Cardioprotective effect of Vitamin D on cardiac hypertrophy through improvement of mitophagy and apoptosis in an experimental rat model of levothyroxine -induced hyperthyroidism.

BACKGROUND: Mitochondria are known to be involved in mediating the calorigenic effects of thyroid hormones. With an abundance of these hormones, alterations in energy metabolism and cellular respiration take place, leading to the development of cardiac hypertrophy. Vitamin D has recently gained attention due to its involvement in the regulation of mitochondrial function, demonstrating promising potential in preserving the integrity and functionality of the mitochondrial network. The present study aimed to investigate the therapeutic potential of Vitamin D on cardiac hypertrophy induced by hyperthyroidism, with a focus on the contributions of mitophagy and apoptosis as possible underlying molecular mechanisms. METHODS AND RESULTS: The rats were divided into three groups: control; hyperthyroid; hyperthyroid + Vitamin D. Hyperthyroidism was induced by Levothyroxine administration for four weeks. Serum thyroid hormones levels, myocardial damage markers, cardiac hypertrophy indices, and histological examination were assessed. The assessment of Malondialdehyde (MDA) levels and the expression of the related genes were conducted using heart tissue samples. Vitamin D pretreatment exhibited a significant improvement in the hyperthyroidism-induced decline in markers indicative of myocardial damage, oxidative stress, and indices of cardiac hypertrophy. Vitamin D pretreatment also improved the downregulation observed in myocardial expression levels of genes involved in the regulation of mitophagy and apoptosis, including PTEN putative kinase 1 (PINK1), Mitofusin-2 (MFN2), Dynamin-related Protein 1 (DRP1), and B cell lymphoma-2 (Bcl-2), induced by hyperthyroidism. CONCLUSIONS: These results suggest that supplementation with Vitamin D could be advantageous in preventing the progression of cardiac hypertrophy and myocardial damage.

Prefrontal working memory signal primarily controls phase-coded information within extrastriate cortex.

In order to understand how prefrontal cortex provides the benefits of working memory (WM) for visual processing we examined the influence of WM on the representation of visual signals in V4 neurons in two macaque monkeys. We found that WM induces strong ß oscillations in V4 and that the timing of action potentials relative to this oscillation reflects sensory information- i.e., a phase coding of visual information. Pharmacologically inactivating the Frontal Eye Field part of prefrontal cortex, we confirmed the necessity of prefrontal signals for the WM-driven boost in phase coding of visual information. Indeed, changes in the average firing rate of V4 neurons could be accounted for by WM-induced oscillatory changes. We present a network model to describe how WM signals can recruit sensory areas primarily by inducing oscillations within these areas and discuss the implications of these findings for a sensory recruitment theory of WM through coherence.

Toxicity of Dibutyl phthalate (DBP) toward isolated human blood lymphocytes: Apoptosis initiated from intracellular calcium enhancement and mitochondrial/lysosomal cross talk.

Dibutyl phthalate (DBP) is a phthalate ester with wide application in industrial products, so human exposure can happen in workplaces and environment. Conflicting results have been acquired in researches which measured the influences of phthalates contact on immune responses in laboratory animals. Nevertheless, the straight influence of DBP on human lymphocytes and entire mechanisms of its effect against these cells continue to be unexplored. The major purpose of present research was to evaluate the mechanisms which lead to the DBP toxicity on human lymphocytes using accelerated cytotoxicity mechanisms screening (ACMS) technique. Cell viability was determined following12h incubation of lymphocytes with 0.05-1 mM DBP, and mechanistic parameters were assessed after 2, 4 and 6 h of lymphocyte treatment with ½ the IC5012h (0.3 mM), the IC5012h (0.6 mM) and twice the IC5012h (1.2 mM) of DBP. The IC5012 h of a chemical/toxicant is defined as concentration that kills 50 % of cells after 12 h of exposure. The results indicate that DBP exerts toxic effects on isolated human lymphocytes, probably through mitochondrial and lysosomal damage induced by glutathione depletion and oxidative stress. In this study, suppression of cytokines (IL2, INF-gamma and TNF-alpha) production and increase in intracellular calcium were also related to DBP induced lymphocyte toxicity.

Uncovering the protective potential of vanillic acid against traumatic brain injury-induced cognitive decline in male rats: Insights into underlying mechanisms.

