Association of glutamine synthetase polymorphisms rs2296521, rs10911021 and rs12136955 with plasma ammonia concentration in valproic acid-treated Egyptian epilepsy patients.

INTRODUCTION: The use of valproic acid (VPA) in the treatment of some psychiatric and neurological disorders such as bipolar disorder, migraines, and epilepsy is associated with hyperammonemia. However, the mechanism of this negative effect of VPA is unclear. In this study, we investigate gene glutamate-ammonia ligase (GLUL) polymorphisms for the glutamine synthetase (GS) enzyme, a key enzyme that catalyzes the removal of ammonia by incorporating it with glutamate to form glutamine, and we investigate whether it has a relationship with the emergence of hyperammonemia during VPA-based therapy. PATIENTS AND METHODS: We enrolled 180 Egyptian epilepsy patients in this study. Patient history, general and neurological examination and blood samples from arm veins were taken. Real time TaqMan PCR polymorphism for three polymorphism SNPs (rs2296521, rs10911021 and rs12136955) of GLUL was done. We assessed the relationship between the patient features, including three GLUL polymorphisms, and the development of hyperammonemia during VPA-based therapy. RESULTS: We found that the ammonia levels showed a positive correlation with VPA treatment duration (p = 0.015) and a negative correlation with carbamazepine total dose per day (p = 0.027) and with WBCs count (p = 0.026). Also, female patients having rs2296521 SNPs with the A allele and patients having rs10911021 SNPs with the C allele were at high risk for elevated plasma ammonia levels. Moreover, patients having rs12136955 SNPs with the A allele or associated hypertension as a co-morbidity were at high risk for elevated plasma ammonia levels. CONCLUSION: Female patients who have rs2296521 with the A allele, rs10911021 with the C allele, or rs12136955 with the A allele, are independent risk factors for elevated plasma ammonia levels during VPA-based therapy. Moreover, carbamazepine combined therapy may protect against the development of hyperammonemia in VPA-treated patients.

Effect of New Antidiabetics on Steatosis in Nerve Tissues and Nerve Conduction Velocity: Possible Role of Nerve Growth Factor (NGF)/Synaptophysin and Nrf2/HO-1 Pathways.

OBJECTIVES: The current study aims to investigate the impact of the GLP1 analog (semaglutide) and SGLT2 inhibitor (dapagliflozin) on nerve functions, morphology, and the underlying mechanisms involving nerve growth factor (NGF)/synaptophysin and Nrf2/HO-1 pathways in obese rats. METHODS: Forty male Sprague Dawley rats, aged six to eight weeks, were classified into five groups; normal group (high-fat diet {HFD} for 12 weeks, metformin group (HFD for 12 weeks + metformin in last four weeks), dapagliflozin group (HFD for 12 weeks +dapagliflozin in last four weeks, semaglutide group (HFD for 12 weeks + semaglutide in last four weeks). At the end of the experiment, the sciatic nerve was collected for nerve conduction study, oxidative stress marker (malondialdehyde, i.e., MDA), real-time polymerase chain reaction (PCR) study (for HO-1 and Nrf2), oil red O staining, electron microscopic examination and immunohistochemistry for NGF and synaptophysin. RESULTS: The HFD group showed a significant rise in blood glucose, serum lipids, homeostatic model assessment (HOMA) index, lipid deposition in nerve tissues, and lipid peroxidation (MDA) in nerve tissues with significant attenuation in nerve conduction velocity (NCV), the expression of Nrf2 and HO-1 genes and significant attenuation in area stained with NGF and synaptophysin. On the other hand, pretreatment with either dapagliflozin or semaglutide led to considerable enhancement in the deteriorated serum and nerve tissue parameters and reversed the pathological changes. CONCLUSION: New antidiabetic drugs like SGLT2 inhibitors (more powerful) and GLP1 analog might have neuroprotective beneficial effects besides controlling the glycemic state in obese rats. This effect may result from reduced oxidative stress and increased Nrf2 levels, HO-1, synaptophysin, and NGF in the nerve tissues of obese rats.

Perforator-based local flaps for cutaneous facial reconstruction.

