Dysregulated transforming growth factor-beta mediates early bone marrow dysfunction in diabetes.

Diabetes affects select organs such as the eyes, kidney, heart, and brain. Our recent studies show that diabetes also enhances adipogenesis in the bone marrow and reduces the number of marrow-resident vascular regenerative stem cells. In the current study, we have performed a detailed spatio-temporal examination to identify the early changes that are induced by diabetes in the bone marrow. Here we show that short-term diabetes causes structural and molecular changes in the marrow, including enhanced adipogenesis in tibiae of mice, prior to stem cell depletion. This enhanced adipogenesis was associated with suppressed transforming growth factor-beta (TGFB) signaling. Using human bone marrow-derived mesenchymal progenitor cells, we show that TGFB pathway suppresses adipogenic differentiation through TGFB-activated kinase 1 (TAK1). These findings may inform the development of novel therapeutic targets for patients with diabetes to restore regenerative stem cell function.

Inhibition of MyD88 attenuates angiotensin II-induced hypertensive kidney disease via regulating renal inflammation.

BACKGROUND: Kidney damage is a frequent event in the course of hypertension. Recent researches highlighted a critical role of non-hemodynamic activities of angiotensin II (Ang II) in hypertension-associated kidney fibrosis and inflammation. These activities are mediated through toll-like receptors (TLRs) but the mechanisms by which Ang II links TLRs to downstream inflammatory and fibrogenic responses is not fully known. In this study, we investigated the role of TLR adapter protein called myeloid differentiation primary-response protein-88 (MyD88) as the potential link. METHODS: C57BL/6 mice were administered Ang II by micro-osmotic pump infusion for 4 weeks to develop nephropathy. Mice were treated with small-molecule MyD88 inhibitor LM8. In vitro, MyD88 was blocked using siRNA or LM8 in Ang II-challenged renal tubular epithelial cells. RESULTS: We show that MyD88 is mainly located in tubular epithelial cells and Ang II increases the interaction between TLR4 and MyD88. This interaction activates MAPKs and nuclear factor-κB (NF-κB), leading to increased production of inflammatory and fibrogenic factors. Inhibition of MyD88 by siRNA or selective inhibitor LM8 supresses MyD88-TLR4 interaction, NF-κB activation, and elaboration of inflammatory cytokines and fibrosis-associated factors. These protective actions resulted in decreased renal pathological changes and preserved renal function in LM8-treated hypertensive mice, without affecting hypertension. CONCLUSION: These results demonstrate that Ang II induces inflammation and fibrosis in renal tubular epithelial cells through MyD88 and present MyD88 as a potential point of intervention for hypertension-associated kidney disease.

Schisandrin B Attenuates Diabetic Cardiomyopathy by Targeting MyD88 and Inhibiting MyD88-Dependent Inflammation.

Diabetes manifests as chronic inflammation and leads to the development diabetic cardiomyopathy (DCM). Targeting key proteins in inflammatory signaling may provide new therapy for DCM. In this study, the authors explore the pharmacological effects and mechanisms of Schisandrin B (Sch B), a natural compound with anti-inflammatory activity against DCM. It is shown that Sch B prevents high-level glucose (HG)-induced hypertrophic and fibrotic responses in cultured cardiomyocytes. RNA sequencing and inflammatory qPCR microarray show that Sch B mainly affects myeloid differentiation primary response 88 (MyD88)-dependent inflammatory gene expression in HG-challenged cardiomyocytes. Further studies indicate that Sch B directly binds to and inhibits MyD88 activation, but does not alter MyD88-independent Toll-like receptor signaling in vivo and in vitro. Inhibiting or silencing MyD88 is associated with reduced levels of HG-induced inflammatory cytokines and myocardial injuries in vitro. Treatment of type 1 and type 2 diabetic mice with Sch B protects heart function, reduces myocardial injuries, and decreases secretion of inflammatory cytokines. Cardiomyocyte-specific MyD88 knockout also protects mice against cardiac inflammation and injury in type 1 diabetic mice. In conclusion, these studies show that cardiomyocyte MyD88 plays an apathogenetic role in DCM and Sch B specifically targets MyD88 to reduce inflammatory DCM.

Ang II (Angiotensin II)-Induced FGFR1 (Fibroblast Growth Factor Receptor 1) Activation in Tubular Epithelial Cells Promotes Hypertensive Kidney Fibrosis and Injury.

