Cathepsin-K inhibition enhances anti-cancerous activity within oral squamous cell carcinoma cells: Uncloaking the potency of new K21 formulation.

BACKGROUND: The ability of cancer cells to be invasive and metastasize depend on several factors, of which the action of protease activity takes center stage in disease progression. PURPOSE/OBJECTIVE: To analyze function of new K21 molecule in the invasive process of oral squamous cell carcinoma (OSCC) cell line. MATERIALS & METHODS: The Fusobacterium (ATCC 23726) streaks were made, and pellets were resuspended in Cal27 (ATCC CRL-2095) OSCC cell line spheroid cell microplate. Cells were seeded and Lysotracker staining performed for CathepsinK red channel. Cell and morphology were evaluated using Transmission Electron microscopy. Thiobarbituric acid assay was performed. OSCC was analyzed for Mic60. Raman spectra were collected from the cancer cell line. L929 dermal fibroblast cells were used for Scratch Assay. ELISA muti arrays were used for cytokines and matrix molecules. Internalization ability of fibroblast cells were also analyzed. Structure of K21 as a surfactant molecule with best docked poses were presented. RESULTS: Decrease in lysosomal staining was observed after 15 and 30 min of 0.1% treatment. Tumor clusters were associated with cell membrane destruction in K21 primed cells. There was functional silencing of Mic60 via K21, especially with 1% concentration with reduced cell migration and invasiveness. Raman intensity differences were seen at 700 cm-1, 1200 cm-1 and 1600 cm-1 regions. EVs were detected within presence of fibroblast cells amongst K21 groups. Wound area and wound closure showed the progress of wound healing. CONCLUSION: Over expression of CatK can be reduced by a newly developed targeted K21 based drug delivery system leading to reduced migration and adhesion of oral squamous cell carcinoma cells. The K21 drug formulation can have great potential for cancer therapies due to targeting and cytotoxicity effects.

Zinc-alpha 2 glycoprotein a diagnostic Biomarker for early stage oral Squamous Cell Carcinoma.

Objectives: In this study, we investigated the expression of zinc alpha-2 glycoprotein in oral squamous cell carcinoma tissue samples. Additionally, ascertained its association to the oral cancer stage and subscale parameters (TNM). Methods: This observational study was conducted at Ziauddin University from January to December 2020. Using the Open-Epi software, the sample size of 120 oral squamous cell carcinomas was calculated at 95% confidence interval and a 5% margin of error. Ethical approval was taken from the Institutional Ethical Review Committee. Histologically diagnosed cases of oral squamous cell carcinoma were obtained from the Histopathology Department of Ziauddin University, Karachi. Study data was analyzed through SPSS version-20 and p-value ≤0.05 considered as significant. One-way ANOVA and Multiple linear regression were applied for analysis of data. Result: In the study, none of the oral squamous cell carcinoma tissue samples from the later stages were stained for ZAG. However 71% (35/49) of the early stage OSCC samples showed positive IHC results for ZAG expression in the cytoplasm. One-way ANOVA indicates that high ZAG expression was significantly associated with smaller tumor size (p<0.001), lymph node involvement (p=0.002), early stages of OSCC (p<0.001) and less differentiated tumor (p=0.001). The site of the tumor was also significantly associated with ZAG staining (p<0.001). Conclusion: Zinc alpha-2 glycoprotein expressed in the early stages of oral cancer development so that effective treatment modalities can be planned as per the patient's status. This may also assist a clinician to achieve tumor-free surgical margins and monitor the post treatment outcomes.

Pre-weaning fluoxetine exposure perturbs social behavior at adulthood via altering hippocampal morphometry and PSD-95 expression in rats.

The depression during and after pregnancy cause significant exposure of fluoxetine to the child at early life through mother. This exposure to the child, during the vulnerable window of development, can have a long lasting impact on overall mental wellbeing. Long term neurobehavioral aspect of developmental toxicity is neglected as the part of testing requirements in the process of drug developmental. In this context, the present study was designed to study the possible effect of pre-weaning fluoxetine exposure on the social behavior of rats upon adulthood followed by assessing hippocampal morphometry (hematoxylin-eosin and silver staining) and post-synaptic density protein 95 (PSD-95) expression (using qPCR). Our data showed that the fluoxetine exposure (10, 50 and 100mg/kg) caused predominant increase in the social behavior of rats; the effect more pronounced in female rats. The morphometric analysis revealed significant increase in cell population and count of dentate gyrus (DG) region of hippocampus along with enhanced dendritic arborization. Furthermore, the PSD-95 expression was found to be down regulated in the fluoxetine treated group as compared to control. In conclusion, the present study demonstrate that the early post-natal exposure to fluoxetine cause hypersociability upon attaining adulthood, which may be attributed to enhanced neuronal proliferation and decrease PSD-95 expression in the hippocampus.