BACKGROUND: Despite the advancement of reconstructive surgical techniques, facial defect reconstruction has been always very challenging, aesthetic satisfaction has often been difficult to achieve due to the unique characteristics and complexity of the facial tissue. There have been various options regarding reconstruction and compensation of soft tissue loss all over the body rather than the face. Regardless of whether skin grafts, local flaps, and free flaps were used in the reconstruction process, each of them has its limitations. Beginning with skin grafts results could not always be satisfactory due to contracture, color, and lack of texture Additionally, local flaps have limitations due to mobility and the availability of overlapping skin and tissue, as well as the bulkiness of the pedicle which may need a second staged surgery and lately the difficulty of the free flaps and being a major surgery. RESULTS: Patients ages ranged between 23 and 77 years old, with a mean age of 58.33 ± 12.47. As regards the patients' sex, 63.3% of our patients were males and 36.7% were females. Co-morbidities were found in 60% of cases (DM 23.3%, HTN 20%, HCV 3.3%, cardiac 3.3%). Most flaps were facial artery perforator flaps 53.3%, then transverse facial artery 26.7%, superficial temporal artery 10%, angular artery 6.7%, and supra-trochlear artery 3.3%. Twenty-ix cases representing 86.7% of cases went uneventful, while complications showed in 4 cases representing 13.3% of cases, 1 case (3.3%) showed venous congestion that was relieved within 24 h after 2 suture releases, another case (3.3%) showed wound dehiscence that was improved after 2 days with regular dressings, the third patient (3.3%) had recurrence after 4 months that was treated by excision and grafting, while last patient (3.3%) had inadequate excision that was treated by radiotherapy. No bleeding or infection occurred. Also, we observed no correlation between flap length and complications. As regards the functional point of view, all patients showed no functional impairment at the donor site, and only one case showed functional impairment at the recipient site. As regards patient satisfaction, all 30 patients achieved positive satisfaction scores using the Likert scale, 18 cases were satisfied, and 12 cases were very satisfied. CONCLUSION: The use of perforator-based flaps can provide a more effective and aesthetically pleasing solution for the reconstruction of small to moderate facial defects, provided that a reliable Perforator is accurately identified and executed by an experienced surgeon.

Evaluation of the outcomes of fistulotomy with primary sphincter reconstruction in the management of high trans-sphincteric fistula and supra-sphincteric fistula-in-ano : A single-center prospective cohort study.

BACKGROUND: Supra-sphincteric and high trans-sphincteric fistula are very challenging procedures for both the patient and the surgeon. We aimed to evaluate the outcomes of anal sphincter repair in the management of supra-sphincteric and high trans-sphincteric fistula-in-ano in terms of postoperative wound infection, bleeding, incontinence to flatus or stool, and recurrence within 1 year. PATIENTS AND METHODS: This single-center prospective cohort trial conducted from June 2020 to December 2023 at the Ain Shams University Hospitals included 20 patients who presented with supra-sphincteric or high trans-sphincteric fistula. There were nine (45%) male and 11 (55%) female patients, with a mean age of 41.5 years postoperatively. RESULTS: The mean duration of the procedure was 90.3 min (SD ± 11.9). During the first 2 weeks, ten (50%) patients scored their postoperative pain as mild, eight (40%) as moderate, and two (10%) as severe. Wound infection occurred in two (10%) patients and postoperative bleeding in three (15%) patients in the form of spotting after defecation. There were no cases of incontinence to stool. However, there were three (15%) cases of incontinence to gases. There were two cases (10%) of recurrence at the 1­year follow-up. Postoperative patient satisfaction was assessed on a 5­point Likert scale after 2 weeks: One patient (5%) was very dissatisfied, three (15%) patients were dissatisfied, and two (10%) patients were unsure, while five (25%) patients were satisfied and nine (45%) were very satisfied. CONCLUSION: Immediate sphincter repair in supra-sphincteric and high trans-sphincteric fistula through a lay-open procedure was determined to be safe, easier than classic operations, and associated with a low incidence of recurrence at the 1­year follow-up and a high quality of life.

Human Wharton's jelly-derived mesenchymal stromal stem cells preconditioned with valproic acid promote cell migration and reduce renal inflammation in ischemia/reperfusion injury by activating the AKT/P13K and SDF1/CXCR4 pathways.