BACKGROUND: Elevated Ang II (angiotensin II) level leads to a range of conditions, including hypertensive kidney disease. Recent evidences indicate that FGFR1 (fibroblast growth factor receptor 1) signaling may be involved in kidney injuries. In this study, we determined whether Ang II alters FGFR1 signaling to mediate renal dysfunction. METHODS: Human archival kidney samples from patients with or without hypertension were examined. Multiple genetic and pharmacological approaches were used to investigate FGFR1-mediated signaling in tubular epithelial NRK-52E cells in response to Ang II stimulation. C57BL/6 mice were infused with Ang II for 28 days to develop hypertensive kidney disease. Mice were treated with either adeno-associated virus expressing FGFR1 shRNA or FGFR1 inhibitor AZD4547. RESULTS: Kidney specimens from subjects with hypertension and mice challenged with Ang II have increased FGFR1 activity in renal epithelial cells. Renal epithelial cells in culture initiate extracellular matrix programming in response to Ang II, through the activation of FGFR1, which is independent of both AT1R (angiotensin II receptor type 1) and AT2R (angiotensin II receptor type 2). The RNA sequencing analysis indicated that disrupting FGFR1 suppresses Ang II-induced fibrogenic responses in epithelial cells. Mechanistically, Ang II-activated FGFR1 leads to STAT3 (signal transducer and activator of transcription 3) activation, which is responsible for fibrogenic factor expression in kidneys. In the mouse model of hypertensive kidney disease, genetic knockdown of FGFR1 or pharmacological inhibition of its activity protected kidneys from dysfunction and fibrosis upon Ang II challenge. CONCLUSIONS: Our studies uncover a novel mechanism causing renal fibrosis in hypertension and indicate FGFR1 as a potential target to preserve renal function and integrity.

Seasonal abundance and distribution of dragonflies in upper Siran valley of District Mansehra Pakistan / Abundância sazonal e distribuição de libélulas no vale superior de Siran, distrito de Mansehra, Paquistão

Abstract Present study was conducted to study seasonal abundance and distribution of dragonflies in upper Siran valley district Mansehra Pakistan. To collect data, eleven localities were visited for three consecutive years (2016-2018). Results come up with a sum of 300 specimens identified under three families, eight genera and twenty species. Highest seasonal abundance recorded during summer and spring were 80.67% and 13.33% respectively while minimum 6.00% was recorded during early autumn. Dominant species observed were, Orthetrum chrysis (14.00%), followed by O. gluacum (12.00%), Palpoleura sexmaculata sexmaculata (11.33%) and O. cancellatum cancellatum (8.00%). However the highest population of dragonflies was found in Munda Gucha with a percentage of 11.33 followed by Jabbar (11.00%) and Sachan (9.67%). The lowest populations were recorded in Suham (6.00%), Dadar (7.67%) and Jabori (7.67%). The surveyed valley showed diverse Anisopterous fauna and thus further extensive surveys are recommended that can come up with more important species from the area.

Resumo O presente estudo foi realizado para verificar a abundância sazonal e a distribuição de libélulas no vale superior de Siran, distrito de Mansehra, Paquistão. Para a coleta de dados, 11 localidades foram visitadas por três anos consecutivos (2016-2018). Os resultados apresentaram uma soma de 300 espécimes identificados em três famílias, 8 gêneros e 20 espécies. A maior abundância sazonal registrada durante o verão e a primavera foi de 80,67% e 13,33%, respectivamente, enquanto o mínimo de 6% foi registrado no início do outono. As espécies dominantes observadas foram Orthetrum chrysis (14%), seguido por O. gluacum (12%), Palpoleura sexmaculata sexmaculata (11,33%) e O. cancellatum cancellatum (8%). No entanto, a maior população de libélulas foi encontrada em Munda Gucha (11,33%), seguida por Jabbar (11%) e Sachan (9,67%). As populações mais baixas foram registradas em Suham (6%), Dadar (7,67%) e Jabori (7,67%). O vale pesquisado mostrou fauna Anisopterous diversificada, e, portanto, recomenda-se a realização de mais pesquisas que possam apresentar mais espécies importantes da área.

Change in malate dehydrogenase and alpha amylase activities in Rubus fruticosus and Valeriana jatamansi treated granary weevil, Sitophilus granarius.

