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Objective: Acrylamide (ACR) is a neurotoxic agent whose damage could be attenuated by antioxidants administration. Crocetin is a saffron-derived antioxidant that has neuroprotective effects. This study evaluates the protective effects of trans-sodium crocetinate (TSC) and its water-soluble derivative, Bis-N-(N-methylpyprazinyl) crocetinate (BMPC) against ACR neurotoxicity.Materials and Methods: PC12 cells were treated with TSC and BMPC (1.95, 3.9, 7.81, 15.62, 31.25, 62.5, 125, 250, 500, and 1000 μM) for 24 hr. ACR was then added at a concentration of 6.5 mM (IC50), and cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. In the in vivo study, male Wistar rats were treated with ACR (50 mg/kg, intraperitoneal (i.p.)) for 11 days alone or in combination with TSC and BMPC (2.5, 5, and 10 mg/kg, i.p.) or vitamin E (200 IU/kg, i.p.). Motor impairments were then evaluated. The cerebral cortex of sacrificed rats was taken for the malondialdehyde (MDA) and glutathione (GSH) levels measurement. Results: In vitro studies showed that TSC at a concentration of 7.81 μM and BMPC at concentrations of 3.9, 7.81, and 15.62 μM exhibited the lowest toxicity in acrylamide administration. In the in vivo study, pretreatment with 2.5, 5, and 10 mg/kg of TSC ameliorated behavioral impairments, but BMPC could not attenuate them. GSH and MDA were improved by 2.5, 5, and 10 mg/kg TSC and 2.5 mg/kg BMPC.Conclusion: TSC and BMPC administration improved behavioral index and oxidative stress injuries in Wistar rats exposed to ACR through MDA reduction and GSH content enhancement in the cerebral cortex.

Abstract The COVID-19 outbreak has triggered a global health and economic crisis, necessitating widespread testing to control viral spread amidst rising cases and fatalities. The recommended testing method, a combined naso- and oropharyngeal swab, poses risks and demands limited protective gear. In response to the COVID-19 pandemic, we developed and tested the first autonomous swab robot station for Naso- and Oropharyngeal Coronavirus Screening (SR-NOCS). A force-sensitive robot running under a Cartesian impedance controller is employed to drive the swab to the sampling area. This groundbreaking device underwent two clinical studies-one conducted during the initial pandemic lockdown in Europe (early 2021) and the other, more recently, in a public place after the pandemic had subsided earlier in the year 2023. In total, 52 patients suspected of COVID-19 infection were included in these clinical studies. The results revealed a complete positive correlation between autonomous and manual sampling. The test subjects exhibited a high acceptance rate, all expressing a willingness to undergo future tests with SR-NOCS. Based on our findings, such systems could enhance testing capabilities, potentially conducting up to 300 tests per robot per day with consistent precision. The tests can be carried out with minimal supervision, reducing infection risks and effectively safeguarding patients and healthcare workers.

Background: During the Covid-19 pandemic, there has been a notable increase in self-medication with antibiotics or other medications due to impaired access to healthcare services. This kind of self-treatment, without comprehending the condition and its related risks, can result in misdiagnosis, overdosing and delaying in acquiring professional medical attention, or may even cause antimicrobial resistance. Additionally, reports have suggested that medical practitioners have prescribed medications inappropriately to patients with Covid-19. To investigate this further, this study compared the medications used by patients with Covid-19 prior to hospitalization with or without a medical recommendation. Methods: Data was extracted a mass survey of patients with of Covid-19 in Mashhad, and the patients were divided into two main groups: those who received medication with guidance from a medical professional (treatment group) and those who self-administered medications without professional oversight (self-treatment group). Statistical analysis was then conducted using SPSS version 26, the Chi-square, and multiple logistic regression test. Results: This study examined 3266 patients, with 1466 included in the analysis. Results showed that men (9.5 %), those living in rural areas (21 %), and those with no academic degree (37.5%) had a higher likelihood to self-medicating. Antibiotics were the most frequently used medications prior to hospitalization (9.5%). Comparing the two groups revealed that three drug categories- antibiotics, antivirals and other medications (medicines that are not in the other 4 main categories)- were utilized more often in the treatment group than in the self-treatment group, with a p-value of