OBJECTIVE: To determine whether WJ-MSCs pretreated with VPA would enhance their migration to improve functional recovery of renal IRI in rats. METHODS: 150 Sprague-Dawley rats were distributed into 5 groups; Sham, IRI, WJ-MSC, VPA, and WJ-MSCs + VPA. 10 rats were sacrificed after 3, 5, and 7 days. Role of WJ-MSCs pretreated with VPA was evaluated by assessment of renal function, antioxidant enzymes together with renal histopathological and immunohistopathological analyses and finally by molecular studies. RESULTS: WJ-MSCs and VPA significantly improved renal function and increased antioxidants compared to IRI group. Regarding gene expression, WJ-MSCs and VPA decreased BAX and TGF-ß1, up-regulated Akt, PI3K, BCL2, SDF1α, and CXCR4 related to IRI. Additionally, WJ-MSCs pretreated with VPA improved the measured parameters more than either treatment alone. CONCLUSION: WJ-MSCs isolated from the umbilical cord and pretreated with VPA defended the kidney against IRI by more easily homing to the site of injury.

Effect of intermittent fasting on adriamycin-induced nephropathy: Possible underlying mechanisms.

PURPOSE: Intermittent fasting (IF) has been shown to induce a well-organized adaptive defense against stress inside the cells, which increases the production of anti-oxidant defenses, repair of DNA, biogenesis of mitochondria, and genes that combat inflammation. So, the goal of the current investigation was to identify the effects of IF on rats with adriamycin (ADR)-induced nephropathy and any potential underlying mechanisms. METHODS: Four groups of 40 mature Sprague-Dawley male rats were allocated as follow; control, fasting, ADR, and ADR plus fasting. After 8 weeks of ADR administration urine, blood samples and kidneys were taken for assessment of serum creatinine (Cr), BUN, urinary proteins, indicators of oxidative damage (malondialdehyde (MDA), reduced glutathione (GSH) and Catalase (CAT) levels), histopathological examinations, immunohistochemical examinations for caspase-3, Sirt1, aquaporin2 (AQP2) and real time PCR for antioxidant genes; Nrf2, HO-1 in kidney tissues. RESULTS: IF significantly improved serum creatinine, BUN and urinary protein excretion, oxidative stress (low MDA with high CAT and GSH), in addition to morphological damage to the renal tubules and glomeruli as well as caspase-3 production during apoptosis. Moreover, IF stimulates significantly the expression of Sirt1 and Nrf2/HO-1 and AQP2. CONCLUSION: AQP2, Sirt1, Nrf2/HO-1 signaling may be upregulated and activated by IF, which alleviates ADR nephropathy. Enhancing endogenous antioxidants, reducing apoptosis and tubulointerstitial damage, and maintaining the glomerular membrane's integrity are other goals.

A comparative study in elective repair of large incisional hernias using on-lay mesh vs. sub-lay mesh: a meta-analysis.

Ventral abdominal wall incisional hernia is defined as a defect in the musculo-fascial layers of the abdominal wall in the region of the postoperative scar. There is a slight increase in the incidence of incisional hernia in the female gender. The higher percentage of incisional hernia in females might be due to laxity of abdominal wall muscles after multiple pregnancies and also an increased incidence of obesity in females. To assess incisional hernia repair using two different techniques: on-lay mesh and sub-lay mesh, as regards operative time, postoperative recurrence, wound infection, seroma, hematoma, and flap necrosis. Pubmed, Web of Science, and Scopus were searched on 15 March 2022. The keywords incisional hernia, sub-lay mesh on-lay mesh, retromuscular mesh, and polypropylene. According to our results, there is a statistical difference between onlay and sublay regarding intra-operative time as sublay mesh is more time-consuming. Regarding postoperative complications, there is no statistical difference in recurrence, seroma, hematoma, flap necrosis, and infection but there is a statistical difference regarding in hospital stay as patients with sub-lay repair stays less than only.

Comparison between stapled hemorrhoidopexy and harmonic scalpel hemorrhoidectomy in the management of third- and fourth-degree piles: a randomized clinical trial.

BACKGROUND: This study compared the results of stapled hemorrhoidopexy (SH) and harmonic scalpel hemorrhoidectomy (HSH) in the management of grade III and grade IV piles regarding the time of the procedure, postoperative pain, patient satisfaction, wound infection, bleeding, incontinence, and recurrence within 1 year. PATIENTS AND METHODS: This was a single-blind, prospective, randomized, controlled, single-center trial conducted from January to December 2022 that included 50 (68.75%) male and 20 (31.25%) female patients with third- and fourth-degree piles. RESULTS: The patients were divided into two groups of 35 patients each. Group I underwent SH and group II underwent HSH. The mean age of group I was 42.94 years and of group II, 42.20 years. The mean time of the procedure was 24.42 min ± 2.367 for SH and 31.48 min ± 2.21 for HSH. Postoperative pain in group I was lower than in group II during the first 2 weeks, but there was persistent mild pain in most patients in group I at the 2­week follow-up. In group II there was significant improvement in pain after 2 weeks, with higher patient satisfaction. Wound infection was detected in 3 (5%) patients in group I and no patients in group II (p = 0.077). Postoperative bleeding occurred in 4 (11.4%) patients in group I in the form of spotting after defecation only during the first postoperative month; no bleeding was detected in group II (p = 0.039). There were 3 (15%) cases of flatus incontinence but after taking a detailed history these were found to be cases of urgency to defecate rather than incontinence. There were 7 (20%) cases of recurrence at the 1­year follow-up in group I and 1 (2.9%) case in group II (p = 0.024). CONCLUSION: Compared with SH, HSH was safer, easier, and associated with a lower incidence of recurrence after 1 year and with higher patient satisfaction.

