Alpha-linolenic acid based nano-suspension protect against lipopolysaccharides induced mastitis by inhibiting NFκBp65, HIF-1α, and mitochondria-mediated apoptotic pathway in albino Wistar rats.

The purpose of this study was to investigate the therapeutic effects and underlying mechanism of alpha-linolenic acid based intra-mammary nano-suspension (ALA-NS) on both in vitro antimicrobial and in vivo activity. The ALA-NS formulated and optimized for parameters like particle size, zeta potential, polydispersity index, sedimentation volume, and stability studies. In vitro, our results showed that ALA-NS (F1 and F2) have the higher zone of inhibition and lower minimum inhibitory concentration (MIC) value than ALA and cefotaxime alone against mastitis-causing pathogens. In vivo, our results showed that ALA-NS (F1 and F2) restored the altered oxidative biomarkers (superoxide dismutase, catalase, glutathione, TBARs, and protein carbonyl) along with histopathological changes in lipopolysaccharides (LPS) treated rats. Western blot results indicated that ALA-NS (F1 and F2) inhibited LPS induced inflammatory proteins (NFκBp65, COX, LOX, and IFN-γ) in rat mammary epithelial cells. ALA-NS (F1 and F2) also suppressed the hypoxia inducible factor-1α (HIF-1α) and upregulated prolyl-hydroxylase (PHD-2), sterol regulatory element binding protein (SREBP-1c), and fatty acid synthase (FASN) protein expression. In addition, ALA-NS upregulated the pro-apoptotic (BAX and BAD) and downregulated anti-apoptotic (BCL-2 and BCL-XL) proteins expression in rat mammary epithelial tissue. In conclusion, we found that ALA-NS (F1 and F2) have in vitro antimicrobial activity and protective effects on LPS-induced mastitis in rats.

Repurposing mechanistic insight of PDE-5 inhibitor in cancer chemoprevention through mitochondrial-oxidative stress intervention and blockade of DuCLOX signalling.

BACKGROUND: This study evaluates the anti-cancer effects of Tadalafil (potent PDE-5 inhibitor) in female albino wistar rats against n-methyl n-nitrosourea induced mammary gland carcinogenesis. METHODS: The animals were selected and randomly divided among four groups and each group contains six animals per group. The animal tissue and serum samples were evaluated for the presence of antioxidant parameters and the cellular morphology was studied using carminic staining, haematoxylin staining and scanning electron microscopy followed by immunoblotting analysis. RESULTS: On the grounds of hemodynamic recordings and morphology, n-methyl n-nitrosourea treated group showed distorted changes along with distorted morphological parameters. For morphological analysis, the mammary gland tissues were evaluated using scanning electron microscopy, whole mount carmine staining, haematoxylin and eosin staining. The serum samples were evaluated for the evaluation of oxidative stress markers and inflammatory markers. The level of caspase 3 and 8 were also evaluated for the estimation of apoptosis. The fatty acid profiling of mammary gland tissue was evaluated using fatty acid methyl esters formation. The mitochondrial mediated apoptosis and inflammatory markers were evaluated using immunoblotting assay. CONCLUSION: The results confirm that Tadalafil treatment restored all the biological markers to the normal and its involvement in mitochondrial mediated death apoptosis pathway along with inhibition of inflammatory markers.

A Young Adult Patient with Rheumatoid Disorder Presents for the Evaluation of Limited Mouth Opening.

Juvenile Idiopathic Arthritis (JIA), formerly known as Juvenile Rheumatoid Arthritis, includes all forms of chronic arthritis with unknown etiology that occurs before the age of sixteen. Clinical practice guidelines for JIA management have been evolving for the past 10 years. JIA affects approximately 1 per 1000 children in the U.S. causing short and long-term disability. Polyarticular JIA represents 30% to 40% of JIA and affects five or more joints within 6 months of onset, including the smaller joints, such as the temporomandibular joint (TMJ). TMJ involvement in JIA is between 17% and 87% and can cause craniofacial abnormality resulting in significant functional and aesthetic complications. It is important for the oral healthcare provider to recognize common signs and symptoms of JIA and facilitate multidisciplinary patient care for time management and better prognosis.

A Patient with Hypothyroidism in Need of Periodontal Connective Tissue Graft Surgery.

Hypothyroidism is a condition characterized by thyroid hormone deficiency and can be caused by a variety of factors. Untreated or chronic hypothyroidism can present in adult patients as myxedema, which is characterized by symptoms including fatigue, generalized slower metabolism, weight gain, depressed mood, dry skin, and brittle hair. Hypothyroidism can have various oral manifestations, particularly in children, in whom it can delay the eruption of the dentition. Dental management of patients with hypothyroidism depends on the etiology and status of the disease and requires the consideration of other organ systems affected.

NF-κB mediated regulation of tumor cell proliferation in hypoxic microenvironment.