Poor storage conditions provide favorable environment to stored grain pests for their growth. The bio-pesticides are the best alternatives to synthetic pesticides. Present study was conducted to compare toxicity of Rubus fruticosus and Valeriana jatamansi against granary weevil, Sitophilus granarius and subsequent changes in enzyme activity responsible for grain damage. In current research 5 g of R. fruticosus fruit and V. jatamansi rhizome powders were tested separately against S. granarius, in 50 g wheat whole grains for seven days in comparison with the control. The enzymatic activity of malate dehydrogenase and α-amylase was observed in the cellular extracts of S. granarius. The insects were crushed and homogenized in phosphate-buffer solution and centrifuged at 10000 rpm for 5 minutes. For the enzymatic measurement supernatant was tested; the spectrophotometer was adjusted at 340 nm. The reagents were mixed and incubated at 25 °C for five minutes. The cuvettes were placed in the experimental and reference sites of spectrophotometer and recorded the change in absorbance for 3-4 minutes. There was 5.60% and 14.92% reduction in the activity of malate dehydrogenase in R. fruticosus and V. jatamansi, treated insects, respectively. The alpha amylase enzyme activity was 6.82% reduced and 63.63% increase in R. fruticosus and V. jatamansi, treated insects, respectively. Present study addresses that both plant powders are effective against granary weevil by altering enzyme activities so both the plant powders can be used as bio-pesticides against the stored grains pests.

Seasonal abundance and distribution of dragonflies in upper Siran valley of District Mansehra Pakistan.

Present study was conducted to study seasonal abundance and distribution of dragonflies in upper Siran valley district Mansehra Pakistan. To collect data, eleven localities were visited for three consecutive years (2016-2018). Results come up with a sum of 300 specimens identified under three families, eight genera and twenty species. Highest seasonal abundance recorded during summer and spring were 80.67% and 13.33% respectively while minimum 6.00% was recorded during early autumn. Dominant species observed were, Orthetrum chrysis (14.00%), followed by O. gluacum (12.00%), Palpoleura sexmaculata sexmaculata (11.33%) and O. cancellatum cancellatum (8.00%). However the highest population of dragonflies was found in Munda Gucha with a percentage of 11.33 followed by Jabbar (11.00%) and Sachan (9.67%). The lowest populations were recorded in Suham (6.00%), Dadar (7.67%) and Jabori (7.67%). The surveyed valley showed diverse Anisopterous fauna and thus further extensive surveys are recommended that can come up with more important species from the area.

Change in malate dehydrogenase and alpha amylase activities in Rubus fruticosus and Valeriana jatamansi treated granary weevil, Sitophilus granarius / Mudança nas atividades de malato desidrogenase e alfa amilase em Rubus fruticosus e gorgulho tratado com Valeriana jatamansi, Sitophilus granarius

Poor storage conditions provide favorable environment to stored grain pests for their growth. The bio-pesticides are the best alternatives to synthetic pesticides. Present study was conducted to compare toxicity of Rubus fruticosus and Valeriana jatamansi against granary weevil, Sitophilus granarius and subsequent changes in enzyme activity responsible for grain damage. In current research 5 g of R. fruticosus fruit and V. jatamansi rhizome powders were tested separately against S. granarius, in 50 g wheat whole grains for seven days in comparison with the control. The enzymatic activity of malate dehydrogenase and α-amylase was observed in the cellular extracts of S. granarius. The insects were crushed and homogenized in phosphate-buffer solution and centrifuged at 10000 rpm for 5 minutes. For the enzymatic measurement supernatant was tested; the spectrophotometer was adjusted at 340 nm. The reagents were mixed and incubated at 25 °C for five minutes. The cuvettes were placed in the experimental and reference sites of spectrophotometer and recorded the change in absorbance for 3-4 minutes. There was 5.60% and 14.92% reduction in the activity of malate dehydrogenase in R. fruticosus and V. jatamansi, treated insects, respectively. The alpha amylase enzyme activity was 6.82% reduced and 63.63% increase in R. fruticosus and V. jatamansi, treated insects, respectively. Present study addresses that both plant powders are effective against granary weevil by altering enzyme activities so both the plant powders can be used as bio-pesticides against the stored grains pests.