Effect of Sofosbuvir on rats' ovaries and the possible protective role of vitamin E: biochemical and immunohistochemical study.

Hepatitis C virus (HCV) infection is a major health problem worldwide and its eradication is mandatory. Direct acting HCV polymerase inhibitors, such as Sofosbuvir (SOF), is an effective regimen. However, it has some side effects like mutagenesis, carcinogenesis, and the impairment of testicular function. It is important to evaluate the safety of SOF on the ovary, as there are no studies yet. Increasing the production of Reactive Oxygen Species (ROS), causes oxidative stress, which affects ovulation process, female reproduction, and fertility. Accumulation of SOF in the cells was demonstrated to promote ROS generation. Vitamin E (Vit E) is an antioxidant agent that has an essential role in the female reproductive system, its deficiency can cause infertility. We explored the effect of SOF treatment alone and co-treated with Vit E on ovarian ROS level and ovarian morphology experimentally using biochemical and immunohistochemical studies. Significant changes in oxidative stress markers; nitric oxide and malondialdehyde lipid peroxidation, antioxidant enzymes; catalase, super oxide dismutase, and reduced glutathione, proliferating markers; proliferation cell nuclear antigen and Ki-67 antigen and caspase 3 apoptotic marker were demonstrated. It was shown that where SOF induced oxidative stress, it also aggravated ovarian dysfunction. The essential role of Vit E as an antioxidant agent in protecting the ovarian tissue from the effect of oxidative stress markers and preserving its function was also displayed. This could be guidance to add Vit E supplements to SOF regimens to limit its injurious effect on ovarian function.

Effect of Melatonin on Alpha Synuclein and Autophagy in Dopaminergic Neuronal Differentiation of Adipose Mesenchymal Stem Cells.

Background: The current work investigated the effect of melatonin on differentiation of adipose mesenchymal stem cells (AD-MSCs) into dopamine producing cells and its effect on autophagy process and alpha-Synuclein (α-Syn) secretion. Methods: AD-MSCs were characterized by flow cytometry and divided into 4 groups; i) control group (AD-MSCs without any treatment), ii) M+MSCs group (MSCs treated with 1 µM melatonin for 12 days), iii) DN group (MSCs cultured in neurobasal A medium and essential neuronal growth factors for 12 days) and iv) DN+M group (MSCs cultured in neurobasal A medium and 1µM melatonin for 12 days. By the end of experiments, the dopamine and α-Syn levels using ELISA, the expression of MAP-2, m-TOR and α-Syn genes at the level of mRNA and detection of autophagosomes formation using transmission electron microscope were performed. Results: We found that the isolated cells were MSCs due to their positivity expression for CD105 and CD90 and negativity expression for CD34 and CD45. The concentration of dopamine was significantly higher and α-Syn concentration was significantly lower in DN+M group when compared to other groups (P< 0.005). Also, this group showed the highly expression for MAP-2 gene and less expression for m-TOR and α-Syn genes (P< 0.005). Moreover, there was significantly increase in autophagosomes formation in this group than another group (P< 0.005). Conclusions: It is concluded that the melatonin promotes the differentiation of rat AD-MSCs into dopaminergic cells via induction of autophagy process and reduction of α-Syn secretion.

Possible Role of Oxidative Stress and Nrf2/HO-1 Pathway in Pentylenetetrazole-induced Epilepsy in Aged Rats.