Bilateral sagittal split osteotomy a versatile approach for correction of facial deformity: A review literature.

Poor facial cosmesis resultant from dysgnathias usually accounts for a range of these individuals' psychological and social problems. Disturbances of both esthetics and function are caused by jaw deformity and associated structures' deformity such as malocclusion. The correction of these deformities is one of the most challenging and intriguing aspects of maxillofacial surgery. Despite having become routine only relatively recently, rigid internal fixation has advanced rapidly, its results are consistent and predictable and thus, its knowledge applies in orthognathic surgery besides other areas of maxillofacial surgery. The bilateral sagittal split osteotomy (BSSO) is a common orthognathic procedure performed on the mandible. First described by Trauner and Obwegeser in 1957, modified by Dal Pont and refined by Epker, several modifications of the BSSO have been introduced aiming to enhance surgical convenience, minimize morbidity, and maximize stability. The aim of this article is to review the literature of this technique from the historical perspective and to present a standard operation technique.

Attenuation of cisplatin-induced acute kidney injury by N-(2-Hydroxyphenyl) acetamide and its gold conjugated nano-formulations in mice.

The attenuation of cisplatin-induced acute kidney injury (AKI) in mice by N-(2-hydroxyphenyl) acetamide (NA-2) and NA-2-conjugated gold nanoparticles (NA2-AuNPs) was investigated. Male BALB/c mice (n = 54) were divided into nine groups having six animals in each group. Animals in groups 3-9 were pre-treated for 5 days with test compounds, whereas, animals in group 1 and 2 received normal saline. On day 4, animals in groups 2, 3, 4, 5, 6 and 9 were given single intra-peritoneal injection of CP at the dose of 5 mg/kg. After 72 hours of CP injection, all animals were sacrificed. Blood was collected for serum urea and creatinine estimation, and kidneys were harvested for histo-pathological examinations and qPCR studies for nuclear factor-κB p50, (NFκB) ; inducible nitric oxide synthase (iNOS); hemeoxygenase-1 (HO-1); and interleukin-6 (IL-6).NA-2 and NA2-AuNPs was observed to decrease the serum urea and creatinine levels. Both the test compounds reduced kidney injury damage score and improved histological architecture in the treated animals in dose dependent manner. Furthermore, the mRNA expressions of NFkB p50, iNOS and IL-6 genes were down-regulated, and HO-1 gene was up-regulated in the animals treated with the test compounds. It is concluded that NA-2 and NA2-AuNPs attenuates CP-induced AKI in mice models through anti-inflammatory and anti-oxidant mechanisms.

Rutin coated gold nanoparticles prevent rhabdomyolysis-induced kidney injury via down-regulation of NF-kB, iNOS, IL-6 and up-regulation of HO-1 and Kim-1 genes in mice.

The aim of this study was to evaluate the protective activity of rutin, and its gold nanoparticles (Ru-AuNPs) in rhabdomyolysis-induced acute kidney injury (AKI) model in mice. Rutin (25 and 50 mg/kg) and Ru-AuNPs (15 and 25 mg/kg) were administered to the animals for four (4) days with water deprivation for 24 hours followed by 50% glycerol injection at the dose of 10 ml/kg intramuscularly. On the next day, animals were dissected and blood and kidneys were collected. Biochemical investigations were performed to evaluate kidney functions, histological studies were carried out to see the changes at tissue level and real-time RT-PCR studies for nuclear factor-κB p50, NFκB; inducible nitric oxide synthase, iNOS; heme oxygenase-1, HO-1; interleukin-6, IL-6; and kidney injury molecule-1, Kim-1 were performed to elucidate the molecular mechanisms. Blood urea and creatinine were found to be decreased in animals treated with rutin and Ru-AuNPs. Down regulation of the mRNA expressions of iNOS, IL-6 and NFkB p50 and up-regulation of Kim-1 and HO-1 genes were observed. The efficacy of Ru-AuNPs was better than rutin alone even at a dose far less than the compound. Rutin and Ru-AuNPs alleviates kidney injury and inflammation in rhabdomyolysis-induced AKI model via anti-inflammatory and anti-oxidant pathways which make it a plausible compound for future studies.

Eugenol and liposome-based nanocarriers loaded with eugenol protect against anxiolytic disorder via down regulation of neurokinin-1 receptors in mice.