Hypoxia is caused by a cancer-promoting milieu characterized by persistent inflammation. NF-κB and HIF-1α are critical participants in this transition. Tumor development and maintenance are aided by NF-κB, while cellular proliferation and adaptability to angiogenic signals are aided by HIF-1α. Prolyl hydroxylase-2 (PHD-2) has been hypothesized to be the key oxygen-dependent regulator of HIF-1α and NF-transcriptional B's activity. Without low oxygen levels, HIF-1α is degraded by the proteasome in a process dependent on oxygen and 2-oxoglutarate. As opposed to the normal NF-κB activation route, where NF-κB is deactivated by PHD-2-mediated hydroxylation of IKK, this method actually activates NF-κB. HIF-1α is protected from degradation by proteasomes in hypoxic cells, where it then activates transcription factors involved in cellular metastasis and angiogenesis. The Pasteur phenomenon causes lactate to build up inside the hypoxic cells. As part of a process known as lactate shuttle, MCT-1 and MCT-4 cells help deliver lactate from the blood to neighboring, non-hypoxic tumour cells. Non-hypoxic tumour cells use lactate, which is converted to pyruvate, as fuel for oxidative phosphorylation. OXOPHOS cancer cells are characterized by a metabolic switch from glucose-facilitated oxidative phosphorylation to lactate-facilitated oxidative phosphorylation. Although PHD-2 was found in OXOPHOS cells. There is no clear explanation for the presence of NF-kappa B activity. The accumulation of the competitive inhibitor of 2-oxo-glutarate, pyruvate, in non-hypoxic tumour cells is well established. So, we conclude that PHD-2 is inactive in non-hypoxic tumour cells due to pyruvate-mediated competitive suppression of 2-oxo-glutarate. This results in canonical activation of NF-κB. In non-hypoxic tumour cells, 2-oxoglutarate serves as a limiting factor, rendering PHD-2 inactive. However, FIH prevents HIF-1α from engaging in its transcriptional actions. Using the existing scientific literature, we conclude in this study that NF-κB is the major regulator of tumour cell growth and proliferation via pyruvate-mediated competitive inhibition of PHD-2.

Cultural and Personal Practices with Unusual Oral Findings: Three Case Reports and a Literature Review.

Due to increased migration, dentists are encountering patients with varied cultural practices. The main aim of this study was to report three cases in which cultural/individual oral practices appeared to be suggestive of disease, leading to initial misdiagnoses. We describe the case findings of three individuals treated at the Oral Diagnosis Clinic at the College of Dentistry at King Saud University in Riyadh, Saudi Arabia. In two cases, the patients presented with a missing uvula and dark maxillary gingiva. The initial diagnoses in both cases were incorrect. Further questioning revealed that the individuals had gingival tattoos and uvulectomies performed for traditional reasons. The patient in the third case presented with a diffuse red and white bilateral lesion on the buccal mucosa. The initial diagnosis was possible speckled leukoplakia. Upon further questioning, a definitive diagnosis of a chemical burn from a coarse salt mouth rinse due to personal oral practices was made. A literature review of these cultural practices is included. Our case report findings and the literature review highlight the need to consider cultural practices that can affect oral health and cause unusual oral findings when recording medical histories. Increasing awareness regarding these practices may help dentists provide appropriate treatment plans and reduce misdiagnoses. Furthermore, by understanding cultural practices, dentists may educate their patients about the harmful effects of some of these traditions.

Appropriateness of Using Vitamin K for the Correction of INR Elevation Secondary to Hepatic Disease in Critically ill Patients: An Observational Study.

BACKGROUND: Using vitamin K for correction of coagulopathy in critically ill patients is controversial with limited evidence. This study aims to evaluate the efficacy and safety of vitamin K in the correction of international normalized ratio (INR) elevation secondary to liver disease in critically ill patients. METHOD: A retrospective study of critically ill patients with coagulopathy secondary to liver disease. The primary outcome was to evaluate the association between vitamin K administration and the incidence of new bleeding events in critically ill patients with INR elevation; other outcomes were considered secondary. Patients were categorized into two groups based on vitamin K administration to correct INR elevation. The propensity score was generated based on disease severity scores and the use of pharmacological DVT prophylaxis. RESULTS: A total of 98 patients were included in the study. Forty-seven patients (48%) received vitamin K during the study period. The odds of the new bleeding event was not statistically different between groups (OR 2.4, 95% CI 0.28-21.67, P = .42). Delta of INR reduction was observed with a median of 0.63 when the first dose is given (P-value: <.0001). However the INR reduction with other subsequent doses of vitamin K was not statistically significant. CONCLUSION: The administration of vitamin K for INR correction in critically ill patients with coagulopathy secondary to liver disease was not associated with a lower odds of new bleeding events. Further studies are needed to assess the value of vitamin K administration in critically ill patients with liver diseases related coagulopathy.

Prolyl hydroxylase 2: a promising target to inhibit hypoxia-induced cellular metabolism in cancer cells.

Hypoxia-inducible factor-1α (HIF-1α) shifts the metabolism of glucose from highly efficient oxidative phosphorylation to less efficient glycolysis. Pyruvic acid thus accumulated is oxidized to lactic acid which is pumped out in the tumor microenvironment. Protons generated from the pentose phosphate pathway (PPP) and upon hydrolysis of ATP further enhance the acidity in the tumor microenvironment. The resultant pH in the tumor microenvironment activates an endoplasmic reticulum protein: sterol regulatory element binding protein-1c (SREBP-1c), which once activated enhances proliferation of the tumor cell. Prolyl hydroxylase 2 (PHD2) is a negative regulator of HIF-1α and causes degradation of HIF-1α in the presence of oxygen. Chemical activation of PHD2 can downregulate HIF-1α and thus restore all its effects. The present review is an attempt to describe PHD2 as the target to combat cancer hypoxia and consequential cellular and metabolic alterations.