Background: To examine the impact of aging on the response of rats to pentylenetetrazole (PTZ)-induction of epilepsy and the possible role of oxidative stress and nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase (HO)-1 pathway in this response. Methods: Forty male albino rats were equally allocated into 4 groups; 1) Young control (YC) group, aged 8-12 weeks, 2) Old control (OC) group, aged 24 months, 3) PTZ-Young group: young rats received PTZ (50 mg/Kg, i.p. every other day) for 2 weeks and 4) PTZ-Old group: as group 3 but rats were old. The seizure score stage and latency to the first jerk were recorded in rats. Redox state markers in brain tissues including malondialdehyde (MDA), catalase and total antioxidant capacity (TAC) were evaluated. Also, the expression of Nrf2 and HO-1 genes were measured in the brain tissues. Results: Old rats showed an early and a significant rise in the seizure score with PTZ administration and a significant drop in the seizure latency compared to young rats (P <0.01). Also, old rats showed a significantly higher MDA concentration and a significantly lower TAC and catalase activity than young rats (P <0.01). Moreover, the expression of Nrf2 and HO-1 was significantly lowered in old rats compared to young rats with PTZ administration (P < 0.01). Conclusion: Aging increases the vulnerability of rats to PTZ-induced epilepsy. An effect might come down to the up-regulation of oxidative stress and the down regulation of antioxidant pathways including Nrf2 and HO-1.

A comparative study between high ligation of the inter-sphincteric fistula tract via lateral Approach Versus Fistulotomy and primary sphincteroplasty in High Trans-Sphincteric Fistula-in-Ano: a randomized clinical trial.

BACKGROUND: Trans-sphincteric fistula management is very challenging and everyday new techniques are introduced to reach the safest and the most effective technique. In this study two of the most effective techniques are compared based on their post-operative outcomes. OBJECTIVE: To compare the efficacy of high ligation of the inter-sphincteric fistula tract by lateral approach (modified LIFT) and Fistulotomy and primary sphincteroplasty (FIPS) in the management of high trans-sphincteric fistula regarding their post-operative outcomes in the form of post-operative pain, time of wound healing in weeks, wound infection, incontinence and recurrence within one year. PATIENTS AND METHODS: The current study is single-blind, prospective, randomized, controlled, single-center trial conducted from June 2020 to June 2022 in the colorectal surgical unit of Ain Shams University Hospitals, which included 80 patients presented with high trans-sphincteric perianal fistula 55 (68.75%) males and 25 (31.25%) including a one-year follow-up postoperative. RESULTS: There were 80 patients in our study 40 patients in each group. The mean age of group (I) is 46.65 with standard deviation 6.6. while, in group (II) the mean age is 45.85 with standard deviation 6.07 (p = 0.576). From the included 80 patients 55(68.7%) were males and 25 (31.25%) were females (p = 0.469). Regarding, postoperative wound infection occurred in 2(5%) Patients in group (I) and 7(17.5%) patients in group (II) (p = 0.154). There were no cases of incontinence in group I. However, there were 6(15%) cases of incontinence to gases only scored by Wexner score 3/20 in group II (p = 0.026) and its significant difference between the two techniques. Postoperative pain was assessed for one week duration by the visual analogue score (VAS) from 0 to 10 in which, zero is the least and 10 is the maximum. In group (I) 18(45%) patients scored their pain mild from 1 to 3, 20(50%) patients scored their pain moderate from 4 to 6 and 2(5%) patients scored severe pain from 7 to 9. While, in group (II) 14(35%) patients scored their pain mild from 1 to 3, 22(55%) patients their pain moderate from 4 to 6 and 4(10%) patients scored their pain severe from 7 to 9 (p = 0.275). Recurrence in one-year follow-up occurred in 13(32.5%) patients in group (I) about 7 patients had recurrence in the form of inter-sphincteric fistula and 6 patients in the form of trans-sphincteric fistula. While, in group II recurrence occurred in 1 (2.5%) patient in the form of subcutaneous fistula at the healing site (p = 0.001). CONCLUSION: Fistulotomy and primary sphincteroplasty is an effective and preferred technique for the trans-sphincteric fistula repair with high statistically significant lower incidence of recurrence in one-year follow-up as compared to modified LIFT technique. Although, there is higher incidence regarding incontinence to gases only post-operative. This work recommends fistulotomy and primary sphincter reconstruction procedure in high trans-sphincteric perianal fistulas to be more popular, to be implemented as a corner stone procedure along various and classic operations for such cases as it's easy, feasible.

Proline hydroxylase 2 (PHD2) promotes brown adipose thermogenesis by enhancing the hydroxylation of UCP1.

