Hasil untuk "Therapeutics. Pharmacology"

Ruiqiang Sun, Miaomiao Chai, Jiahao Man et al.

N-glycosylation, a critical quality attribute of monoclonal antibodies, plays a pivotal role in regulating pharmacokinetics and pharmacodynamics through high-mannose (Man5) glycoform modulation. While our previous work demonstrated that N-acetyl-D-mannosamine (ManNAc) supplementation effectively reduces Man5 levels without compromising antibody yield or other critical quality attributes, the mechanistic basis remained unclear. This study systematically investigates ManNAc’s regulatory mechanism through a multi-parametric analysis. Cellular uptake studies revealed a 3-day latency period preceding Man5 reduction post-ManNAc administration. Subsequent transcriptional profiling showed no significant alterations in Man5-associated enzyme expression (Mgat1, Mgat2, Man2a1, SLC35A3), while metabolomic analysis demonstrated marked elevation of intracellular ManNAc, uridine-diphosphate-N-acetylglucosamine (UDP-GlcNAc), and cytidine-5’-monophospho-N-acetylneuraminic acid (CMP-Neu5Ac) levels. Mechanistic studies revealed two critical findings: (1) Chinese hamster ovary cells exhibit minimal endogenous N-acetyl-D-glucosamine-2-epimerase expression, and (2) CMP-Neu5Ac exerts potent inhibition on glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) activity in vitro, despite ManNAc’s lack of transcriptional regulation on GNE. We propose a metabolic flux redirection model, where ManNAc-derived CMP-Neu5Ac accumulation inhibits GNE activity, thereby shunting UDP-GlcNAc from sialic acid biosynthesis toward N-glycosylation pathways to reduce Man5 levels. This work not only identifies UDP-GlcNAc substrate limitation as a key constraint in antibody glycosylation but also establishes exogenous monosaccharide supplementation as a novel metabolic engineering strategy for Man5 optimization. These findings provide critical mechanistic insights for precision glycoengineering of therapeutic antibodies.

Ibtissam Talha, Noureddine Elkhoudri, Abderraouf Hilali

Background. Epidemiological studies conducted in extensive population cohorts have led to the creation of numerous cardiovascular risk predictor models. However, these tools have certain limitations that restrict its applicability. The aim behind the following work is to summarize today’s best-known limitations of cardiovascular risk assessment models through presenting the critical analyses conducted in this area, with the intention of offering practitioners a comprehensive understanding of these restrictions. Critical analyses revealed that these scales exhibit numerous limitations that could impact their performance. Most of these models evaluate cardiovascular risk based on classic risk factors and other restrictions, thereby negatively affecting their sensitivity. Scientists have made significant advancements in improving cardiovascular risk models, tailoring them to accommodate a wide range of populations and devising scales for estimating cardiovascular risks that can account for all prevailing restrictions. Better understanding these limitations could improve the cardiovascular risk stratification.

Ida Tomomi, Hiroyuki Kanzaki, Miho Shimoyama et al.

Calcification plays a key role in biological processes, and breakdown of the regulatory mechanism results in a pathological state such as ectopic calcification. We hypothesized that ENPP1, the enzyme that produces the calcification inhibitor pyrophosphate, is transcriptionally regulated by Nrf2, and that Nrf2 activation augments ENPP1 expression to inhibit ectopic calcification. Cell culture experiments were performed using mouse osteoblastic cell line MC3T3-E1. Nrf2 was activated by 5-aminolevulinic acid and sodium ferrous citrate. Nrf2 overexpression was induced by the transient transfection of an Nrf2 expression plasmid. ENPP1 expression was monitored by real-time RT-PCR. Because the promoter region of ENPP1 contains several Nrf2-binding sites, chromatin immunoprecipitation using an anti-Nrf2 antibody followed by real-time PCR (ChIP-qPCR) was performed. The relationship between Nrf2 activation and osteoblastic differentiation was examined by alkaline phosphatase (ALP) and Alizarin red staining. We used mice with a hypomorphic mutation in ENPP1 (ttw mice) to analyze whether Nrf2 activation inhibits ectopic calcification. Nrf2 and Nrf2 overexpression augmented ENPP1 expression and inhibited osteoblastic differentiation, as indicated by ALP expression and calcium deposits. ChIP-qPCR showed that some putative Nrf2-binding sites in the ENPP1 promoter region were bound by Nrf2. Nrf2 activation inhibited ectopic calcification in mice. ENPP1 gene expression was transcriptionally regulated by Nrf2, and Nrf2 activation augmented ENPP1 expression, leading to the attenuation of osteoblastic differentiation and ectopic calcification in vitro and in vivo. Nrf2 activation has a therapeutic potential for preventing ectopic calcification.

