Efficacy of 15% lysine cream in treating diabetic foot ulcers: a randomized interventional study.

BACKGROUND AND OBJECTIVE: Lysine is an essential amino acid involved in several biochemical pathways. It has been shown to enhance blood supply and target growth factors, leading to improved wound healing. The present study aimed to evaluate the efficacy and tolerability of a 15% lysine cream in treating diabetic foot ulcers, as measured by the Bates-Jensen Wound Assessment Tool (BWAT). MATERIALS AND METHOD: A randomized, open-label, interventional study was conducted on 40 volunteers with diabetic ulcers. The treatment group (n=20) received well-known treatment along with lysine cream (15%) twice daily, while the control group (n=20) received standard therapy alone. Wound healing was evaluated using the BWAT. The student t-test and one-way ANOVA were used to compare the clinical assessment parameters to the baseline. RESULTS: Both groups showed a significant decrease in ulcer size, depth, edges, undermining, necrotic tissue type, necrotic tissue amount, exudate type, and exudate amount over six weeks, with no significant difference between the groups after the first week. The lysine-treated group showed a significant improvement in wound healing compared to the control group (P<0.05). CONCLUSION: The present study demonstrates that a 15% lysine cream can significantly improve wound healing in diabetic foot ulcer patients, as measured by the BWAT, compared to standard treatment alone. Further research is needed to confirm these findings and to explore the underlying mechanisms of lysine's therapeutic effects.

Hypoglycemic and hypolipidemic effects of Garcinia cambogia extracts in streptozotocin-nicotinamide induced diabetic rat model.

BACKGROUND AND OBJECTIVES: Diabetes mellitus, a global health problem, is associated with metabolic complications such as hyperglycemia, hyperlipidemia, hypertension, cardiovascular diseases, and loss of vision. The present study evaluated the antidiabetic and antihyperlipidemic effects of ethanol extract of Garcinia cambogia (L.) N. Robson (G. cambogia) fruit rind in a streptozotocin-nicotinamide induced diabetic Wistar Rat model. MATERIALS AND METHODS: Streptozotocin-nicotinamide was injected intraperitoneally to induce diabetes in Wistar rats. Five groups of rats (n=6) - normal control, diabetic, diabetic treated with G. cambogia at 400 mg/kg and 800 mg/kg body weight, and diabetic treated with metformin at 500 mg/kg body weight, were studied. Blood samples were collected after three weeks of treatment. Random blood glucose (RBG), Serum total cholesterol levels (TCL), serum total triglyceride levels (TGL), high-density lipoprotein levels, and body weight were measured. RESULTS: Although G. cambogia treatment did not have any antidiabetic activity (p>0.05) rind in the streptozotocin-nicotinamide induced diabetic Wistar Rat model, it decreased the serum TCL, and body weight significantly (P<0.05). CONCLUSIONS: Ethanolic extract of G. cambogia fruit rind possesses anti-obesity activity and significantly reduces total cholesterol but does not have antidiabetic activity.

Acute and chronic toxicity studies on ethanolic leaf extracts of Clerodendrum viscosum and Leucas indica in Swiss albino mice.

BACKGROUND AND OBJECTIVES: To evaluate the safe dose range of Clerodendrum viscosum (C. viscosum) and Leucas indica (L. indica) ethanolic leaf extracts of acute and chronic oral toxicity study in Swiss Albino mice. MATERIALS AND METHODS: The Organization for Economic Co-operation and Development guideline was used for the toxicity studies. C. viscosum and L. indica plant extract were administered orally in a single dose of 2000 mg/kg, and general behavior, adverse effects, and mortality were studied for 72 h. For the chronic toxicity study, both plant extracts were administered orally to a separate set of animals at 300 mg/kg doses for 90 days. Animals body weight was taken out, blood and gastric juice were collected for biochemical parameters, and vital organs were collected for histopathological studies after sacrificing test and control group animals. RESULTS: Both in acute and chronic toxicity assay, there was no significant alteration in body weight, physical signs, symptoms, hematological, biochemical parameters, and body organ weights compared to the normal group. The liver, kidney, and stomach histology did not show any drug-induced lesion. CONCLUSIONS: The result indicates that the oral administration of C. viscosum and L. indica ethanolic plant extract did not cause any toxicological effects. Hence it could be regarded as a safe natural product for therapeutic use.

Characterization of antidepressant activity of Saraca asoca flower (Roxb.) Wilde in mice subjected to acute restraint stress.