OBJECTIVE: Brown adipose tissue (BAT) plays a crucial role in regulating non-shivering thermogenesis under cold exposure. Proline hydroxylases (PHDs) were found to be involved in adipocyte differentiation and lipid deposition. However, the effects of PHDs on regulatory mechanisms of BAT thermogenesis are not fully understood. METHODS: We detected the expression of PHDs in different adipose tissues by using immunoblotting and real-time PCR. Further, immunoblotting, real-time PCR, and immunostaining were performed to determine the correlation between proline hydroxylase 2 (PHD2) and UCP1 expression. Inhibitor of PHDs and PHD2-sgRNA viruses were used to construct the PHD2-deficiency model in vivo and in vitro to investigate the impacts of PHD2 on BAT thermogenesis. Afterward, the interaction between UCP1 and PHD2 and the hydroxylation modification level of UCP1 were verified by Co-IP assays and immunoblotting. Finally, the effect of specific proline hydroxylation on the expression/activity of UCP1 was further confirmed by site-directed mutation of UCP1 and mass spectrometry analysis. RESULTS: PHD2, but not PHD1 and PHD3, was highly enriched in BAT, colocalized, and positively correlated with UCP1. Inhibition or knockdown of PHD2 significantly suppressed BAT thermogenesis under cold exposure and aggravated obesity of mice fed HFD. Mechanistically, mitochondrial PHD2 bound to UCP1 and regulated the hydroxylation level of UCP1, which was enhanced by thermogenic activation and attenuated by PHD2 knockdown. Furthermore, PHD2-dependent hydroxylation of UCP1 promoted the expression and stability of UCP1 protein. Mutation of the specific prolines (Pro-33, 133, and 232) in UCP1 significantly mitigated the PHD2-elevated UCP1 hydroxylation level and reversed the PHD2-increased UCP1 stability. CONCLUSIONS: This study suggested an important role for PHD2 in BAT thermogenesis regulation by enhancing the hydroxylation of UCP1.

LC/MS analysis of mushrooms provided new insights into dietary management of diabetes mellitus in rats.

Mushrooms possess antihyperglycemic effect on diabetic individuals due to their nonfibrous and fibrous bioactive compounds. This study aimed to reveal the effect of different types of mushrooms on plasma glucose level and gut microbiota composition in diabetic individuals. The effects of five different mushroom species (Ganoderma lucidum, GLM; Pleurotus ostreatus, POM; Pleurotus citrinopileatus, PCM; Lentinus edodes, LEM; or Hypsizigus marmoreus, HMM) on alloxan-induced diabetic rats were investigated in this study. The results indicated that LEM and HMM treatments showed lower plasma glucose levels. For the microbiota composition, ACE, Chao1, Shannon, and Simpson were significantly affected by PCM and LEM treatments (p < .05), while ACE, Shannon, and Simpson indexes were affected by HMM treatment (p < .01). Simpson index was affected in positive control (C+) and POM groups. All these four indices were lower in GLM treatment (p < .05). Dietary supplementation of mushrooms reduced plasma glucose level directly through mushrooms' bioactive compounds (agmatine, sphingosine, pyridoxine, linolenic, and alanine) and indirectly through stachyose (oligosaccharide) and gut microbiota modulation. In conclusion, LEM and HMM can be used as food additives to improve plasma glucose level and gut microbiome composition in diabetic individuals.

Inhibitory effect of natural compounds on Dihydropteroate synthase of Mycobacterium leprae: Molecular dynamic study.

Leprosy is a chronic infectious disease caused by a bacillus, Mycobacterium leprae. According to official data from 139 countries in the 6 WHO Regions, there were 127558 new leprosy cases worldwide in 2020. Leprosy mainly affects the skin, the peripheral nerves, mucosa of the upper respiratory tract, and the eyes. If this disease is left untreated, can harm the skin, nerves, limbs, eyes, and skin permanently. The disease is curable with multidrug therapy. Over a period of time Mycobacterium leprae has become resistant to these drugs. Therefore, new therapeutic molecules are warranted. This study was aimed to carry out the in-silico analysis to determine the inhibitory effect of natural compounds on Dihydropteroate synthase (DHPS) of Mycobacterium leprae. The DHPS is a key enzyme in the folate biosynthesis pathway in M. leprae and acts as a competitive inhibitor of PABA. The 3D structure of DHPS protein was modeled using homology modeling and was validated. Molecular docking and simulation along with other in-silico methods were employed to determine the inhibitory effect of ligand molecules towards DHPS target protein. Results revealed ZINC03830554 molecule as a potential inhibitor of DHPS. Binding experiments and bioassays utilizing this strong inhibitor molecule against purified DHPS protein are necessary to validate these early findings.Communicated by Ramaswamy H. Sarma.