Maher Monir Akl, Amr Ahmed

The Warburg effect, first observed by Otto Warburg in the 1920s, delineates a metabolic phenomenon in which cancer cells exhibit heightened glucose uptake and lactate production, even under normoxic conditions. This metabolic shift towards glycolysis, despite the presence of oxygen, fuels the energy demands of rapidly proliferating cancer cells. Dysregulated glucose metabolism, characterized by the overexpression of glucose transporters and the redirection of metabolic pathways towards glycolysis, lies at the crux of this metabolic reprogramming. Consequently, the accumulation of lactate as a byproduct contributes to the creation of an acidic tumor microenvironment, fostering tumor progression and metastasis. However, recent research, notably proposed by Maher Akl, introduces a novel perspective regarding the role of glycolipids in cancer metabolism. Akl’s glucolipotoxicity hypothesis posits that aberrant glycolipid metabolism, specifically the intracellular buildup of glycolipids, significantly influences tumor initiation and progression. This hypothesis underscores the disruptive impact of accumulated glycolipids on cellular homeostasis, thereby activating oncogenic pathways and promoting carcinogenesis. This perspective aims to synthesize the intricate mechanisms underlying both the Warburg effect and glucolipotoxicity, elucidating their collective contributions to tumor growth and malignancy. By comprehensively understanding these metabolic aberrations, novel avenues for therapeutic intervention targeting the fundamental drivers of cancer initiation and progression emerge, holding promise for more efficacious treatment strategies in the future.

article Editorial

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Noora Kadhim Hadi Alyasari, Wisam Hussein Selman

The objective of this investigation was to find out whether L-carnitine-loaded nanoparticle (LCn) could reduce the reproductive toxicity of cypermethrin (CYP), the widely used insecticide in veterinary medicine in male rats. Twenty male Wistar rats that weighed between 210 and 240 g were split into four groups and treated daily for 2 months. The control group was given 0.9% normal saline solution daily. The second group received CYP (3.83 mg/kg b. w. p. o.) daily. The third group was administered with LCn and CYP (50 mg/kg b. wt. p. o. and 3.83 mg/kg b. wt. p. o., respectively) daily, whereas the fourth group received LCn alone (50 mg/kg b. wt. p. o.) daily. On day 60, all rats were sacrificed and samples were collected. CYP-treated animals exhibited inhibition of testicular anti-oxidative stress mechanisms, testicular steroidogenesis enzyme activity (3β-hydroxysteroid dehydrogenase [3β-HSD] and 17β-HSD), and downregulation of steroidogenic acute regulatory (StAR) gene expression. In addition, it decreased testosterone, follicle-stimulating hormone, and LH levels and had detrimental consequences for sperm quality. LCn attenuated CYP-induced reproductive toxicity via the alleviation of testicular oxidative stress status, improvement of steroidogenic enzyme activity, and upregulation of StAR gene expression, which are probably responsible for the concomitant improvement in testicular hormonal levels and improvement in sperm properties. Intriguingly, LCn treatment alone could enhance the functions of the male reproductive system.

Hao Han, Yawei Zhao, Junda Du et al.