Anxiety disorder is a psychiatric disorder characterized by extreme fear or worry. It is highly prevalent worldwide which affects daily life and is also an enormous health burden. Neurokinin 1 receptor (NK1R) is a G protein coupled receptor, expressed in both central and peripheral nervous system, involved in affective behaviors. NK1R has established role in anxiety and it is also an important target for pathogenesis of anxiety disorder. Therefore, it has been hypothesized in previous studies that the blockades of NK1R may have antidepressant and anxiolytic effects. The present study deals with the molecular mechanism of protective activity of eugenol against anxiolytic disorder. A pre-clinical animal study was performed on 42 BALB/c mice. Animals were given stress through conventional restrain model. The mRNA expression of NK1R was analyzed by real time RT-PCR. Moreover, the NK1R protein expression was also examined by immunohistochemistry in whole brain and mean density was calculated. The mRNA and protein expressions were found to be increased in animals given anxiety as compared to the normal control. Whereas, the expressions were decreased in the animals treated with eugenol and its liposome-based nanocarriers in a dose dependent manner. However, the results were better in animals treated with nanocarriers as compared to the compound alone. It is concluded that the eugenol and its liposome-based nanocarriers exert anxiolytic activity by down-regulating NK1R protein expression in mice.

Prevalence and 20-year epidemiological trends of glomerular diseases in the adult Saudi population: a multicenter study.

BACKGROUND: Recent international reports have shown significant changes in the incidence of different glomerular diseases. OBJECTIVE: Examine temporal and demographic trends of biopsy-diagnosed glomerular diseases in the adult population of Saudi Arabia over the last two decades. DESIGN: Medical record review. SETTINGS: Four tertiary medical centers in Saudi Arabia. PATIENTS AND METHODS: We identified all patients that underwent native kidney biopsy between 1998 and 2017. MAIN OUTCOME MEASURES: The frequency and the disease trends in four biopsy eras (1998-2002, 2003-2007, 2008-2011, and 2012-2017) for different glomerular diseases. SAMPLE SIZE AND CHARACTERISTICS: 1070 patients, 18-65 years of age; 54.1% female. RESULTS: Of 1760 patients who underwent native kidney biopsies, 1070 met inclusion criteria. Focal segmental glomerulosclerosis was the most common biopsy-diagnosed disease, with comparable frequencies over the four eras (23.6%, 19.8%, 24.1%, and 17.1, respectively [ P value for trend=.07]). The frequency of immunoglobulin A nephropathy increased progressively. The incidence of membranoproliferative glomerulonephritis declined significantly. Among the secondary types of glomerular diseases, systemic lupus erythematosus-associated lupus nephritis was the most common, followed by diabetic nephropathy. The prevalence of diabetic nephropathy increased from 1.4% in the first era to 10.2% in the last one. CONCLUSIONS: Trends in biopsy-diagnosed glomerular disease have changed. While focal segmental glomerulosclerosis remains the most common glomerular disease, there has been a significant rise in the prevalence of immunoglobulin A nephropathy and diabetic nephropathy. In contrast, membranoproliferative glomerulonephritis has declined. LIMITATIONS: Retrospective methodologies are vulnerable to lost data. CONFLICT OF INTEREST: None.

N-(2-hydroxyphenyl)acetamide and its gold nanoparticle conjugation prevent glycerol-induced acute kidney injury by attenuating inflammation and oxidative injury in mice.

The protective activity of N-(2-hydroxyphenyl)acetamide (NA-2) and NA-2-coated gold nanoparticles (NA-2-AuNPs) in glycerol-treated model of acute kidney injury (AKI) in mice was investigated. NA-2 (50 mg/kg) and NA-2-AuNPs (30 mg/kg) were given to the animals for four days followed by 24-h water deprivation and injection of 50% glycerol (10 ml/kg im). The animals were sacrificed on the next day. Blood and kidneys were collected for biochemical investigations (urea and creatinine), histological studies (hematoxylin and eosin; and periodic acid-Schiff staining), immunohistochemistry (actin and cyclooxygenase-2, Cox-2), and real-time RT-PCR (inducible nitric oxide synthase, iNOS; nuclear factor-κB p50, NFκB; hemeoxygenase-1, HO-1; and kidney injury molecule-1, Kim-1). NA-2 protected renal tubular necrosis and inflammation, though the result of NA-2-AuNPs was better than compound alone and it also exhibited the activity at far less dose. The test compound and its gold nano-formulation decreased the levels of serum urea and creatinine level in the treated animals. Both NA-2 and NA-2-AuNPs also conserved actin cytoskeleton, and lowered COX-2 protein expression. Moreover, the mRNA expressions of iNOS and NFkB p50 were down-regulated, and HO-1 and Kim-1 genes were up-regulated. We conclude that NA-2 and NA-2-AuNPs ameliorates kidney inflammation and injury in glycerol-induced AKI animal model via anti-oxidant and anti-inflammatory mechanisms which make it a suitable candidate for further studies. We believe that these findings will contribute in the understanding of the mechanism of action of paracetamol-like drugs and can be considered for clinical research for the prevention of AKI.