BACKGROUND: Long-term stress and chronic stress events play an important role in the etiology of depression. The study aimed to investigate the antidepressant-like effect of freshly prepared crude ethanolic extract of Saraca asoca flower (ESAF) in a mice model of acute restraint stress. METHODOLOGY: Rhamnazin, Myricetin and Quercetin were analytically characterized through liquid chromatography-mass spectrometry and high-performance liquid chromatography from Saraca asoca flower in a 0.1% acetic acid fraction of ethanol. The antidepressant effect was tested by repeated administration of freshly prepared ESAF on mice subjected to repeated and different forms of stress induction for 2 hours every day in the morning and night for seven consecutive days. The antidepressant activity was measured by known behavioral animal models: forced swim test (FST) and tail suspension test (TST). At the end of the experiment, each group of mice was sacrificed by cervical dislocation, followed by an estimation of the biochemical data. RESULTS: The oral administration of ESAF in doses of 50, 100, & 250 mg/kg for seven consecutive days gave a significant decrease in the time of immobility (P<0.05) and reversed the depression-like behavior induced by acute restraint methods and behavioral models. ESAF treated groups showed a significant increase in glutathione peroxidase (GSH-PX) activity in the hippocampus of the acutely restrained mice. In addition, ESAF 250 mg/kg reduced plasma corticosterone levels in mice subjected to different forms of acute restraint stress compared to other groups, comparable to the standard imipramine. CONCLUSION: Our study showed the antidepressant activity of the ESAF. This effect may be attributed to the presence of antioxidant bioflavonoids namely, Rhamnazin, Myricetin and quercetin. Reduction in the plasma corticosterone levels along with an increase in the antioxidant enzymatic activity such as GSP-PX and SOD in the mice's hippocampus is the proposed molecular hypothesis for its neuroprotective mechanism.

Effect of iron deficiency anaemia over glycated hemoglobin in non-diabetic women.

BACKGROUND: Glycated hemoglobin (HbA1c) is a form of hemoglobin bound to glucose and used as an index of glycaemic control reflecting glucose levels of the previous three months. Iron deficiency anemia (IDA) is the commonest form of anemia that affects HbA1c. Reports on the effects of IDA on HbA1c levels are inconsistent in India. Therefore, the study correlated the HbA1c and IDA in non-diabetic female patients. METHODS: A correlative study between HbA1c and IDA was carried out at the Department of Biochemistry, A. J. Institute of Medical Sciences, Mangaluru, India. A total of 50 non-diabetic female patients, aged between 20-50 years, with decreased levels of Hb, MCV and MCHC were selected. Their ferritin levels were determined by ELISA method to confirm IDA. Forty confirmed iron-deficient samples whose serum ferritin levels were <90 pg/dL, were tested for HbA1c levels by nephelometry method. RESULTS: HbA1c correlated positively with serum ferritin, Hb, MCV, MCH and MCHC (P<0.05). There was a significant decrease in mean value of HbA1c in those with severe anemia (4.50±0.34) compared to those with moderate anemia (5.18±0.35) (P<0.001). CONCLUSION: Results showed positive correlation of HbA1c with ferritin and hemoglobin. Therefore, iron status should be considered during the interpretation of the HbA1c concentrations in diabetes mellitus.

Inhibition of bone morphogenetic proteins signaling suppresses metastasis melanoma: a proteomics approach.

BACKGROUND: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-ß superfamily, known to promote the tumor invasion and metastasis. There are continual progresses in understanding the role of BMP signaling pathways in carcinogenesis. However, the biological significance of BMPs in human melanoma has received very little attention. The study aimed to explore the effect of BMP inhibition on melanoma treated with LDN193189 (BMP inhibitor) using a quantitative proteomics approach in a melanoma xenograft model. MATERIALS AND METHODS: Melanoma tumor was induced in C57BL6 mice and treated intraperitoneally with LDN193189 for ten consecutive days. Post-treatment, tumors were collected, and comparative proteomics was performed using a high-resolution Orbitrap Fusion Tribrid mass spectrometer. RESULTS: Treatment of melanoma with LDN193189 at 3 mg/kg body weight twice daily showed a significant decrease in the growth rate of the tumor compared to the other doses tested. Quantitative proteomic profiling identified 3231 proteins. Bioinformatics analysis of the 131 differentially expressed proteins selected by their relative abundance revealed that LDN193189 induces alterations in the cellular and metabolic process and the proteins that are involved in protein binding and catalytic activity in melanoma. CONCLUSIONS: Down-regulation of metallothionein (MT) 1 and MT2, emerging proteins for their role in tumor formation, progression, and drug resistance and transcription factor EB that plays a crucial role in the regulation of basic cellular processes, such as lysosomal biogenesis and autophagy, were identified upon inhibition of the BMP pathway in melanoma, suggesting their roles in melanoma growth. Understanding the role of these proteins will provide new directions for treating cancer.