Background and Purpose: Exercise and obesity alter angiogenesis in adipose tissue, resulting in large changes in metabolic processes. The aim of this study was to compare the effect of eight weeks of resistance training and high-intensity intermittent aerobic training (HIIAT) on the expression of microRNAs associated with adipose tissue angiogenesis and antiangiogenesis in rats fed a high-fat diet.Materials and Methods: In the experimental study, 60 six-week-old male wistar rats (mean body weight = 192.40 ± 11.35) were obtained from Pasteur Institute of Iran. The animals were randomly divided into six equal groups after transfer to the laboratory environment and one week of exposure to the new environment: 1. Normal diet (CO), 2. Normal diet + Resistance training (NRT), 3. Normal diet + HIIAT (NHT), 4. High-fat diet (HF), 5. High-fat diet + Resistance training (HFRT), 6. High-fat diet + HIIAT (HFHT) (n = 10 per group). The training groups performed their training protocol for eight weeks and five sessions per week. Resistance training included climbing a 1-meter ladder with a 90-degree slope and 46 steps. Initially, the weight attached to the rats' tails was 30% of their body weight and gradually reached about 180% of their body weight in the final week. The exercises were performed in five sets of four repetitions. High-intensity intermittent aerobic training was started on the treadmill at an initial speed of 15 meters per minute, and in each session, one to two meters per minute was added to the treadmill speed, depending on the ability of the rats. During the Pabani week, the exercise reached six stages of three minutes of running at a speed of 40 meters per minute with a slope of 15 degrees. To evaluate the effect of resistance training and high-intensity intermittent aerobic training and high-fat diet (58% of calories in the form of fat) on miR-221, miR-222, miR-329 and VEGF variables, subjects in each group were killed 48 hours after the last training session. Sampling of mesenteric adipose tissue was performed immediately after killing the animals. Data analysis was performed using independent t-test, one-way and two-way ANOVA at the significant level (P ≥ 0.05). Scheffe post hoc test was used to compare the pairwise .Results: The miR-221, miR-222 and VEGF in the Normal diet + Resistance training, Normal diet + HIIT and High-fat diet + Resistance training groups a significant increase was observed compared to the control group (P ≥ 0.01). However, miR-329 was significantly higher only in the high-fat diet group than in the normal diet + HIIAT group (P = 0.022).Conclusion: The results showed that resistance training and HIIAT by increasing miR-221, miR-222, and decreasing miR329 led to the activation of pathways that increased VEGF protein and ultimately increased angiogenesis in rats with a high-fat and normal diets. Therefore, these exercises are an important factor in angiogenesis and mechanism in adipose tissue, which may be able to cause significant changes in adipose tissue during this process. However, in order to confirm this point and generalize it to humans, more research is needed, especially on human specimens. Also, since the effect of resistance training on miRNAs was greater than HIIAT, these exercises can be a good alternative to HIIAT.

Abstract Background Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typical facial gestalt and cardiovascular defects. LZTR1 variants have been recently described in patients with NS and schwannomatosis, but the association, inheritance pattern and management strategy has not been fully elucidated. Here, we review the contribution of LZTR1 in NS and describe a patient with a novel, likely pathogenic variant in LZTR1. Case presentation A female patient was diagnosed with clinical NS at 8 months of age. She presented in adulthood when a brain and spine MRI identified plexiform neurofibromas; however, she did not meet the clinical criteria for Neurofibromatosis type 1. No pathogenic variants were identified through molecular genetic analysis of NF1, SPRED1 and a multigene NS panel. Whole exome sequencing at age 23 identified a novel de novo likely pathogenic heterozygous variant in the LZTR1 gene denoted as c.743G>A (p.Gly248Glu). Serial MRIs have shown stable imaging findings and the patient is being followed clinically by cardiology, neurology and medical genetics. Conclusions We identified a novel mutation in the LZTR1 gene, not previously reported in association with NS. This report provides additional evidence to support for the assessment of schwannomatosis in patients with LZTR1-NS and may have overlap with Neurofibromatosis type 1.

