200Gy and 0.4% EMS) increased seed trigonelline content to 0.71mg/g dry weight. Among the SCoT markers, SCoT-9 was the most efficient, segregating the populations into three clusters. The first three principal components in the PCoA explained 20% of the total variance, leading to seven subgroup populations distinction. These findings underscore the potential of induced mutagenesis in enhancing desirable traits in fenugreek.

Dosing of antidepressants in relation to body weight in children and adolescents with overweight.

Overweight and obesity in children and adolescents may impact pharmacokinetics and drug exposure. The aim of the present study was to evaluate doses of antidepressants in relation to body weight in children. We used data from the BMI Epidemiology Study (BEST) Gothenburg cohort and the National Prescribed Drug Register and included children and adolescents with a prescription of fluoxetine (n = 347) or sertraline (n = 733) and a weight measurement. For fluoxetine, individuals with overweight or obesity received slightly lower doses at first prescriptions, but not in iterated prescriptions. The weight-normalized dose was lower in individuals with overweight or obesity in first and iterated prescriptions, compared with normal weight (p < 0.01). For sertraline, there were no significant dose differences between individuals with overweight or obesity, compared with normal weight. However, pronounced differences were seen in dose per kilogram body weight in both first and iterated prescriptions (p < 0.01). We conclude that the doses of fluoxetine and sertraline were essentially similar in individuals with overweight or obesity, but the weight-normalized doses were clearly lower. Given the ongoing obesity epidemic, larger studies addressing optimal dosing in individuals with elevated weight are warranted.

Efficacy and utility of isocycloseram a novel isoxazoline insecticide against urban pests and public health disease vectors.

Isoxazolines inhibit γ-aminobutyric acid chloride channels in insects and acarids by binding to postsynaptic receptors. This prevents chloride influx, leading to depolarization/hyperexcitation, paralysis, and death. Here, we evaluated the potential utility of a novel isoxazoline, isocycloseram, against several urban insect pests. Isocycloseram was active at low doses against the German cockroach, Blattella germanica (L.)[median lethal dose (LD50) 5-15 ng per insect at 72 h, topical assays]; Argentine ant (Linepithema humile Mayr), Pharaoh ant (Monomorium pharaonis (L.), common bed bug (Cimex lectularius (L.) (approximately 40 mg m-2, residual surface spray); Eastern subterranean termite (Reticulitermes flavipes (Kollar)and Formosan subterranean termite (Coptotermes formosanus Shiraki) (5 μg g-1 w/w, tunneling assays); and mosquito, Anopheles stephensi Liston (120 and 150 mg m-2 treated surfaces, aged indoors for 9 months). Additionally, cockroach gel bait at 1% isocycloseram (w/w) caused 95-100% mortality in German, American (Periplaneta americana (L.), and oriental (Blatta orientalis (L.) cockroaches within 5-14 days. Isocycloseram proved to be active against both laboratory and field populations of German cockroaches at doses lower or equal to those of other chemicals. Ants, bed bugs, and mosquitoes readily acquired lethal doses of isocycloseram from different surfaces treated with formulated products. Given its non-repellent nature, delayed effects, and activity at low rates, isocycloseram can be a very effective compound against subsocial, social, and other human disease vector insect pests. © 2024 Society of Chemical Industry.