Cinnamic acid exerts anti-diabetic activity by improving glucose tolerance in vivo and by stimulating insulin secretion in vitro.

Although the anti-diabetic activity of cinnamic acid, a pure compound from cinnamon, has been reported but its mechanism(s) is not yet clear. The present study was designed to explore the possible mechanism(s) of anti-diabetic activity of cinnamic acid in in vitro and in vivo non-obese type 2 diabetic rats. Non-obese type 2 diabetes was developed by injecting 90 mg/kg streptozotocin in 2-day-old Wistar pups. Cinnamic acid and cinnamaldehyde were administered orally to diabetic rats for assessing acute blood glucose lowering effect and improvement of glucose tolerance. Additionally, insulin secretory activity of cinnamic acid and cinnamaldehyde was evaluated in isolated mice islets. Cinnamic acid, but not cinnamaldehyde, decreased blood glucose levels in diabetic rats in a time- and dose-dependent manner. Oral administration of cinnamic acid with 5 and 10 mg/kg doses to diabetic rats improved glucose tolerance in a dose-dependent manner. The improvement by 10 mg/kg cinnamic acid was comparable to that of standard drug glibenclamide (5 mg/kg). Further in vitro studies showed that cinnamaldehyde has little or no effect on glucose-stimulated insulin secretion; however, cinnamic acid significantly enhanced glucose-stimulated insulin secretion in isolated islets. In conclusion, it can be said that cinnamic acid exerts anti-diabetic activity by improving glucose tolerance in vivo and stimulating insulin secretion in vitro.

Sources of arsenic and fluoride in highly contaminated soils causing groundwater contamination in Punjab, Pakistan.

Highly contaminated groundwater, with arsenic (As) and fluoride (F(-)) concentrations of up to 2.4 and 22.8 mg/L, respectively, has been traced to anthropogenic inputs to the soil. In the present study, samples collected from the soil surface and sediments from the most heavily polluted area of Punjab were analyzed to determine the F(-) and As distribution in the soil. The surface soils mainly comprise permeable aeolian sediment on a Pleistocene terrace and layers of sand and silt on an alluvial flood plain. Although the alluvial sediments contain low levels of F, the terrace soils contain high concentrations of soluble F(-) (maximum, 16 mg/kg; mean, 4 mg/kg; pH > 8.0). Three anthropogenic sources were identified as fertilizers, combusted coal, and industrial waste, with phosphate fertilizer being the most significance source of F(-) accumulated in the soil. The mean concentration of As in the surface soil samples was 10.2 mg/kg, with the highest concentration being 35 mg/kg. The presence of high levels of As in the surface soil implies the contribution of air pollutants derived from coal combustion and the use of fertilizers. Intensive mineral weathering under oxidizing conditions produces highly alkaline water that dissolves the F(-) and As adsorbed on the soil, thus releasing it into the local groundwater.

Ondansetron and dexamethasone in middle ear procedures.

A randomised, double-blind study was conducted on 90 ASA I & II patients undergoing middle ear surgery to compare the efficacy of ondansetron, dexamethasone and a combination of Ondansett on+dexamethasone for the prevention of postoperative nausea and vomiting. Group I patients received ondansetron (0. 1 mg/kg), group IIpatients received dexamethasone(0.1z mg./Kg) while group III received ondansetron (0.1 mg./kg) + dexamethasone (0.15 mg/kg), 10 minute before induction of general anaesthesia. A standardised general anaesthetic technique was employed through out. A complete response, defined as no postoperative nausea and vomiting and no need for another rescue antiemetic during the first 4 hours after anaesthesia was achieved in 58%, 55% and 83% of patients who had received ondansetron, dexamethasone and ondansetron + dexamethasone respectively. The corresponding incidence during the next 20 hours after anaesthesia was 54%, 47% and 85%. No clinically important adverse effects were observed in any of the groups. We conclude that prophylactic therapy with ondansetron +dexamethasone,one is superior in the prevention of postoperative nausea and vomiting after middle ear surgery.

Nasal mucosa changes in students exposed to formaldehyde vapour.

Formaldehyde has been used since ages in the various laboratories. Recently, interest has developed in the possible role of formaldehyde in the development of Squamous Cell Carcinoma. In this study 53 students (undergraduates and postgraduates) were exposed to formaldehyde and they were compared with 25 students (control group) unexposed to formaldehyde. Results have shown that students who were exposed to formaldehyde for a longer time showed mucosal changes as compared to the control group.