As más condições de armazenamento proporcionam um ambiente favorável às pragas armazenadas para o crescimento. Os biopesticidas são as melhores alternativas aos pesticidas sintéticos. O presente estudo foi conduzido para comparar a toxicidade de Rubus fruticosus e Valeriana jatamansi contra gorgulhos, Sitophilus granarius e subsequentes alterações na atividade enzimática responsáveis ​​por danos aos grãos. Na pesquisa atual, 5 g de frutos de R. fruticosus e pós de rizoma de V. jatamansi foram testados separadamente contra S. granarius, em 50 g de grãos integrais de trigo por sete dias, em comparação com o controle. A atividade enzimática da malato desidrogenase e α-amilase foi observada nos extratos celulares de S. granarius. Os insetos foram esmagados e homogeneizados em solução tampão fosfato e centrifugados a 10000 rpm por 5 minutos. Para a medição enzimática, o sobrenadante foi testado; o espectrofotômetro foi ajustado a 340 nm. Os reagentes foram misturados e incubados a 25 °C por cinco minutos. As cubetas foram colocadas nos locais experimentais e de referência do espectrofotômetro e registradas as alterações na absorbância por 3-4 minutos. Houve redução de 5,60% e 14,92% na atividade da malato desidrogenase em R. fruticosus e V. jatamansi, insetos tratados, respectivamente. A atividade da enzima alfa amilase foi reduzida em 6,82% e aumento de 63,63% em R. fruticosus e V. jatamansi, insetos tratados, respectivamente. O presente estudo aborda que ambos os pós de plantas são eficazes contra o gorgulho do celeiro, alterando as atividades enzimáticas, de modo que ambos os pós de plantas possam ser usados ​​como biopesticidas contra pragas de grãos armazenados.

Checklist of the dragonflies and damselflies (Insecta: Odonata) of Bangladesh, Bhutan, India, Nepal, Pakistan and Sri Lanka.

A checklist of the dragonflies and damselflies occurring in Bangladesh, Bhutan, India (including Andaman and Nicobar Islands), Nepal, Pakistan and Sri Lanka is presented. In total 588 (including 559 full species) taxa are known to occur in the region of which 251 taxa (species subspecies) are single country endemics. Recent taxonomic changes relevant to the area are summarized. Sixteen taxa are synonymized and a checklist of all synonyms established since 1950 is provided. Information is given on available larval descriptions including a list of genera present in the region for which no larvae have yet been described. Numerous species occurring in the area are still poorly known and a list of genera for which a revision is urgently needed is provided.                The following new synonyms are established: Calicnemia sudhaae Mitra, 1994 = Calicnemia imitans Lieftinck, 1948 syn. nov.; Ceriagrion fallax cerinomelas Lieftinck, 1927 = Ceriagrion fallax Ris, 1914 syn. nov.; Ceriagrion fallax pendleburyi Laidlaw, 1931 = Ceriagrion fallax Ris, 1914 syn. nov.; Coenagrion kashmirus Chowdhary Das, 1975 = Ischnura forcipata Morton, 1907 syn. nov.; Enallagma insula Fraser, 1920 = Aciagrion occidentale Laidlaw, 1919 syn. nov.; Himalagrion pithoragarhicum Sahni, 1964 = Ceriagrion fallax Ris, 1914 syn. nov.; Ischnura bhimtalensis Sahni, 1965 = Ischnura rubilio Selys, 1876 syn. nov.; Onychargia indica Sahni, 1964 = Paracercion calamorum (Ris, 1916) syn. nov.; Anaciaeschna kashmirense Singh Baijal, 1954 = Anaciaeschna martini (Selys, 1897) syn. nov.; Cyclogomphus vesiculosus Selys, 1854 = Cyclogomphus ypsilon Selys, 1954 syn. nov.; Chlorogomphus brittoi Navás, 1934 = Chlorogomphus xanthoptera (Fraser, 1919) syn. nov.; Hylaeothemis indica Fraser, 1946 = Hylaeothemis apicalis Fraser, 1924 syn. nov.; Sympetrum durum Bartenef, 1916 = Sympetrum striolatum commixtum Selys, 1884 syn. nov.; Sympetrum himalayanum Navás, 1934 = Sympetrum hypomelas (Selys, 1884) syn. nov.; Sympetrum haematoneura Fraser, 1924 = Sympetrum speciosum Oguma, 1915 syn. nov.; Sympetrum speciosum taiwanum Asahina, 1951 = Sympetrum speciosum Oguma, 1915 syn. nov.                In addition, Periaeschna lebasi Navás, 1930 is regarded a nomen nudum. The following new combinations are proposed: Onychogomphus acinaces Laidlaw, 1922 is transferred to the genus Melligomphus Chao, 1990 resulting in Melligomphus acinaces (Laidlaw, 1922) comb. nov. Onychogomphus saundersii Selys, 1854 is transferred to the genus Nychogomphus Carle, 1986 resulting in Nychogomphus saundersii (Selys, 1854) comb. nov..