Abstract Background Exercise is postulated to be a promising non-pharmacological intervention for the improvement of neurodegenerative disease pathology. However, the mechanism of beneficial effects of exercise on the brain remains to be further explored. In this study, we investigated the effect of an exercise-induced metabolite, lactate, on the microglia phenotype and its association with learning and memory. Results Microglia were hyperactivated in the brains of AlCl3/D-gal-treated mice, which was associated with cognitive decline. Running exercise ameliorated the hyperactivation and increased the anti-inflammatory/reparative phenotype of microglia and improved cognition. Mice were injected intraperitoneally with sodium lactate (NaLA) had similar beneficial effects as that of exercise training. Exogenous NaLA addition to cultured BV2 cells promoted their transition from a pro-inflammatory to a reparative phenotype. Conclusion The elevated lactate acted as an “accelerator” of the endogenous “lactate timer” in microglia promoting this transition of microglia polarization balance through lactylation. These findings demonstrate that exercise-induced lactate accelerates the phenotypic transition of microglia, which plays a key role in reducing neuroinflammation and improving cognitive function.

Kun-mei Liu, Kun-mei Liu, Kun-mei Liu et al.

Temporal lobe epilepsy (TLE) is characterized as an impaired ability of learning and memory with periodic and unpredictable seizures. Status epilepticus (SE) is one of the main causes of TLE. Neuroinflammation and oxidative stress are directly involved in epileptogenesis and neurodegeneration, promoting chronic epilepsy and cognitive deficit. Previous studies have shown that ursolic acid (UA) represses inflammation and oxidative stress, contributing to neuroprotection. Herein, we demonstrated that UA treatment alleviated seizure behavior and cognitive impairment induced by epilepsy. Moreover, UA treatment rescued hippocampal neuronal damage, aberrant neurogenesis, and ectopic migration, which are commonly accompanied by epilepsy occurrence. Our study also demonstrated that UA treatment remarkably suppressed the SE-induced neuroinflammation, evidenced by activated microglial cells and decreased inflammation factors, including TNF-α and IL-1β. Likewise, the expression levels of oxidative stress damage markers and oxidative phosphorylation (OXPHOS) enzyme complexes of mitochondria were also remarkably downregulated following the UA treatment, suggesting that UA suppressed the damage caused by the high oxidative stress and the defect mitochondrial function induced by SE. Furthermore, UA treatment attenuated GABAergic interneuron loss. In summary, our study clarified the notable anti-seizure and neuroprotective properties of UA in pilocarpine-induced epileptic rats, which is mainly achieved by abilities of anti-inflammation and anti-oxidation. Our study indicates the potential advantage of UA application in ameliorating epileptic sequelae.

Yanrong Long, Hongbin Chen, Junchao Deng et al.

Disrupted neonatal lung angiogenesis and alveologenesis often give rise to bronchopulmonary dysplasia (BPD), the most common chronic lung disease in children. Hyperoxia-induced pulmonary vascular and alveolar damage in premature infants is one of the most common and frequent factors contributing to BPD. The purpose of the present study was to explore the key molecules and the underlying mechanisms in hyperoxia-induced lung injury in neonatal mice and to provide a new strategy for the treatment of BPD. In this work, we reported that hyperoxia decreased the proportion of endothelial cells (ECs) in the lungs of neonatal mice. In hyperoxic lung ECs of neonatal mice, we detected upregulated fibroblast growth factor receptor 1 (FGFR1) expression, accompanied by upregulation of the classic downstream signaling pathway of activated FGFR1, including the ERK/MAPK signaling pathway and PI3K-Akt signaling pathway. Specific deletion of Fgfr1 in the ECs of neonatal mice protected the lungs from hyperoxia-induced lung injury, with improved angiogenesis, alveologenesis and respiratory metrics. Intriguingly, the increased Fgfr1 expression was mainly attributed to aerosol capillary endothelial (aCap) cells rather than general capillary endothelial (gCap) cells. Deletion of endothelial Fgfr1 increased the expression of gCap cell markers but decreased the expression of aCap cell markers. Additionally, inhibition of FGFR1 by an FGFR1 inhibitor improved alveologenesis and respiratory metrics. In summary, this study suggests that in neonatal mice, hyperoxia increases the expression of endothelial FGFR1 in lung ECs and that deficiency of endothelial Fgfr1 can ameliorate hyperoxia-induced BPD. These data suggest that FGFR1 may be a potential therapeutic target for BPD, which will provide a new strategy for the prevention and treatment of BPD.