Possible Mechanisms of the Neuroprotective Actions of Date Palm Fruits Aqueous Extracts against Valproic Acid-Induced Autism in Rats.

The current study aimed to determine how palm date aqueous fruit extracts (AFE) affected the autistic-like behaviors brought on by valproic acid (VPA) injection, as well as any potential contributions from Sirt-1, oxidative stress, apoptosis, and autophagy. The pregnant Sprague Dawley females were treated with VPA at 12.5th gestation day and pregnant females and their offspring were treated with AFE orally at doses of 4 mg/Kg by gastric gavage for 45 days after birth. The elevated plus-T maze, water maze, and rotarod tests were used to examine autism-like behaviors. At the end of the study, the expression of Nrf2, heme oxygenase (HO-1), Sirt-1, caspase-3 (a marker of apoptosis), LC3 (a marker of autophagy), and NFκB (inflammatory cytokines) were evaluated along with the oxidative stress in brain tissues and the histological changes in the cerebellum and hippocampus. The neurobehavioral assessments significantly declined due to VPA, which also significantly increased oxidative stress in the brain tissues and significantly decreased Nrf2 and HO-1 expression. Additionally, VPA administration caused significant increase in the expression of caspase-3 in the cerebellar cortex, not in the hippocampus; LC3 and NFκB in the hippocampus, not in the cerebellar cortex; and significant reduction in the expression of Sirt-1 in the hippocampus, not in the cerebellum. On the other hand, AFE treatment significantly improved the neurobehavioral changes as well as it improved significantly the oxidative stress and the expression of LC3, NFκB, NrF2, HO-1, and Sirt-1 in the cerebellum and hippocampus. Conclusions: AFE administration might improve the autistic-like symptoms induced by VPA in rats via attenuation of the oxidative stress, upregulation of Nrf2 and HO-1, Sirt-1 and LC3 expression with downregulation of caspase-3, and NFκB expression in the cerebellum and hippocampus.

Identification of potential inhibitor molecule against MabA protein of Mycobacterium leprae by integrated in silico approach.

Leprosy is one of the chronic diseases with which humanity has struggled globally for millennia. The potent anti-leprosy medications rifampicin, clofazimine and dapsone, among others, are used to treat leprosy. Nevertheless, even in regions of the world where these drugs have been successfully implemented, resistance continues to be observed. Due to the problems with the current treatments, this disease should be fought at every level of society with new drugs. The purpose of this research was to identify natural candidates with the ability to inhibit MabA (gene-fabG1) with fewer negative effects. The work was accomplished through molecular docking, followed by a dynamic investigation of protein-ligand, which play a significant role in the design of pharmaceuticals. After modelling the protein structure with MODELLER 9.21v, AutoDock Vina was used to perform molecular docking with 13 3 D anti-leprosy medicines and a zinc library to determine the optimal protein-ligand interaction. In addition, the docking result was filtered based on binding energy, ADMET characteristics, PASS analysis and the most crucial binding residues. The ZINC08101051 chemical compound was prioritized for further study. Using an all-atom 100 ns MD simulation, the binding pattern and conformational changes in protein upon ligand binding were studied. Recommendation for subsequent validation based on deviation, fluctuation, gyration and hydrogen bond analysis, followed by main component and free energy landscape.Communicated by Ramaswamy H. Sarma.

Vanillic Acid Ameliorates Demyelination in a Cuprizone-Induced Multiple Sclerosis Rat Model: Possible Underlying Mechanisms.