Hyperphosphorylation of HDAC2 promotes drug resistance in a novel dual drug resistant mouse melanoma cell line model: an in vitro study.

Drug-resistant melanoma is very difficult to treat, and a novel approach is needed to overcome resistance. The present study aims at identifying the alternate pathways utilized in the dual drug-resistant mouse melanoma cells (B16F10R) for their survival and proliferation. The dual drug-resistant mouse melanoma, B16F10R, was established by treating the cells with a combination of U0126 (MEK1/2 inhibitor) and LY294002 (PI3K-AKT kinase inhibitor) in a dose-escalating manner till they attained a resistance fold factor of ≥2. The altered phosphoproteome in the B16F10R, as compared to the parental B16F10C, was analyzed using a high-resolution Orbitrap Fusion Tribrid mass spectrometer. Histone deacetylases 2 (HDAC2) was validated for its role in drug resistance by using its inhibitor, valproic acid (VPA). In the B16F10R cells, 363 altered phosphoproteins were identified, among which 126 were hyperphosphorylated, and 137 were hypophosphorylated (1.5-fold change). Pathway analysis shows the altered phosphoproteins are from RNA metabolism and cell cycle proteins. Inhibition of HDAC2 by VPA induces apoptosis in B16F10C and B16F10R. The present study highlights the role of HDAC2, a cell cycle regulator, in the development of resistance to dual drugs in murine melanoma. Therefore, designing leads for targeting HDAC2 along with key signaling pathways may be explored in treatment strategies.

Serum and salivary immunoglobulin G4 levels in children with autism spectrum disorder from south India: a case-control study.

BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with wide spectrum of symptoms and few effective therapies. Evidence is suggestive of an association between immune system dysfunction and autism spectrum disorders (ASD) among children with ASD. Immunoglobulins (Ig) are found to be increased in the circulation of individuals with autism. The prospective study was aimed to estimate and correlate the levels of IgG4 in blood and saliva of children with autism. METHODOLOGY: Blood and unstimulated saliva were collected from 172 children (55 ASD, 57 healthy control, and 60 suspected parasitic infection) aged 0-18 years. Routine blood investigations were done. Serum and salivary IgG4 levels were analyzed using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. Data were subjected to statistical analysis. RESULTS: ELISA tests showed that the IgG4 levels in serum and saliva were significantly increased (P<0.05) in children with ASD as compared to normal control children. Both serum and saliva IgG4 levels showed a significant positive correlation (P<0.05). CONCLUSION: IgG4 can be used as a potential biomarker for the early detection of ASD. Further, saliva can be a diagnostic, noninvasive assessment tool for health monitoring of children with autism. Lay summary: The collection of saliva is easy and painless compared to other sample collection methods. The present study shows that, among children with autism, brain-reactive antibody, immunoglobulin G4 (gG4), is increased both in blood and saliva, and there is a significant correlation between the two levels. Therefore, the study recommends IgG4 as a potential biomarker for the early detection of autism, and saliva can be helpful in diagnosis and health monitoring of children with ASD.

Serum Ischemia-Modified Albumin, Fibrinogen, High Sensitivity C- Reactive Proteins in Type-2 Diabetes Mellitus without Hypertension and Diabetes Mellitus with Hypertension: A Case-Control Study.