Bojana B. Vidović, Danijel D. Milinčić, Mirjana D. Marčetić et al.

Goji berries have long been used for their nutritional value and medicinal purposes in Asian countries. In the last two decades, goji berries have become popular around the world and are consumed as a functional food due to wide-range bioactive compounds with health-promoting properties. In addition, they are gaining increased research attention as a source of functional ingredients with potential industrial applications. This review focuses on the antioxidant properties of goji berries, scientific evidence on their health effects based on human interventional studies, safety concerns, goji berry processing technologies, and applications of goji berry-based ingredients in developing functional food products.

Milton D. Chiang, Chao-Yuan Chang, Hung-Jen Shih et al.

Endoplasmic reticulum (ER) stress mediates the effects of obesity on aggravating sepsis-induced lung injury. We investigated whether exosomes from human placenta choriodecidual membrane-derived mesenchymal stem cells (pcMSCs) can mitigate pulmonary ER stress, lung injury, and the mechanisms of inflammation, oxidation, and apoptosis in lipopolysaccharide-treated obese mice. Diet-induced obese (DIO) mice (adult male C57BL/6J mice fed with a 12-week high-fat diet) received lipopolysaccharide (10 mg/kg, i.p.; DIOLPS group) or lipopolysaccharide plus exosomes (1 × 10⁸ particles/mouse, i.p.; DIOLPSExo group). Our data demonstrated lower levels of ER stress (upregulation of glucose-regulated protein 78, phosphorylated eukaryotic initiation factor 2α, and C/EBP homologous protein; <i>p</i> = 0.038, <0.001, and <0.001, respectively), inflammation (activation of nuclear factor-kB, hypoxia-inducible factor-1α, macrophages, and NLR family pyrin domain containing 3; upregulation of tumor necrosis factor-α, interleukin-1β, and interleukin-6; <i>p</i> = 0.03, <0.001, <0.001, <0.001, <0.001, <0.001, and <0.001, respectively), lipid peroxidation (<i>p</i> < 0.001), and apoptosis (DNA fragmentation, <i>p</i> = 0.003) in lung tissues, as well as lower lung injury level (decreases in tidal volume, peak inspiratory flow, and end expiratory volume; increases in resistance, injury score, and tissue water content; <i>p</i> < 0.001, <0.001, <0.001, <0.001, <0.001, and =0.002, respectively) in the DIOLPSExo group than in the DIOLPS group. In conclusion, exosomes from human pcMSCs mitigate pulmonary ER stress, inflammation, oxidation, apoptosis, and lung injury in lipopolysaccharide-treated obese mice.

Ancuta Nartea, Benedetta Fanesi, Pasquale Massimiliano Falcone et al.

The effect of steam and <i>sous-vide</i> oven procedures on liposoluble antioxidants of colored cauliflower (orange and purple) was assessed for the first time and compared with domestic practice (boiling). In raw samples, the total carotenoid content was 10-fold higher in <i>Cheddar</i> than in <i>Depurple</i> (20.9 ± 2.1 vs. 2.3 ± 0.5 mg/kg dry weight), whereas the level of tocopherols was similar (28.5 ± 4.4 vs. 33 ± 5.2 mg/kg dry weight). The <i>Cheddar</i> liposoluble antioxidant matter contained violaxanthin, neoxanthin, α-carotene and δ-tocopherol, not detected in <i>Depurple</i>. All tests increased the bioactive compounds extractability with steam oven and <i>sous-vide</i> displaying similar effects, lower than boiling. In boiled <i>Cheddar</i> cauliflower, the total carotenoids and tocopherols contents increased with cooking time until they were 13-fold and 6-fold more than in raw cauliflower, respectively. Conversely, in the <i>Depurple</i> variety, contents increased by half with respect to the orange variety. However, from a nutritional point of view, no differences were revealed among the three different cooking treatments in terms of vitamin A and E levels expressed in μg/100 g of fresh vegetable because of the higher water content of boiled samples that must be considered when evaluating the effect of thermal treatment on cauliflower nutritional traits.