OBJECTIVE: To investigate the effect of vanillic acid (VA) on a Cuprizone (Cup) demyelinating rat model and the mechanisms behind such effect. METHODS: Thirty adult male Sprague Dawley (SD) rats were randomly divided into three groups: control, Cuprizone, and VA groups. Cuprizone was administrated at a dose of 450 mg/kg per day orally via gastric gavage for 5 weeks. The nerve conduction velocity (NCV) was studied in an isolated sciatic nerve, and then the sciatic nerve was isolated for histopathological examination, electron microscope examination, immunohistochemical staining, and biochemical and PCR assay. The level of IL17 was detected using ELISA, while the antioxidant genes Nrf2, HO-1 expression at the level of mRNA, expression of the myelin basic protein (MBP), interferon-gamma factor (INF)-γ and tumor necrosis factor (TNF)-α, and apoptotic marker (caspase-3) were measured using immunohistochemistry in the sciatic nerve. RESULTS: There was a significant reduction in NCV in Cup compared to normal rats (p < 0.001), which was markedly improved in the VA group (p < 0.001). EM and histopathological examination revealed significant demyelination and deterioration of the sciatic nerve fibers with significant improvement in the VA group. The level of IL17 as well as the expression of INF-γ and caspase-3 were significantly increased with a significant reduction in the expression of MBP, Nrf2, and HO-1 in the sciatic nerve (p < 0.01), and VA treatment significantly improved the studied parameters (p < 0.01). CONCLUSION: The current study demonstrated a neuroprotective effect for VA against the Cup-induced demyelinating rat model. This effect might be precipitated by the inhibition of inflammation, oxidative stress, and apoptosis.

New Insight into the Possible Roles of L-Carnitine in a Rat Model of Multiple Sclerosis.

OBJECTIVE: We investigated the effect of L-carnitine (LC) on cuprizone (Cup) demyelinating rat model and its possible underlying mechanisms. METHODS: Thirty male Sprague-Dawley (SD) rats were randomly allocated to three groups: the normal control group; the Cup group, in which Cup was administrated at a dose of 450 mg/kg per day orally via gastric gavage for 5 weeks; and the Cup + LC group, which received the same dose of Cup as the Cup group, except that the rats were treated additionally with LC 100 mg/kg/day orally for 5 weeks. The nerve conduction (NCV) in isolated sciatic nerves was measured; then, the sciatic nerves were isolated for H&E staining and electron microscope examination. The expression of myelin basic protein (MBP), IL-1ß, p53, iNOS, and NF-KB by immunohistochemistry was detected in the isolated nerves. A PCR assay was also performed to detect the expression of antioxidant genes Nrf2 and HO-1. In addition, the level of IL-17 was measured by ELISA. RESULTS: There was a significant reduction in NCV in the Cup group compared to normal rats (p < 0.001), which was significantly improved in the LC group (p < 0.001). EM and histopathological examination revealed significant demyelination and deterioration of the sciatic nerve fibers, with significant improvement in the LC group. The level of IL-17 as well as the expression of IL-1ß, p53, iNOS, and NF-KB were significantly increased, with significant reduction expression of MBP in the sciatic nerves (p < 0.01), and LC treatment significantly improved the studied parameters (p < 0.01). CONCLUSION: The current study demonstrates a neuroprotective effect of LC in a Cup-induced demyelinating rat model. This effect might be due to its anti-inflammatory and antioxidant actions.

Impact of Cerium Oxide Nanoparticles on Metabolic, Apoptotic, Autophagic and Antioxidant Changes in Doxorubicin-Induced Cardiomyopathy: Possible Underlying Mechanisms.

Background: In the current study, the effects of cerium oxide nanoparticles (nanocerium; NC) on doxorubicin (DOX)-induced cardiomyopathy and its possible underlying mechanisms were addressed. Methods: 32 adult male rats were allocated into 4 groups; i) control group, ii) NC group; rats received NC (0.2 mg/kg, i.p., daily), iii) DOX group; rats received DOX 4 mg/kg (2 injections with a 14-day interval), and iv) DOX+NC group as DOX but rats received NC. At the end of the experiment, ECG and ECHO recordings and assessments of the levels of cardiac enzymes (CK-MB, LDH), and myocardial oxidative stress (MDA, catalase, and GSH), the expression of LC3 and beclin1 (markers of autophagy), caspase3 (marker of apoptosis) by immunohistochemistry, the expression of acetyl-CoA carboxylase alpha (ACCA) by PCR, and 5'adenosine monophosphate-activated protein kinase (AMPK) levels in the heart tissues were performed. Results: The DOX group displayed a prolonged corrected QT interval, an increase in cardiac enzymes (CK-MB and LDH), myocardial oxidative stress (high MDA with low catalase and GSH), expression of ACCA, caspase-3, beclin1, and LC3 in myocardial tissues, with reduction in myocardial AMPK levels, and myocardial contractility (low ejection fraction, and fractional shortening). On the other hand, administration of NC with DOX resulted in significant improvement of all studied parameters. Conclusion: NC offers a cardioprotective effect against DOX-induced cardiomyopathy. This effect might be due to its antioxidant and antiapoptotic effects as well as to the modulation of autophagy and metabolic dysfunctions induced by DOX in the heart tissues.