BACKGROUND: The objective of this study was to determine the levels of serum ischemia-modified albumin (IMA), fibrinogen (FIB) and high sensitivity C-reactive protein (hs-CRP) in type 2 diabetes mellitus (T2DM) patients with hypertension (HT) (DMT2HTN) and without HT (DMT2). Also, their association with certain biochemical and physical factors were studied to identify possible risk factors that lead to cardiovascular complications. METHODS: Fasting blood samples were collected from 35 DMT2 or DMT2HTN patients each to analyze differences in serum and plasma levels of IMA, hs-CRP, FIB, total cholesterol (TC), high and low density lipoproteins (HDL and LDL), triglyceride (TG), hemoglobin A1c (HbA1C), glycated hemoglobin and creatinine. RESULTS: In DMT2 and DMT2HTN patients, IMA, hs-CRP, FIB, TC, TG, HDL, LDL, glycated hemoglobin and creatinine levels, including body mass index (BMI) and waist-to-hip ratio (WHR), were significantly higher relative to healthy controls. In addition, the levels of IMA, hs-CRP and FIB levels showed a strong link to BMI, WHR, TC, TG, LDL and glycated hemoglobin. Lastly, both DMT2 and DMT2HTN patients demonstrated a significant reduction in HDL. CONCLUSION: DMT2 and DMT2HTN patients have a greater risk of developing cardiovascular related complications. This study suggests that quantifying hs-CRP, IMA and FIB levels can help diagnose the risk of developing complications during the early stages of metabolic and cardiovascular disease. Overall, the specific risk factors may be used for early identification of cardiovascular complications to decrease mortality and morbidity in T2DM patients.

Diabetogenic effect of gluten in Wistar albino rats: a preliminary preclinical screening.

BACKGROUND AND AIMS: Gluten-related disease affects less than 1% population and is not considered of relevance at the public health level. However, the consumption of a gluten-free diet has been most commonly adopted as a special diet worldwide in the recent past. In the present study, we investigated the association of gluten intake and diabetes in Wistar albino rats. METHODS: Thirty adult Wistar rats were randomly divided into five groups: control, diabetic, and test treated with pure gluten (100, 200 and 400 mg/kg body weight). Diabetes was induced in rats by intraperitoneal injection of Streptozotocin (65 mg/kg) after a dose of nicotinamide (110 mg/kg). Body weight, fasting blood glucose levels, postprandial blood glucose levels and histopathology of the pancreas were compared. RESULTS: Fasting blood glucose levels and postprandial blood glucose were significantly higher in diabetes animals but there were no significant changes in gluten treated groups. Other parameters were not significantly changed among different groups. CONCLUSIONS: Gluten at doses 100 mg/kg, 200 mg/kg and 400 mg/kg is not a diabetogenic diet and hence it needs not be excluded from diet for the prevention and management of Type 2 diabetes mellitus.

Molecular characterization of carbapenem-resistant Acinetobacter baumannii strains from a tertiary care center in South India / Caracterización molecular de cepas de Acinetobacter baumannii carbapenem-resistante en un centro de atención terciaria en el sur de la India

Objectives: Carbapenem resistantAcinetobacter baumannii is an important therapeutic and infection control challenge worldwide. In this study, we investigated the prevalence and distribution of molecular mechanisms of resistance among carbapenem resistant A. baumannii species at a tertiary care setting in South India. Materials and Methods: A total of 89 non-duplicate clinical isolates of carbapenem-resistantA. baumannii were collected from critical care units of St. John's Medical College Hospital, Bengaluru, India. Polymerase chain reaction (PCR) was performed to detect blaOXA type carbapenemase blaOXA-51-like, blaOXA-23-like, blaOXA-24-like and bla OXA-58-like, MBL genes blaNDM, blaIMP, and blaVIM genes. Molecular typing of carbapenem-resistant A. baumannii strains was performed by using Rep-PCR. Results: Eighty-seven of the isolates were found to carry the blaOXA-51 gene and 81 (91%) isolates were found to have blaOXA-51-like gene and blaOXA-23, gene. The bla OXA-24 like gene was detected in two isolates of which one also carried blaOXA-51 like and one isolate carried blaVIM coding gene. The prevalence of blaNDM, blaIMP, bla VIM genes was 12(13%),14 (16%) and 57(64%) respectively. Cluster analyses revealed a 90% similarity and were divided into 5 clusters. Most of the isolates containing carbapenemases coding genes grouped under cluster A, C and UC. Considerable heterogeneity was observed within UC cluster indicating circulation of multiple strains of A. baumannii within our institution. Conclusions: Carbapenemase coding blaOXA-23, blaOXA-24 and blaOXA-51 -like were more common than blaVIM and blaNDM. The presence of blaNDM with other genes coding for carbapenemases indicate the ability of the strains to acquire novel genes despite having its share of the blaOXA like carbapenemase.