MD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy.

Hyperglycemia activates toll-like receptor 4 (TLR4) to induce inflammation in diabetic cardiomyopathy (DCM). However, the mechanisms of TLR4 activation remain unclear. Here we examine the role of myeloid differentiation 2 (MD2), a co-receptor of TLR4, in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. We show increased MD2 in heart tissues of diabetic mice and serum of human diabetic subjects. MD2 deficiency in mice inhibits TLR4 pathway activation, which correlates with reduced myocardial remodeling and improved cardiac function. Mechanistically, we show that HG induces extracellular advanced glycation end products (AGEs), which bind directly to MD2, leading to formation of AGEs-MD2-TLR4 complex and initiation of pro-inflammatory pathways. We further detect elevated AGE-MD2 complexes in heart tissues and serum of diabetic mice and human subjects with DCM. In summary, we uncover a new mechanism of HG-induced inflammatory responses and myocardial injury, in which AGE products directly bind MD2 to drive inflammatory DCM.

Celastrol Attenuates Angiotensin II-Induced Cardiac Remodeling by Targeting STAT3.

RATIONALE: Excessive Ang II (angiotensin II) levels lead to a profibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II-induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure. OBJECTIVE: We have examined the potential effect of celastrol-a bioactive compound derived from the Celastraceae family-on Ang II-induced cardiac dysfunction. METHODS AND RESULTS: In rat primary cardiomyocytes and H9C2 (rat cardiomyocyte-like H9C2) cells, celastrol attenuates Ang II-induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of celastrol. Our data showed that celastrol directly binds to and inhibits STAT (signal transducer and activator of transcription)-3 phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of celastrol treatment in mice challenged with Ang II and in the transverse aortic constriction model. We show that celastrol administration protected heart function in Ang II-challenged and transverse aortic constriction-challenged mice by inhibiting cardiac fibrosis and hypertrophy. CONCLUSIONS: Our studies show that celastrol inhibits Ang II-induced cardiac dysfunction by inhibiting STAT3 activity.

Arachidonic acid inhibits inflammatory responses by binding to myeloid differentiation factor-2 (MD2) and preventing MD2/toll-like receptor 4 signaling activation.

Arachidonic acid (AA) plays a fundamental role in the function of all cells. Metabolites of AA contribute to inflammation as well as for resolving inflammation. Although AA-derived metabolites exhibit well-substantiated bioactivity, it is not known whether AA regulates inflammatory responses independent of its metabolites. With the recent discovery that saturated fatty acids activate toll-like receptor-4 (TLR4), we tested the hypothesis that AA directly regulates inflammatory responses through modulating the activity of TLR4. In cultured cardiomyocytes and macrophages, we found that AA prevents saturated fatty acid-induced TLR4 complex formation with accessory proteins and the induction of proinflammatory cytokines. We discovered that AA directly binds to TLR4 co-receptor, myeloid differentiation factor 2 (MD2) and prevents saturated fatty acids from activating TLR4 pro-inflammatory signaling pathway. Similarly, AA reduced lipopolysaccharide (LPS)-induced inflammation in macrophages and septic death in mice through binding to MD2. In high-fat diet mouse model of obesity and LPS-induced model of acute lung injury, both mediating inflammatory responses through TLR4, treatment with AA prevented MD2/TLR4 dimerization, induction of inflammatory factors, and tissue injuries. In summary, we have discovered that AA interacts with MD2 and disrupts TLR4 activation by LPS and saturated fatty acids. These findings provide experimental evidence for a direct mechanism of AA-induced regulation of inflammation.

Surrogate markers for high-risk human papillomavirus infection in oral epithelial dysplasia: A comparison of p16, Ki-67, and ProExC.