Matthew Butler, Felicity Bano, Marilia Calcia et al.

There is both uncertainty regarding the safety of clozapine in COVID-19 patients owing to limited published data and a lack of consensus on continuing clozapine in patients with severe respiratory infections. COVID-19 is known to induce an acute immune response which can affect haematological parameters associated with clozapine monitoring, and systemic infection may reduce clozapine clearance. Clozapine, which has been associated with worse outcomes in some pneumonias, may in theory worsen outcomes in COVID-19. Despite these concerns, there are some data to indicate it is safe to continue clozapine in COVID-19 infection. In this retrospective case series, we describe our experiences of clozapine prescribing and disease progression of eight SARS-CoV-2 positive patients on medical wards in a major London teaching hospital. In four cases clozapine was stopped during the hospital admission. A COVID-19 pneumonia developed in four patients: three of these required intensive care unit admission for an average of 34 days. At the time of writing, three patients had died (two directly from COVID-19 pneumonia), two remained in general hospital wards, two were recovering in the community and one had been transferred to an inpatient psychiatric hospital. Follow-up length varied but in each case was not more than 104 days. Delirium was the most common adverse neuropsychiatric event, and in one case a relapse of psychosis occurred after cessation of clozapine. This retrospective case series illustrates the safe use of clozapine during COVID-19 infection. Our experiences suggest that consideration should be made to continuing clozapine even in those most unwell with COVID-19. We also identify areas which require larger scale hypothesis-testing research.

Nada S. Habib, Mohamed H. EL-Hefnawy, Hala O. El-Mesallamy

Wnt-inducible signaling pathway protein 1 (WISP1) is a recently identified adipokine that is thought to be involved in mechanisms linking obesity and type 2 diabetes mellitus (T2DM). This study is designed to investigate the correlation between WISP1 serum levels and glycemic parameters in Egyptian population subjects for the first time. Anthropometric parameters, routine biochemical markers, serum levels of WISP1, insulin, proinsulin, and high sensitivity C-reactive protein (hs-CRP) were measured by ELISA kits in 90 subjects (24 non-obese patients with T2DM and 22 obese patients with T2DM compared with 24 healthy volunteers and 20 obese volunteers without T2DM. Serum WISP1 levels were significantly higher in obese patients compared with healthy controls (p<0.05). WISP1 was significantly correlated to waist circumference (WC) and serum triglycerides (TG). In conclusion, WISP1 might be a pivotal biomarker linking obesity and T2DM.

AL-Wajeeh NS, Hajrezaei M, Al-Henhena N et al.

Nahla Saeed Al-Wajeeh,1 Maryam Hajrezaie,1 Nawal Al-Henhena,1 Sareh Kamran,1 Elham Bagheri,1 Maryam Zahedifard,1 Kamelia Saremi,1 Suzita Mohd Noor,1 Hapipah Mohd Ali,2 Mahmood Ameen Abdulla11Department of Biomedical Science, Faculty of Medicine, 2Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, MalaysiaAbstract: Cibotium barometz is a pharmaceutical plant customarily used in traditional medicine in Malaysia for the treatment of different diseases, such as gastric ulcer. The gastroprotective effect of C. barometz leaves against ethanol-induced gastric hemorrhagic abrasions in Sprague Dawley rats has been evaluated in terms of medicinal properties. Seven groups of rats (normal control and ulcerated control groups, omeprazole 20 mg/kg, 62.5, 125, 250, and 500 mg/kg of C. barometz correspondingly) were used in antiulcer experiment and pretreated with 10% Tween&nbsp;20. After 1 hour, the normal group was orally administered 10% Tween 20, whereas absolute alcohol was fed orally to ulcerated control, omeprazole, and experimental groups. Gastric&rsquo;s homogenate were assessed for endogenous enzymes activities. Stomachs were examined macroscopically and histologically. Grossly, the data demonstrated a significant decrease in the ulcer area of rats pretreated with plant extract in a dose-dependent manner with respect to the ulcerated group. Homogenates of the gastric tissue exhibited significantly increased endogenous enzymes activities in rats pretreated with C. barometz extract associated with the ulcerated control group. Histology of rats pretreated with C. barometz extract group using hematoxylin and eosin staining exhibited a moderate-to-mild disruption of the surface epithelium with reduction in submucosal edema and leucocyte infiltration in a dose-dependent manner. In addition, it showed heat shock protein70 protein up-expression and BCL2-associated X protein downexpression. These outcomes might be attributed to the gastroprotective and antioxidative effects of the plant. Keywords: Cibotium barometz leaves, antioxidants, acute toxicity, antiulcer, histology