Objetivos: El Acinetobacter baumannii resistente a Carbapenem es un reto importante en todo el mundo para su tratamiento y para el control de infecciones hospitalarias. Nosotros estudiamos la prevalencia y los mecanismos de resistencia en aislados de un centro de atención terciario, en el sur de la India Materiales y Métodos: Se estudiaron 89 aislados clínicos de A. baumannii recolectados en unidades de cuidado crítico del Hospital St. John's Medical College en Bengaluru, India. Se realizó amplificación por PCR (Reacción en Cadena de Polimerasa) y luego tipificación molecular con la técnica Rep-PCR (PCR de elementos repetitivos palindromicos) para detectar los genes de carbapenemasa blaOXA, blaOXA-51, blaOXA-23, blaOXA-24, blaOXA-58, MBL, blaNDM, blaIMP y blaVIM. Resultados: Se encontraron 87 aislados que llevaban el gen blaOXA-51 y de ellos en 81 (91%) se encontró blaOXA-51 y blaOXA-23. El blaOXA-24 se detectó en dos aislados de los cuales uno de ellos llevaba blaOXA-51 y otro blaVIM. Los genes blaNDM, blaIMP y blaVIM se encontraron en 12 (13%),14 (16%) y 57(64%) de los aislados, respectivamente. El análisis de agrupamiento reveló un 90% de similitud entre los aislados y que podían asignarse a 5 agrupamientos. La mayoría de aislados llevaban genes de carbapenemasas de los grupos A, C y UC. Se observó mucha heterogeneidad dentro del agrupamiento UC indicando que existe circulación de múltiples cepas de A. baumannii dentro de nuestra institución. Conclusiones: Las carbapenemasas que codifican para blaOXA-23, blaOXA-24 y blaOXA-51 son más comunes que blaVIM y blaNDM en nuestra institución. La presencia de NDM con otros genes codificando para carbapenemasas indica la capacidad que tienen este tipo de aislados para adquirir nuevos genes a pesar de contar con blaOXA.

Estimation of Salivary sCD14 in Children with Early Childhood Caries in Association with Pneumonia.

BACKGROUND: Dental caries is a chronic disease among children and pneumonia is often seen in young children. Soluble CD14 (sCD14) protein is released by monocytes and changes in periodontal infection. The study aimed to estimate the level of salivary sCD14 in children with early childhood caries in association with pneumonia. METHODS: This case-control study was conducted on 52 children aged between 2 to 5 years. A total of 17 children who were caries free, with no past systemic illness; 17 children with dental caries with no history of systemic illness or dental treatment for caries, and 18 children with caries and pneumonia were included in the control and test groups respectively. Unstimulated saliva of all children was collected. All samples were tested using a commercial available sCD14 ELISA kit. RESULTS: The sCD14 level was elevated in all three groups. One-way ANOVA was used to compare the mean level of sCD14 values between the groups. Control group had the highest mean sCD14 values (15070.99 ± 4296.44), followed by the caries group (13629.83 ± 5603.76) and pneumonia group (8566.86 ± 4778.81). There is a significant difference between the groups with p=0.001. CONCLUSION: Based on the results of the study, it can be concluded that sCD14 can be used as an indicator of the healthy functioning of the oral cavity.

Oxidative stress in cervical cancer and its response to chemoradiation.

OBJECTIVES: Cervical cancer (CaCx) is one of the leading causes of cancer-related death among women worldwide, with the great social and economic burden. Diagnoses in early stages can decrease mortality and morbidity rates. This study was conducted to evaluate the status of serum total antioxidant capacity (TAC), and malondialdehyde (MDA) and copper concentrations among patients with CaCx to determine the level of oxidative stress and effect on which of chemoradiation. MATERIALS AND METHODS: Fifty patients with histopathologically proven CaCx who visited the department of oncology & gynaecology and 50 age-matched healthy females were selected for the study. Serum TAC, MDA, and copper were estimated in both study groups. The effect of chemoradiation on these was estimated in patients with CaCx. RESULTS: The mean ± standard deviation age of the patients was 43.98±6.38 years, whereas that of the controls was 31.56±6.84 years. The mean serum copper and MDA concentrations in the patients was significantly higher as compared with the controls, whereas the mean TAC in the patients was reduced when compared with the controls. After chemoradiation, there was a significant increase and decrease in TAC and MDA, respectively, after chemoradiotherapy, whereas the changes in the copper concentrations were insignificant. CONCLUSION: These results suggest that patients with CaCx were in oxidative stress because the oxidative parameters in serum (copper, MDA) were increased and the defensive TAC was decreased in patients with CaCx and chemoradiotherapy improved their anti-oxidant capacity. Further studies are needed to evaluate the concurrent use of antioxidants with chemoradiotherapy for improving the disease prognosis.