Abstract Background Lipoxygenases are one of the critical signaling mediators which can be targeted for human prostate cancer (PC) therapy. In this study, 4-methyl-2-(4-methylpiperazinyl)pyrimido[4,5-b]benzothiazine (4-MMPB) and its two analogs, 4-propyl-2-(4-methylpiperazinyl)pyrimido[4,5-b]benzothiazine (4-PMPB) and 4-ethyl-2-(4-methylpiperazinyl)pyrimido[4,5-b]benzothiazine (4-EMPB), were proposed to have anti-tumor properties in prostate cancer. Methods After synthesizing the compounds, cytotoxic effects of 4-MMPB and its two analogs against PC-3 cancerous and HDF normal cells were investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and then mechanism of cell death was assessed by flow cytometry. Finally, the anti-tumor effects of the mentioned compounds were investigated in an immunocompromised C57BL/6 mouse model. Results 4-PMPB and 4-EMPB had similar anti-cancer effects on PC-3 cells as compared with 4-MMPB, while they were not effective on normal cells. Moreover, apoptosis and ferroptosis were the main mechanisms of induced cell death in these cancerous cells. Furthermore, in vivo results indicated that both analogs had similar anti-cancer effects as 4-MMPB, leading to delayed tumor growth without any noticeable side effects in weight loss and histological investigations. Conclusion Thus, our results suggest that specific targeting of lipoxygenases via 4-MMPB analogs can be considered as a treatment of choice for PC therapy, although it requires further investigations.

Objective(s): Allylbenzenes have been recently developed as inhibitors of lipoxygenases. They decrease peroxidation activity via mimicking 1,4-unsaturated bonds of fatty acids by their allyl portion. We designed and synthesized new derivatives of allyl benzenes (6a-f) with isopropoxy and amide substituents at ortho and meta positions towards allyl group, respectively. The inhibitory potency of the synthetized allylbenzenes against soybean 15-lipoxygenase (SLO) and subsequently structure-activity relationships was assessed.Materials and Methods: 3-allyl-4-isopropoxybenzenamine (5) as starting material was synthesized by coupling of 4-nitropheol with allyl bromide, performing Claisen rearrangement and finally reduction of the nitro moiety. Final products 6a-f were prepared via amidation of 5 with the desired acyl chloride.Results: Among the compounds, N-(3-allyl-4-isopropoxyphenyl)adamantan carboxamide (6f) potentially showed best inhibition (IC50 = 1.35 µM) while 6a with cyclopropyl carboxamide moiety was the weakest inhibitor and 6e with phenyl carboxamide moiety showed no effect. Energy minimized 3D structures of the compounds were docked into the active site pocket of SLO. For the aliphatic amides, docking results showed compatibility between inhibitory potency and average Ki of the cluster conformers, in which their allyl moiety oriented towards SLO iron core. For the aliphatic analogs, by enlargement of the amide moiety size the inhibitory potency was increased.Conclusion: Docking results showed that orientation of the amide and allyl moieties of the inhibitors in the active site pocket is the major factor in inhibitory potency variation. Based on the mentioned orientation, for cycloaliphatic amides, by enlargement of the amide moiety both inhibition potency and calculated binding energy increases.