OBJECTIVE: The aim of this study was to determine the utility of surrogate markers of human papillomavirus (HPV) infection in the diagnosis of HPV-associated oral epithelial dysplasia (OED). STUDY DESIGN: Twelve cases of oral dysplasia with histologic features of HPV infection were stained with surrogate markers for HPV (p16, Ki-67, and ProExC) on immunohistochemistry. A second group of 12 cases of oral dysplasia without histologic features of HPV infection was used for comparison. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to confirm the presence of high-risk HPV (HR HPV) in p16-positive cases. RESULTS: All of the surrogate markers showed a statistically significant association with HPV-positive OED (P < .001). The agreement between p16 and HPV positivity was the strongest (κ = 1.00), whereas Ki-67 showed very good association with HPV (κ = 0.83), and ProExC showed good association (κ = 0.75). In each case, the agreement was statistically significant (P < .001). Overall, each of the 3 markers showed good sensitivity; however, ProExC showed the lowest specificity. CONCLUSIONS: The clinicopathologic features of 12 cases of HPV OED are reported. Diffuse p16 positivity is an accurate and reliable method for predicting HR HPV infection in both high and low grade cases of epithelial dysplasia with histopathologic features of HPV OED. The use of Ki-67 and ProExC did not demonstrate any additional diagnostic benefit in the diagnosis HPV OED.

Identifying Candidate Biomarkers for Pleomorphic Adenoma: A Case-Control Study.

Pleomorphic adenoma (PA) is the most common benign salivary gland tumor. Kallikrein-related peptidases have been identified as biomarkers in many human tumors and may influence tumor behavior. We investigated KLK1-15 messenger ribonucleic acid and proteins in PA specimens to determine a KLK expression profile for this tumor. Fresh frozen PA tissue specimens (n = 26) and matched controls were subjected to quantitative real-time reverse transcription polymerase chain reaction to detect KLK1-15 mRNA. Expression of KLK1, KLK12, KLK13, and KLK8 proteins were then evaluated via immunostaining techniques. Statistical analyses were performed with the level of significance set at P < .05. We observed downregulation of KLK1, KLK12, and KLK13 mRNA expression, and immunostaining studies revealed downregulation of the corresponding proteins. Histologic evidence of capsular perforation was associated with increased KLK1 protein expression. Tumor size was not associated with capsular invasion and/or perforation. This study is the first to detail a KLK expression profile for PA at both the transcriptional level and the protein level. Future work is required to develop clinical applications of these findings.

Curcumin Analogs Reduce Stress and Inflammation Indices in Experimental Models of Diabetes.

Chronic inflammation and oxidative stress lead to a multitude of adverse cellular responses in target organs of chronic diabetic complications. Curcumin, a highly investigated phytochemical, has been shown to exhibit both anti-inflammatory and antioxidant activities. However, the clinical application of curcumin has been greatly limited due to a poor pharmacokinetic profile. To overcome these limitations, we have generated analogs of curcumin to enhance bioavailability and offer a preferable pharmacokinetic profile. Here, we explored the effects of two mono-carbonyl curcumin analogs, L2H21 and L50H46, in alleviating indices of inflammation and oxidative stress in cell culture and mouse model of diabetic complications. Our results show that L2H21 and L50H46 normalize inflammatory mediators (IL-6 and TNF-α), extracellular matrix proteins (FN and COL4α1), vasoactive factors (VEGF and ET-1) and a key transcriptional coactivator (p300) in cultured human retinal microvascular endothelial cells (HRECs) and dermal-derived microvascular endothelial cells (HMVECs) challenged with high levels of glucose. These curcumin analogs also reduced glucose-induced oxidative DNA damage as evidenced by 8-OHdG labeling. We further show that treatment of streptozotocin-induced diabetic mice with curcumin analogs prevents cardiac and renal dysfunction. The preservation of target tissue function was associated with normalization of pro-inflammatory cytokines and matrix proteins. Collectively, our results show that L2H21 and L50H46 offer the anti-inflammatory and antioxidant activities as has been reported for curcumin, and may provide a clinically applicable therapeutic option for the treatment of diabetic complications.

11ß-HSD1 inhibition ameliorates diabetes-induced cardiomyocyte hypertrophy and cardiac fibrosis through modulation of EGFR activity.