Traumatic brain injury (TBI) is a significant contributor to global mortality and disability, and there is still no specific drug available to treat cognitive deficits in survivors. Vanillic acid (VA), a bioactive phenolic compound, has shown protective effects in various models of neurodegeneration; however, its impact on TBI outcomes remains elusive. Therefore, this study aimed to elucidate the possible role of VA in ameliorating TBI-induced cognitive decline and to reveal the mechanisms involved. TBI was induced using the Marmarou impact acceleration model to deliver an impact force of 300 g, and treatment with VA (50 mg/kg; P.O.) was initiated 30 minutes post-TBI. The cognitive performance, hippocampal long-term potentiation (LTP), oxidative stress markers, neurological function, cerebral edema, and morphological changes were assessed at scheduled points in time. TBI resulted in cognitive decline in the passive avoidance task, impaired LTP in the perforant path-dentate gyrus (PP-DG) pathway, increased hippocampal oxidative stress, cerebral edema, neurological deficits, and neuronal loss in the rat hippocampus. In contrast, acute VA administration mitigated all the aforementioned TBI outcomes. The data suggest that reducing synaptic plasticity impairment, regulating oxidative and antioxidant defense, alleviating cerebral edema, and preventing neuronal loss by VA can be at least partially attributed to its protection against TBI-induced cognitive decline.

Novel pentafluorosulfanyl-containing triclocarban analogs selectively kill Gram-positive bacteria.

Novel antimicrobial agents are needed to combat antimicrobial resistance. This study tested novel pentafluorosulfanyl-containing triclocarban analogs for their potential antibacterial efficacy. Standard procedures were used to produce pentafluorosulfanyl-containing triclocarban analogs. Twenty new compounds were tested against seven Gram-positive and Gram-negative indicator strains as well as 10 clinical isolates for their antibacterial and antibiofilm activity. Mechanistic investigations focused on damage to cell membrane, oxidizing reduced thiols, iron-sulfur clusters, and oxidative stress to explain the compounds' activity. Safety profiles were assessed using cytotoxicity experiments in eukaryotic cell lines. Following screening, selected components had significantly better antibacterial and antibiofilm activity against Gram-positive bacteria in lower concentrations in comparison to ciprofloxacin and gentamycin. For instance, one compound had a minimum inhibitory concentration of <0.0003 mM, but ciprofloxacin had 0.08 mM. Mechanistic studies show that these novel compounds do not affect reduced thiol content, iron-sulfur clusters, or hydrogen peroxide pathways. Their impact comes from Gram-positive bacterial cell membrane damage. Tests on cell culture toxicity and host component safety showed promise. Novel diarylurea compounds show promise as Gram-positive antimicrobials. These compounds offer prospects for study and optimization. IMPORTANCE: The rise of antibiotic resistance among bacterial pathogens poses a significant threat to global health, underscoring the urgent need for novel antimicrobial agents. This study presents research on a promising class of novel compounds with potent antibacterial properties against Gram-positive bacteria, notably Staphylococcus aureus and MRSA. What sets these novel analogs apart is their superior efficacy at substantially lower concentrations compared with commonly used antibiotics like ciprofloxacin and gentamycin. Importantly, these compounds act by disrupting the bacterial cell membrane, offering a unique mechanism that could potentially circumvent existing resistance mechanisms. Preliminary safety assessments also highlight their potential for therapeutic use. This study not only opens new avenues for combating antibiotic-resistant infections but also underscores the importance of innovative chemical approaches in addressing the global antimicrobial resistance crisis.

A case report of pediatric-onset MS associated uveitis.

BACKGROUND: To report a case of Pediatric-onset MS associated uveitis managed with local and systemic medications. CASE PRESENTATION: An 11-year-old boy who was diagnosed with Pediatric-onset MS (POMS) with the first presentation of left optic neuritis in another center, was referred to our clinic with the complaint of non-improved vision in the left eye despite receiving IV 5gr methylprednisolone. After the ophthalmologic examinations, the patient was diagnosed as bilateral POMS-associated intermediate uveitis, and local treatment with corticosteroid was administered to both eyes. He was continued on systemic therapy such as Rituximab and five sessions of plasmapheresis. After four months, the patient's vision improved from FC at 50cm to 9/10 in the left eye. The intensity of intraocular inflammation decreased in both eyes. In fluorescein angiography findings, the optic disc, as well as vascular leakage, subsided bilaterally. CONCLUSION: Despite its rarity, POMS-associated uveitis presents a considerable challenge that necessitates the collaborative efforts of neurologists and ophthalmologists to achieve the most effective treatment outcomes.