Media and artistic animation is a combination of other elements of the arts. This feature, in addition to the possibility of creating a fantasy universe, has a special charm that can address all age groups. In this regard, the necessity of publishing scientific and educational texts and adapting them to the latest findings, in view of the ever-increasing development of production methods, doubles the importance of this investigation. In this regard, the issue of the elements of attractiveness in the animation cinema is necessary, useful, and valuable. Despite its drawbacks, this work is one of the sources of Farsi help for students and animation enthusiasts. However, by studying the configuration of the topics and the content of the book, it can be noted that the correction is effective in advancing the goals and strengthening the content. These include lack of light unity in the structure of the content, lack of clarity in the presentation of the content for a particular or general audience, lack of attention to the impact of contemporary achievements, the need for appropriate images for the completion and explanation of the topics and the lack of proper communication between some The images presented with the text have been criticized in various ways. This paper, after introducing some points, reviews the content of the book and analyzes the contents of the book.

Loop-mediated isothermal amplification is a promising candidate for the rapid detection of Mycobacterium tuberculosis. However, the high potential for carry-over contamination is the main obstacle to its routine use. Here, a closed tube LAMP was intended for the visual detection of Mtb to compare turbidimetric and two more favorable colorimetric methods using calcein and hydroxy naphthol blue (HNB). Additionally, a less studied dye (i.e., eriochrome black T (EBT)) was optimized in detail in the reaction for the first time. Mtb purified DNA and 30 clinical specimens were used to respectively determine the analytical and diagnostic sensitivities of each method. The turbidimetric method resulted in the best analytical sensitivity (100 fg DNA/reaction), diagnostic sensitivity and specificity (100%), and time-to-positivity of the test (15 min). However, this method is highly prone to subjective error in reading the results. Moreover, HNB-, calcein-, and EBT-LAMP could respectively detect 100 fg, 1 pg, and 1 pg DNA/reaction (the analytical sensitivities) in 30, 15, and 30 min, while the diagnostic sensitivity and specificity were respectively 93.3% and 100% for them all. Interestingly, EBT-LAMP showed the lowest potential for subjective error in reading the results. This report helps judiciously choose the most appropriate visual method, taking a step forward toward the field applicability of LAMP for the detection of Mtb, particularly in resource-limited settings.

Objective(s): 15-Lipoxygenases are one of the iron-containing proteins capable of performing peroxidation of unsaturated fatty acids in animals and plants. The critical role of enzymes in the formation of inflammations, sensitivities, and some cancers has been demonstrated in mammals. The importance of enzymes has led to the development of mechanistic studies, product analysis, and synthesis of inhibitors. Materials and Methods: The inhibitory activity of all synthetic compounds against SLO (soybean 15-lipoxygenase: L1; EC 1,13,11,12) was determined using the peroxide formation method. In this method, the basis of evaluation of lipoxygenase activity is measuring the concentration of fatty acid peroxide. All measurements were compared with 4-​methyl-​2-​(4-​methylpiperazinyl)pyrimido[4,​5-​b]benzothiazine (4-MMPB) as one of the known lipoxygenase inhibitors. The radical scavenging ability of all synthetic compounds using stable free radicals (DPPH: 2,2-diphenyl-1-picrylhydrazyl) was measured for further investigation.Results: In this study, a series of esters from phenolic acids with terpenoid alcohols was synthesized and their inhibitory potency against soybean 15-lipoxygenase and their free radical scavenging properties were determined. Among the synthetic compounds, adamantyl protocatetuate 2j and bornyl protocatetuate 2o showed the most potent inhibitory activity with IC50 values of 0.95 and 0.78 μm, respectively.Conclusion: By changing the alcohol and acyl portions of stylosin, it was found that electronic properties play main role in lipoxygenase inhibition potency in contrast with steric features. Insertion of more reductive phenolic moiety such as catechuate and gallate lead to more lipoxygenase inhibition potency of the esters as observed in their radical scavenging activity.