Paolo Bonanni, Giampietro Chiamenti, Giorgio Conforti et al.

Medical scientific societies have the core mission of producing, pooling and disseminating solid and updated scientific information. We report the successful experience of the partnership of four national Medical Scientific Societies active in Italy in producing scientific advice on vaccines and vaccination. In particular, i) the Italian Society of Hygiene, Preventive Medicine and Public Health; SitI, ii) the Italian Society of Paediatrics; SIP, iii) the “Italian Federation of General Practitioners”; FIMP, and iv) the Italian Federation of General Medicine FIMMG) have worked together since 2012 to produce shared evidence-based recommendations on vaccination schedules, namely the “Lifetime Immunization Schedule” which introduced for the first time in Italy a life-course approach to vaccination. The 2014 edition of the “Lifetime Immunization Schedule” was used as a basis to develop the 2017–2019 Italian National Prevention Plan, approved by The Italian Ministry of Health in February 2017. In this report, we present the structure, content and supporting evidence of the new 2016 “Lifetime Immunization Schedule” and we expand on the influential role of medical scientific societies in researching and advocating for effective and safe vaccination programmes’ implementation at the national level.

Ghasem Rahmatpour Rokni, Massoud Golpour, Alimorad Heidari Gorji et al.

Vitiligo is one of the most primitive well-known dermatoid disorders with different suggested therapies. Therefore, this study investigated the efficiency and safety of topical tacrolimus in treatment of patients with vitiligo. This study was a clinical randomized designed study pre- post-test method, has been conducted on thirty cases with vitiligo who have referred to polyclinic and dermatology clinic. Participant′s evaluated and demographic information recorded in designed checklist. In the next stage, the disease activity scored by vitiligo index disease activity system. Photography and depigmentation percent has recorded before treatment and further in 4 th , 8 th , 12 th , 16 th , 20 th , and 24 th weeks. Finally, gathered data compared through SPSS-20 software. The final sample comprised 30 persons including: 12 men (40%) and 18 women (60%). The average of patient′s age in this study was 26/13 ΁ 18/20 (2-76-year-old). Eleven persons was ≤15 years old and rest was older than 15. Sixty-six lesions have funded in patients that maximum has accrued on face and neck (37/87%) and trunk (21/21%). In addition, minimum of lesions is related to genitalia (9/09%). In the in 4 th , 8 th , 12 th , 16 th weeks, improvement in face and neck had increased significantly, into the past weeks. In the 20 th and 24 th weeks, the improvement has increased although it was not significant enhancement. Also about trunk, in the 4 th week the improvement does not have significant increasing in compare to the past week. In the eighth, 12 th , 16 th , 20 th , and 24 th weeks the improvement has been increased significantly in compare to the past weeks. Although in the case of limbs and genitalia, the improvement was lower. There was no significant difference between male and females and age. Although the improvement was, slow in older persons. Study results, has presented applying topical tacrolimus in vitiligo, particularly in face and neck, could be effective and does not seen any specified adverse effects during consumption of tacrolimus, it could be effective in decreasing effects in use of corticosteroid.