Teachers and educators' experiences and perceptions of artificial-powered interventions for autism groups.

BACKGROUND: Artificial intelligence-powered interventions have emerged as promising tools to support autistic individuals. However, more research must examine how teachers and educators perceive and experience these AI systems when implemented. OBJECTIVES: The first objective was to investigate informants' perceptions and experiences of AI-empowered interventions for children with autism. Mainly, it explores the informants' perceived benefits and challenges of using AI-empowered interventions and their recommendations for avoiding the perceived challenges. METHODOLOGY: A qualitative phenomenological approach was used. Twenty educators and parents with experience implementing AI interventions for autism were recruited through purposive sampling. Semi-structured and focus group interviews conducted, transcribed verbatim, and analyzed using thematic analysis. FINDINGS: The analysis identified four major themes: perceived benefits of AI interventions, implementation challenges, needed support, and recommendations for improvement. Benefits included increased engagement and personalized learning. Challenges included technology issues, training needs, and data privacy concerns. CONCLUSIONS: AI-powered interventions show potential to improve autism support, but significant challenges must be addressed to ensure effective implementation from an educator's perspective. The benefits of personalized learning and student engagement demonstrate the potential value of these technologies. However, with adequate training, technical support, and measures to ensure data privacy, many educators will likely find integrating AI systems into their daily practices easier. IMPLICATIONS: To realize the full benefits of AI for autism, developers must work closely with educators to understand their needs, optimize implementation, and build trust through transparent privacy policies and procedures. With proper support, AI interventions can transform how autistic individuals are educated by tailoring instruction to each student's unique profile and needs.

Identification of a Novel Homozygous Mutation in PRDM12 Gene in a Patient with Hereditary Sensory and Autonomic Neuropathy Type VIII.

Hereditary sensory autonomic neuropathy type VIII (HSAN-VIII) is a rare genetic disease that occurs due to mutations in the PRDM12 gene. Here, we describe a novel homozygous mutation c.826_840dupTGCAACCGCCGCTTC (p.Cys276_Phe280dup) on exon 5 in the PRDM12 gene identified by WES and confirmed using Sanger sequencing method.

Evaluating the Efficacy and Safety of Aflibercept Biosimilar (P041) Compared with Originator Product in Patients with Neovascular Age-Related Macular Degeneration.

OBJECTIVE: To assess the noninferiority of biosimilar aflibercept (P041, CinnaGen) to the originator aflibercept (AFL, Regeneron) in terms of efficacy, safety, and immunogenicity. DESIGN: This was a phase Ш, 52-week, multicenter, randomized, double-masked, and active control trial involving eyes in a 1:1 ratio. SUBJECTS: Patients with active subfoveal choroidal neovascularization secondary to age-related macular degeneration randomized into the 2 groups of P041 and AFL. METHODS: Patients received an injection of aflibercept every 4 weeks for 3 doses, followed by administration every 8 weeks up to week 48. MAIN OUTCOME MEASURES: The primary outcome was the noninferiority analysis of eyes maintaining vision at week 52. Secondary outcomes included the changes in visual acuity and retinal thickness, safety evaluation, and immunogenicity during the study. RESULTS: In total, 168 eyes of 168 patients were included. At week 52, the proportion of patients maintaining vision was 94.44% in the P041 group compared with 94.52% in the AFL group. The 95% confidence interval (CI) for the difference of maintaining vision from baseline did not exceed the predefined noninferiority margin of 10% (difference, -0.0008; 95% CI, -0.074 to 0.074; P = 0.98). Secondary outcomes indicated similar results in both arms (all P > 0.05). Safety measured outcomes and immunogenicity were similar between the 2 study groups. CONCLUSIONS: Biosimilar aflibercept was noninferior to AFL in eyes with neovascular age-related macular degeneration. Other efficacy and safety findings also indicated the similarity of 2 products. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

GDF11: An emerging therapeutic target for liver diseases and fibrosis.

Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP11), has been identified as a key player in various biological processes, including embryonic development, aging, metabolic disorders and cancers. GDF11 has also emerged as a critical component in liver development, injury and fibrosis. However, the effects of GDF11 on liver physiology and pathology have been a subject of debate among researchers due to conflicting reported outcomes. While some studies suggest that GDF11 has anti-aging properties, others have documented its senescence-inducing effects. Similarly, while GDF11 has been implicated in exacerbating liver injury, it has also been shown to have the potential to reduce liver fibrosis. In this narrative review, we present a comprehensive report of recent evidence elucidating the diverse roles of GDF11 in liver development, hepatic injury, regeneration and associated diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis and hepatocellular carcinoma. We also explore the therapeutic potential of GDF11 in managing various liver pathologies.

Sustainable freshwater production using novel cascade solar still with phase change material, serpentine water path, and copper fins.

Heat losses in solar stills are high, which has led to a decrease in their thermal efficiency. Also, the production of these devices is limited to the presence of the sun, and their production stops during cloudy hours or at night. To solve these problems, in this experimental study, two cascade solar stills are examined under relatively similar conditions for sustainable freshwater production. One of these solar stills is modified with the phase change material and copper fins, and another one is a conventional cascade solar still without using the phase change material and copper fins. Paraffin was selected as a heat storage material to increase the time of desalination of water by the solar still. In addition, the copper fins are used to increase the conduction heat transfer in phase change material and provide better melting and solidification processes. To prolong the water path along the steps, the serpentine water path was considered. The results showed that at sunset hours, desalination efficiency with phase changing material and fins was increased. At 5 pm, the efficiency of the modified device was increased by 29% (on average) as compared to the conventional solar still without using phase changing material and fins. The rate of water production in conventional solar still in midday was higher compared to the modified solar still. However, in the sunset and night hours, the modified solar still has a higher production rate due to heat released from the thermal storage system.

Underlying mechanisms behind the neuroprotective effect of vanillic acid against diabetes-associated cognitive decline: An in vivo study in a rat model.

Hippocampal synaptic dysfunction, oxidative stress, neuroinflammation, and neuronal loss play critical roles in the pathophysiology of diabetes-associated cognitive decline (DACD). The study aimed to investigate the effects of vanillic acid (VA), a phenolic compound, against DACD and explore the potential underlying mechanisms. Following confirmation of diabetes, rats were treated with VA (50 mg/kg/day; P.O.) or insulin (6 IU/rat/day; S.C.) for 8 consecutive weeks. The cognitive performance of the rats was evaluated using passive-avoidance and water-maze tasks. Long-term potentiation (LTP) was induced at hippocampal dentate gyrus (DG) synapses in response to high-frequency stimulation (HFS) applied to the perforant pathway (PP) to evaluate synaptic plasticity. Oxidative stress factors, inflammatory markers, and histological changes were evaluated in the rat hippocampus. This study showed that streptozotocin (STZ)-induced diabetes caused cognitive decline that was associated with inhibition of LTP induction, suppression of enzymatic antioxidant activities, enhanced lipid peroxidation, elevated levels of inflammatory proteins, and neuronal loss. Interestingly, chronic treatment with VA alleviated blood glucose levels, improved cognitive decline, ameliorated LTP impairment, modulated oxidative-antioxidative status, inhibited inflammatory response, and prevented neuronal loss in diabetic rats at a level comparable to insulin therapy. The results suggest that the antihyperglycemic, antioxidative, anti-inflammatory, and neuroplastic properties of VA may be the mechanisms behind its neuroprotective effect against DACD.

Computational fluid dynamics simulation of a jet crystallizer for continuous crystallization of lovastatin.