Objective(s): Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), stayed a global health thread with high mortality rate. Since TB has a long-term treatment, it leads high risk of drug resistant development, and there is an urgent to find new drugs. The aim of this study was designing new inhibitors for a new drug target, iron dependent regulator, IdeR. Materials and Methods: Based on the interaction most populated amino acids of IdeR to the related gene operators, 50 short peptides were modeled. Bonding affinity of short peptides toward DNA were studied by docking. Top 10 best predicted bonding affinity were selected. DNA binding assay, microplate alamar blue assay, colony counting, quantitative real time- PCR (qRT-PCR) of IdeR corresponding genes, cell wall-associated mycobactin and whole-cell iron estimation were done to prove the predicted mechanism of in silico potent constructs. Results: Amongst the 10 synthesized short peptide candidates, glycine-valine-proline-glycine (GVPG) and arginine-proline-arginine (RPR) inhibited Mtb in vitro at 200 µM concentration. qRT-PCR showed mbtB 58-fold over expression that resulted in Mtb growth inhibition. Cell wall-associated mycobactin and whole-cell iron estimation confirmed the results of qRT-PCR. Conclusion: We introduced two new lead compounds to inhibit Mtb that are promising for the development of more potent anti-tubercular therapies.

Objective(s): Recently, we showed that some new synthetic compounds structurally related to cilostamide (4-(1,2-dihydro-2-oxoquinolin-6-hydroxy)- N-cyclohexyl-N-methylbutanamide), a selective phosphodiesterase 3 (PDE3) inhibitor, produce inotropic effect comparable to that of IBMX (3-isobutyl-1-methylxanthine), a non-selective PDE inhibitor, but with differential chronotropic effect. In this investigation, we compared the pharmacological effects of these compounds as potential cardiotonic agents using the spontaneously beating atria model. Materials and Methods: In each experiment, rats were treated with reserpine. The atrium was isolated and mounted in an organ bath. We assessed chronotropic and inotropic effects using cumulativelogconcentration-response curves of isoprenaline alone or in combination of each test-compound. Results: Majority of test compounds augment atria contraction force (ACF) significantly but with different potencies on atrium contraction rate. Cilostamide, MCPIP ([4-(4-methyl piperazin-1-yl)-4-oxobutoxy)-4-methylquinolin-2(1H)-one]), methyl carbostyril compounds- (mc1), mc2 and mc5 increased the isoprenaline effect on ACF synergistically. But, mc6 failed to potentiate the effect of isoprenalin; mc3 and mc4 did not increase ACF, which may be because of their higher hydrophilic nature. It was interesting that mc2, alone or in combination with isoprenaline, produced the highest inotropic effect while it did not affect the basal contraction rate and almost blocked the isoprenaline chronotropic effect. Conclusion: Combination of mc2 with isoprenaline had synergistic effect on inotropic effect, but this combination reduced isoprenaline chronotropic effect; therefore, these effects cannot be related to reducing B-adrenergic receptors activity. These compounds showed different effects; probably all of them were not mediated via PDE3 inhibition and other mechanisms are involving.

Objective(s): Despite treatment with antibiotics and vaccination with BCG, tuberculosis (TB) is still considered as one of the most important public health problems in the world. Therefore, designing and producing a more effective vaccine against TB seems urgently. In this study, immunogenicity of a fusion protein which consisting or comprising CFP-10 from Mycobacterium tuberculosis and the Fc-domain of mouse IgG2a was evaluated as a novel subunit vaccine candidate against TB. Materials and Methods: The genetic constructs were cloned in pPICZαA expression vector and recombinant vectors (pPICZαA-CFP-10: Fcγ2a and pPICZαA-CFP-10:His) were transformed into Pichia pastoris. To evaluate the expression of recombinant proteins, SDS-PAGE and immunoblotting were used. The immunogenicity of recombinant proteins, with and without BCG were assessed in BALB/c mice and specific cytokines against recombinant proteins (IFN-γ, IL-12, IL-4, IL-17 and TGF-β) were evaluated. Results: The levels of IFN-γ and IL-12 in mice that received recombinant proteins was higher than the control groups (BCG and PBS). Thus, both recombinant proteins (CFP-10:Fcγ2a and CFP-10:His) could excite good response in Th1-cells. The Fc-tagged protein had a stronger Th1 response with low levels of IL-4, as compared to CFP-10:His. However, the highest level of Th1 response was observed in groups that were vaccinated with BCG (prime) and then received recombinant protein CFP-10: Fcγ2a (booster). Conclusion: The results demonstrated that binding mice Fc-domain to CFP-10 protein can increase the immunogenicity of the subunit vaccine. Further studies, might be able to design and produce a new generation of subunit vaccines based on the Fc-fused immunogen.