Prevalence of respiratory syncytial virus infection among children hospitalized with acute lower respiratory tract infections in Southern India.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory infections among children. AIM: To investigate the proportion of RSV and non-RSV respiratory viral infections among hospitalized children ≤ 5 years. METHODS: Hospitalized children aged < 5 years, with a diagnosis of acute lower respiratory infections (ALRI), admitted between August 2011-August 2013, were included. Cases were defined as laboratory-confirmed RSV and non-RSV respiratory viruses by direct fluorescence assay from the nasopharyngeal wash. RESULTS: Of 383 1-59 mo old children hospitalized with an acute lower respiratory infection, 33.9% (130/383) had evidence of viral infection, and RSV was detected in 24.5% (94/383). Co-infections with RSV and other respiratory viruses (influenza A or B, adenovirus, para influenza 1, 2 or 3) were seen in children 5.5% (21/383). Over 90% of the RSV-positive children were under 2 years of age. RSV was detected throughout the year with peaks seen after the monsoon season. Children hospitalized with RSV infection were more likely to have been exposed to a shorter duration of breastfeeding of less than 3 mo. RSV positive children had a shorter hospital stay, although there were significant complications requiring intensive care. Use of antibiotics was high among those with RSV and non-RSV viral infections. CONCLUSION: Our study provides evidence of a high proportion of RSV and other virus-associated ALRI among hospitalized children in India. RSV infection was associated with fewer days of hospital stay compared to other causes of lower respiratory infections. A high level of antibiotic use was seen among all respiratory virus-associated hospitalizations. These results suggest the need for implementing routine diagnostics for respiratory pathogens in order to minimize the use of unnecessary antibiotics and plan prevention strategies among pediatric populations.

HDAC2 Inhibitor Valproic Acid Increases Radiation Sensitivity of Drug-Resistant Melanoma Cells.

Resistance to anticancer drugs limits the effectiveness of chemotherapy in cancers. Melanoma cell lines B16F10C and A375C (parental) and B16F10R and A375R (drug-resistant sublines) were used to test radiation sensitization potential of valproic acid (VPA), an inhibitor of Histone deacetylase2 (HDAC2) and LDN193189 (BMP inhibitor). Inhibitors of other signaling pathways were tested for cross-resistance with the resistant cell lines. Cells were pretreated with low concentrations of VPA/ LDN193189 and exposed to 2 Gy radiation for radiation sensitization experiments. Assays-3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT), live/dead, clonogenic, and melanin estimation were performed to test the effects of radiation sensitization. Interactions of VPA and HDAC2 were studied in silico. Dose-dependent growth inhibition was observed with all tested drugs. Radiation sensitization of melanoma cells with low dose of VPA induced synergistic cell death, decreased clonogenicity, and decreased melanin content. In silico docking showed two stable interactions between Arg39 of HDAC2 and VPA. In conclusion, pretreatment with low doses of VPA has a potential for sensitizing melanoma cells to low doses of radiation. The binding of VPA to HDAC2 reverses the drug resistance in melanoma and induces the cell death. Sensitization effects of VPA can be used for targeting drug-resistant cancers.

Synthesis and evaluation of thiazolidinone-pyrazole conjugates as anticancer and antimicrobial agents.

AIM: To synthesize a series of new thiazolidinone-pyrazole hybrids (5a-o) and assess their anticancer (in vitro and in vivo) and antimicrobial activities. RESULTS: The compounds 5h (against Ehrlich ascites carcinoma cells), 5e and 5i (against the human breast cancer [MDA-MB231] cell line) exhibited potent anticancer activity. All the compounds except 5g and 5e found to be less toxic for the human dermal fibroblast cells. The effective interactions of the compounds in silico with MDM2 exemplified their inhibitory potency. The derivatives also showed moderate antimicrobial activity. CONCLUSION: The halogen atoms on various positions of the N-arylamino ring played an advantageous role in elevating the potency of the molecules. Thus, these conjugates could be used as a lead for further optimization to achieve promising therapeutics.

Inhibition of ERK1/2 or AKT Activity Equally Enhances Radiation Sensitization in B16F10 Cells.