Continuous crystallization of lovastatin from a lovastatin-methanol solution and water as the anti-solvent in an impinging jet crystallizer is investigated using a computational fluid dynamics model. To capture the important phenomena, the model is coupled with micro-mixing, population balance, and related energy balance equations. It is implemented in OpenFOAM and validated against experimental data, where a fairly good agreement is found. The effects of key process parameters on the crystallization performance are also studied using the validated model. The results show that increasing the inlet jet velocity from 1 to 4 m/s yields a much narrower size distribution and 70% reduction in the mean crystal size. The four-fold increase in the inlet jet velocity also reduces the crystal production rate by one order of magnitude. Also, it is found that increasing the inlet supersaturation ratio from 6.8 to 8.8 nearly doubles the mean crystal size. Moreover, it results in a wider size distribution and a six-fold increase in the crystal production rate. The simulations also confirm that lower solution to anti-solvent mass flow ratios yield a wider size distribution, a larger mean crystal size and a higher crystal production rate. Increasing this ratio from 0.5 to 2 reduces the production rate by two orders of magnitude.

Effect of diminazene on cardiac hypertrophy through mitophagy in rat models with hyperthyroidism induced by levothyroxine.

Hyperthyroidism is associated with the alteration in molecular pathways involved in the regulation of mitochondrial mass and apoptosis, which contribute to the development of cardiac hypertrophy. Diminazene (DIZE) is an animal anti-infection drug that has shown promising effects on improving cardiovascular disease. The aim of the present study was to investigate the therapeutic effect of DIZE on cardiac hypertrophy and the signaling pathways involved in this process in the hyperthyroid rat model. Twenty male Wistar rats were equally divided into four groups: control, hyperthyroid, DIZE, and hyperthyroid + DIZE. After 28 days of treatment, serum thyroxine (T4) and thyroid stimulating hormone (TSH) level, cardiac hypertrophy indices, cardiac damage markers, cardiac malondialdehyde (MDA), and superoxide dismutase (SOD) level, the mRNA expression level of mitochondrial and apoptotic genes were evaluated. Hyperthyroidism significantly decreased the cardiac expression level of SIRT1/PGC1α and its downstream involved in the regulation of mitochondrial biogenesis, mitophagy, and antioxidant enzyme activities including TFAM, PINK1/MFN2, Drp1, and Nrf2, respectively, as well as stimulated mitochondrial-dependent apoptosis by reducing Bcl-2 expression and increasing Bax expression. Treatment with DIZE significantly reversed the downregulation of SIRT1, PGC1α, PINK1, MFN2, Drp1, and Nrf2 but did not significantly change the TFAM expression. Moreover, DIZE suppressed apoptosis by normalizing the cardiac expression levels of Bax and Bcl-2. DIZE is effective in attenuating hyperthyroidism-induced cardiac hypertrophy by modulating the mitophagy-related pathway, suppressing apoptosis and oxidative stress.

Comparison of low-level laser therapy and standard treatment for temporomandibular disorders: An assessment of therapeutic and placebo effects.

BACKGROUND: Despite extensive research on the use of low-power lasers for TMD treatment, the extent of their effectiveness remains uncertain. OBJECTIVE: This study aimed to investigate the therapeutic or placebo effect of LLLT for TMD, and to compare it with standard treatment methods. A unique aspect of this study was the inclusion of a control group that received only standard treatment, allowing for an assessment of the placebo effect of LLLT. METHODS: A total of 42 patients with TMD were referred to Kerman Dental School Pain Clinic and were randomly assigned to three groups: group A received LLLT, group B was a placebo group and group C was a control group that received only standard treatment. The laser groups received gallium-aluminium-arsenide laser treatment twice a week for 10 sessions. Patients' jaw movement rate indicators and VAS index were evaluated at the start of treatment, and indicators were re-recorded every week for 5 weeks. SPSS 21 was used for statistical analysis, including ANOVA and Tukey's post hoc tests for inter-group comparisons. The repeated measurement test was used to analyse the data. RESULTS: All groups showed significant improvement in VAS indicators (p = .0001), lateral jaw movements (p = .0001), forward jaw movement (p = .007) but not for maximum mouth opening. No significant difference was observed between the groups at the end of the study (p = .000). CONCLUSION: Our study provides insights into LLLT's effectiveness for TMD, suggesting it cannot replace standard treatment alone. These findings contribute to the literature and emphasise the importance of including a control group in future studies to assess the placebo effect of LLLT.

The Advantages of 4-rod Construct over the 2-rod Techniques in Adult Spinal Deformity Patients who Underwent Pedicle Subtraction Osteotomy: A Multicenter Retrospective Comparative Study.