Objective(s): Recently we reported that the soybean 15-lipoxygenase (SLO) inhibitory activity of pyrimido[4,5-b][l,4]benzothiazines largely depends on the orientation of sulfur atom of thiazine core towards FeIII-OH in the active site pocket of the enzyme with subsequent oxidation of sulfur to sulfoxide. In this paper the results of a comparative study on the SLO inhibitory activities of the mentioned compounds using ab initio calculations and docking analyses has been reported. Materials and Methods: Structure optimization and docking analyses were performed using HyperChem 7.5 and AutoDock Tools 4.0 respectively. Enzyme assessment was reduced using spectrophotometric MBTH-DMAB method. Results : The inhibitory activity of synthetic 2-substituted pyrimido[4,5-b][l,4]benzothiazines against soybean 15-lipoxygenase (SLO) was evaluated and structure activity relationships and binding modes of their 4-H and 4-methyl analogs were studied using docking analysis and ab initio calculations. Discussion: The results of these studies showed that the lack of 4-methyl substituent in the pyrimido[4,5-b][1,4]benzothiazine molecules greatly reduces their lipoxygenase inhibitory activities and it was also found that the HOMO energy difference between the 4-H and 4-Methyl analogs can be responsible for the observed inhibitory activity reduction. Conclusion: Our molecular modeling studies shows that by using more flexible amino acids during the docking process, more rational results can be obtained. The method of measuring the lipoxygenase activity is also of prime importance for the study of structure activity relationship.

Allyloxy, Isopentenyloxy, geranyloxy and farnesyloxy derivatives of 3-carboxycoumarin, at position 5, 6, 7, and 8, were synthesized and their inhibitory potency against human 15-lipoxygenase-1 (human 15-LOX-1) were determined. Among the synthetic coumarins, O-allyl and O-isopentenyl derivatives demonstrated no considerable lipoxygenase inhibition while O-geranyl and O-farnesyl derivatives demonstrated potent inhibitory activity. 5-farnesyloxy-3-carboxycoumarin demonstrated the most potent inhibitory activity by IC50 = 0.74 μM while 6-farnesyloxy-3-carboxycoumarin was the weakest inhibitor among farnesyl analogs (IC50 = 10.4 μM). Bonding affinity of the designed molecular structures toward 15-LOX-1 3D structure complexed with RS75091, as potent 15-LOX-1 inhibitor, was studied by utilizing docking analysis. There was a direct relationship between lipoxygenase inhibitory potency and prenyl length chain. The ability of the prenyl portion to fill the lipophilic pocket which is formed by Ile663, Ala404, Arg403, Ile400, Ile173 and Phe167 side chains can explain the observed relationship. Similarity rate between the docked models and complexed form of RS75091, from point of view of configuration and conformation, could explain inhibitory potency variation between each prenyloxy substitution of 3-carboxycoumarins.

Paraneoplastic neurological disorders (PNDs) are a rare and diverse group of neurological conditions that can involve any part of the nervous system. Diagnosis is facilitated by finding well-recognized autoantibodies directed against neural antigens in the sera and the cerebrospinal fluid. Identifying and eliminating the underlying malignancy is the mainstay of treatment. Immunomodulatory treatment is gaining more acceptance especially, where a malignancy could not be identified, oncology treatment is completed, or along with cancer treatment. Literature review shows only a handful of systematic prospective case series. Multicenter, prospective controlled clinical trials are needed for future therapeutic advances.