BACKGROUND: The aim of the study was to evaluate the radiation sensitizing ability of ERK1/2, PI3K-AKT and JNK inhibitors in highly radiation resistant and metastatic B16F10 cells which carry wild-type Ras and Braf. METHODS: Mouse melanoma cell line B16F10 was exposed to 1.0, 2.0 and 3.0 Gy of electron beam radiation. Phosphorylated ERK1/2, AKT and JNK levels were estimated by ELISA. Cells were exposed to 2.0 and 3.0 Gy of radiation with or without prior pharmacological inhibition of ERK1/2, AKT as well as JNK pathways. Cell death induced by radiation as well as upon inhibition of these pathways was measured by TUNEL assay using flow cytometry. RESULTS: Exposure of B16F10 cells to 1.0, 2.0 and 3.0 Gy of electron beam irradiation triggered an increase in all the three phosphorylated proteins compared to sham-treated and control groups. B16F10 cells pre-treated with either ERK1/2 or AKT inhibitors equally enhanced radiation-induced cell death at 2.0 as well as 3.0 Gy (P < 0.001), while inhibition of JNK pathway increased radiation-induced cell death to a lesser extent. Interestingly combined inhibition of ERK1/2 or AKT pathways did not show additional cell death compared to individual ERK1/2 or AKT inhibition. This indicates that ERK1/2 or AKT mediates radiation resistance through common downstream molecules in B16F10 cells. CONCLUSIONS: Even without activating mutations in Ras or Braf genes, ERK1/2 and AKT play a critical role in B16F10 cell survival upon radiation exposure and possibly act through common downstream effector/s.

Streptococcus pneumoniae serotype prevalence and antibiotic resistance among young children with invasive pneumococcal disease: experience from a tertiary care center in South India.

INTRODUCTION: We performed a study to describe the clinical profile, antimicrobial susceptibility and prevalent serotypes of pneumococcal isolates from children with suspected invasive pneumococcal disease (IPD) admitted to a tertiary care hospital in South India. METHODS: Hospitalized children, ≤ 5 years with fever (>38 °C); increased respiratory rate or neurological symptoms were recruited, (as part of the Alliance for Surveillance of Invasive Pneumococci - ASIP - project) from January 2011 to March 2013. Identification of pneumococcal isolates from blood or cerebrospinal fluid samples was done by routine culture methods. Isolates were analyzed for antimicrobial susceptibility, and confirmed by serotyping (using Quellung's test) and multiplex PCR. RESULTS: Out of the 171 samples received in the lab, 17 grew pneumococci identified by standard methods. Fourteen of them were confirmed by multiplex PCR. Maximum recruitment was observed during the months of January and February (36.4%, 28.6%). The average age of affected subjects was 21 months. The common clinical presentation was pneumonia (42.8%). Two isolates belonging to the 19F and 19B serotypes were resistant to penicillin (on Etest). The observed serotype distribution was 6B and 19F (2 each), and 1, 2, 6A, 9V, 10A, 14, 15A, 19B, 21, 35F (1 each). The overall fatality rate was 14.3% (n=2); the S. pneumoniae isolates from these two patients belonged to the non-vaccine serotype 19B and vaccine serotype 19F and demonstrated in vitro resistance to penicillin and erythromycin. CONCLUSION: Our study demonstrates the presence of invasive pneumococcal disease among under-5-year-old children in India caused by serotypes that are in large part covered by available pneumococcal vaccines.

Chemotherapy Resistance Mechanisms in Advanced Skin Cancer.

Melanoma is a most dangerous and deadly type of skin cancer, and considered intrinsically resistant to both radiotherapy and chemotherapy. It has become a major public health concern as the incidence of melanoma has been rising steadily over recent decades with a 5-year survival remaining less than 5%. Detection of the disease in early stage may be curable, but late stage metastatic disease that has spread to other organs has an extremely poor prognosis with a median survival of less than 10 months. Since metastatic melanoma is unresponsive to therapy that is currently available, research is now focused on different treatment strategies such as combinations of surgery, chemotherapy and radiotherapy. The molecular basis of resistance to chemotherapy seen in melanoma is multifactorial; defective drug transport system, altered apoptotic pathway, deregulation of apoptosis and/or changes in enzymatic systems that mediate cellular metabolic machinery. Understanding of alterations in molecular processes involved in drug resistance may help in developing new therapeutic approaches to treatment of malignant melanoma.