OBJECTIVE: In this retrospective study we compared clinicoradiologic outcomes and complication profiles of the traditional 2-rod construct versus the 4-rod construct in patients with adult spinal deformity (ASD) who underwent pedicle subtraction osteotomy (PSO). METHODS: We performed a retrospective review of 208 ASD patients at 2 referral centers who underwent lumbar PSO and long fusion from thoracic to the pelvis. Two different techniques, including the 4-rod construct and the traditional 2-rod technique, were used at the PSO level. Clinicoradiologic outcomes and complication profiles of the patients were documented and compared statistically between the groups. RESULTS: The 4-rod construct was associated with statistically lower rates of rod fracture (44.8% vs. 26.4%, P < 0.01), pedicular screw loosening at the PSO level (25.3% vs. 14.0%, P = 0.04), and reoperation (49.4% vs. 33.9%, P = 0.02). Radiologically, the 4-rod construct was associated with higher degree of lumbar lordosis (LL) (-37.4°vs. -26.8°; P < 0.01) and improved pelvic tilt (PT) (-17.2° vs. -9.9°; P < 0.01) and sacral vertical axis (SVA) corrections (-211.5° vs. -192.2°; P = 0.04). Overall, the 4-rod construct was associated with improved quality of life (P = 0.04) and statistically lower Oswestry Disability Index score at 12 months postoperatively (P < 0.01). CONCLUSIONS: Our results showed that the 4-rod construct was associated with statistically lower rates of rod fracture and pedicular screw loosening at the osteotomy level, higher degree of LL correction and improved PT and SVA than the 2-rod technique. The 4-rod construct was also associated with improved quality of life and Oswestry Disability Index and lower complication profiles.

The nephrotoxicity of Aristolochia rotunda L. in rats: Mitochondrion as a target for renal toxicity of Aristolochic acids-containing plants.

In recent years, there has been a growing trend in the usage of traditional medicine and herbal treatments. However, the misconception that they are completely safe resulted in irreversible complications and damages. The present study was conducted to investigate the potential renal toxicity of a commonly used drug in Iran's traditional medicine and pharmacy, known as Zaravand Gerd or Nokhod Alvand (Aristolochia rotunda L.). In Iranian traditional medicine, Zaravand Gerd is used as a remedy for respiratory system ailments, back pain, anxiety, headache and septic wounds. Fifty-six male rats were divided into seven groups (n = 8). The first group served as the control and received normal saline, while the second to seventh groups were administered varying doses of the aqueous extract of Zaravand Gerd (0.1, 0.5, 1.25, 2.5, and 5 g/kg) for a period of three weeks. Various parameters were measured to evaluate the potential kidney damage caused by the extract, including serum creatinine and BUN levels, as well as urine protein and glucose levels, which were analyzed using an autoanalyzer. Additionally, kidney tissue samples were examined pathologically, and mitochondria from the kidney tissue were isolated to assess mitochondrial parameters. The results of this study revealed that high doses of Zaravand Gerd extract led to a significant increase in urinary glucose and protein excretion compared to the control group. Pathological examination of the isolated kidney tissues indicated that the concentrations of 2.5 and 5 g/kg of Zaravand Gerd extract resulted in kidney damage and dilation of proximal convoluted tubules. Furthermore, the study demonstrated that high doses of the extract (2.5 and 5 g/kg) caused damage to the mitochondria. Based on the findings of this study, it can be concluded that the administration of high doses of Zaravand Gerd extract, which are not commonly used in traditional medicine, can have toxic effects on the kidneys in rats as an animal model. These results highlight the importance of considering the potential risks associated with herbal medicines and the necessity of usage based on scientific evidence.

Elafibranor upregulates the EMT-inducer S100A4 via PPARß/δ.

Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and ß/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient high-fat diet (CD-HFD), a model of metabolic dysfunction-associated steatohepatitis (MASH) that presents obesity and insulin resistance. Our findings revealed that elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in the livers of CD-HFD-fed mice. Unexpectedly, elafibranor also increased the levels of the epithelial-mesenchymal transition (EMT)-promoting protein S100A4 via PPARß/δ activation. The increase in S100A4 protein levels caused by elafibranor was accompanied by changes in the levels of markers associated with the EMT program. The S100A4 induction caused by elafibranor was confirmed in the BRL-3A rat liver cells and a mouse primary hepatocyte culture. Furthermore, elafibranor reduced the levels of ASB2, a protein that promotes S100A4 degradation, while ASB2 overexpression prevented the stimulating effect of elafibranor on S100A4. Collectively, these findings reveal an unexpected hepatic effect of elafibranor on increasing S100A4 and promoting the EMT program.

Mitochondrial biogenesis and apoptosis as underlying mechanisms involved in the cardioprotective effects of Gallic acid against D-galactose-induced aging.

BACKGROUND: Aging is a main risk factor for the development of cardiovascular diseases (CVDs). Gallic acid (GA) is a phenolic compound derived from a wide range of fruits. GA has a wide spectrum of pharmacological properties, including anti-oxidative, anti-inflammatory, and cardioprotective effects. This research was conducted to determine the cardioprotective effect of GA on cardiac hypertrophy in aged rats. METHODS AND RESULTS: Following histological evaluation and through observing the heart, we found that GA improved the cardiac hypertrophy induced by D-galactose (D-GAL) in cardiac cells. To clarify the causes for this anti-aging effect, we evaluated the malonic dialdehyde levels and antioxidant enzyme activity in rat cardiac tissue. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK-MB) in serum were measured. The levels of genes related to mitochondrial biogenesis, mitophagy, and apoptosis in cardiac tissue were surveyed. The findings represented that GA ameliorated antioxidant enzyme activity while significantly decreasing the malonic dialdehyde levels. Real-time PCR analysis proposed that GA effectively improved mitochondrial biogenesis in the heart via regulating the expression levels of Sirtuin 1 (SIRT1), PPARγ coactivator 1α (PGC1-α), nuclear factor erythroid 2-related factor 2 (Nrf2), and mitochondrial transcription factor A (TFAM). GA also mitigated apoptosis in the heart by modulating the expression levels of B-cell lymphoma protein 2 (Bcl-2) and Bcl-2-associated X (Bax). In addition, GA improved serum LDH and CK-MB levels. CONCLUSIONS: GA may alleviate aging-induced cardiac hypertrophy via anti-oxidative, mitoprotective, and anti-apoptotic mechanisms.

Comparing Two Naloxone Tapering Methods in Management of Methadone Intoxication; a Quasi-experimental Study.

Introduction: Even though naloxone is the main treatment for methadone poisoning treatment there are controversies about the proper method of its tapering. This study aimed to compare two methods in this regard. Method: This study was a prospective, single-blind pilot quasi-experimental study on non-addicted adult patients poisoned with methadone. Patients were randomly divided into 2 groups. In one group, after stabilization of respiratory conditions and consciousness, naloxone was tapered using the half-life of methadone and in the other group, naloxone was tapered using the half-life of naloxone. Recurrence of symptoms and changes in venous blood gas parameters were compared between groups as outcome. Results: 52 patients were included (51.92% female). 31 cases entered Group A (tapering based on methadone's half-life) and 21 cases entered Group B (tapering based on naloxone's half-life). The two groups were similar regarding mean age (p = 0.575), gender distribution (p = 0.535), the cause of methadone use (p = 0.599), previous medical history (p = 0.529), previous methadone use (p = 0.654), drug use history (p = 0.444), and vital signs on arrival to emergency department (p = 0.054). The cases of re-decreasing consciousness during tapering (52.38% vs. 25.81%; p = 0.049) and after discontinuation of naloxone (72.73% vs. 37.50%; p = 0.050) were higher in the tapering based on naloxone half-life group. The relative risk reduction (RRR) for naloxone half-life group was -1.03 and for methadone half-life group was 0.51. The absolute risk reduction (ARR) was 0.27 (95% confidence interval (CI) = 0.01-0.53) and the number needed to treat (NNT) was 3.7 (95% CI= 1.87- 150.53). There was not any statistically significant difference between groups regarding pH, HCO3, and PCO2 changes during tapering and after naloxone discontinuation (p > 0.05). However, repeated measures analysis of variance (ANOVA), showed that in the tapering based on methadone's half-life group, the number of changes and stability in the normal range were better (p < 0.001). Conclusion: It seems that, by tapering naloxone based on methadone's half-life, not only blood acid-base disorders are treated, but they also remain stable after discontinuation and the possibility of symptom recurrence is reduced.