11ß-HSD1 has been recognized as a potential therapeutic target for type 2 diabetes. Recent studies have shown that hyperglycemia leads to activation of 11ß-HSD1, increasing the intracellular glucocorticoid levels. Excess glucocorticoids may lead to the clinical manifestations of cardiac injury. Therefore, the aim of this study is to investigate whether 11ß-HSD1 activation contributes to the development of diabetic cardiomyopathy. To investigate the role of 11ß-HSD1, we administered a selective 11ß-HSD1 inhibitor in type 1 and type 2 murine models of diabetes and in cultured cardiomyocytes. Our results show that diabetes increases cortisone levels in heart tissues. 11ß-HSD1 inhibitor decreased cortisone levels and ameliorated all structural and functional features of diabetic cardiomyopathy including fibrosis and hypertrophy. We also show that high levels of glucose caused cardiomyocyte hypertrophy and increased matrix protein deposition in culture. Importantly, inhibition of 11ß-HSD1 attenuated these changes. Moreover, we show that 11ß-HSD1 activation mediates these changes through modulating EGFR phosphorylation and activity. Our findings demonstrate that 11ß-HSD1 contributes to the development of diabetic cardiomyopathy through activation of glucocorticoid and EGFR signaling pathway. These results suggest that inhibition of 11ß-HSD1 might be a therapeutic strategy for diabetic cardiomyopathy, which is independent of its effects on glucose homeostasis.

Change in malate dehydrogenase and alpha amylase activities in Rubus fruticosus and Valeriana jatamansi treated granary weevil, Sitophilus granarius

Abstract Poor storage conditions provide favorable environment to stored grain pests for their growth. The bio-pesticides are the best alternatives to synthetic pesticides. Present study was conducted to compare toxicity of Rubus fruticosus and Valeriana jatamansi against granary weevil, Sitophilus granarius and subsequent changes in enzyme activity responsible for grain damage. In current research 5 g of R. fruticosus fruit and V. jatamansi rhizome powders were tested separately against S. granarius, in 50 g wheat whole grains for seven days in comparison with the control. The enzymatic activity of malate dehydrogenase and -amylase was observed in the cellular extracts of S. granarius. The insects were crushed and homogenized in phosphate-buffer solution and centrifuged at 10000 rpm for 5 minutes. For the enzymatic measurement supernatant was tested; the spectrophotometer was adjusted at 340 nm. The reagents were mixed and incubated at 25 °C for five minutes. The cuvettes were placed in the experimental and reference sites of spectrophotometer and recorded the change in absorbance for 3-4 minutes. There was 5.60% and 14.92% reduction in the activity of malate dehydrogenase in R. fruticosus and V. jatamansi, treated insects, respectively. The alpha amylase enzyme activity was 6.82% reduced and 63.63% increase in R. fruticosus and V. jatamansi, treated insects, respectively. Present study addresses that both plant powders are effective against granary weevil by altering enzyme activities so both the plant powders can be used as bio-pesticides against the stored grains pests.

Resumo As más condições de armazenamento proporcionam um ambiente favorável às pragas armazenadas para o crescimento. Os biopesticidas são as melhores alternativas aos pesticidas sintéticos. O presente estudo foi conduzido para comparar a toxicidade de Rubus fruticosus e Valeriana jatamansi contra gorgulhos, Sitophilus granarius e subsequentes alterações na atividade enzimática responsáveis por danos aos grãos. Na pesquisa atual, 5 g de frutos de R. fruticosus e pós de rizoma de V. jatamansi foram testados separadamente contra S. granarius, em 50 g de grãos integrais de trigo por sete dias, em comparação com o controle. A atividade enzimática da malato desidrogenase e -amilase foi observada nos extratos celulares de S. granarius. Os insetos foram esmagados e homogeneizados em solução tampão fosfato e centrifugados a 10000 rpm por 5 minutos. Para a medição enzimática, o sobrenadante foi testado; o espectrofotômetro foi ajustado a 340 nm. Os reagentes foram misturados e incubados a 25 °C por cinco minutos. As cubetas foram colocadas nos locais experimentais e de referência do espectrofotômetro e registradas as alterações na absorbância por 3-4 minutos. Houve redução de 5,60% e 14,92% na atividade da malato desidrogenase em R. fruticosus e V. jatamansi, insetos tratados, respectivamente. A atividade da enzima alfa amilase foi reduzida em 6,82% e aumento de 63,63% em R. fruticosus e V. jatamansi, insetos tratados, respectivamente. O presente estudo aborda que ambos os pós de plantas são eficazes contra o gorgulho do celeiro, alterando as atividades enzimáticas, de modo que ambos os pós de plantas possam ser usados como biopesticidas contra pragas de grãos armazenados.

Seasonal abundance and distribution of dragonflies in upper Siran valley of District Mansehra Pakistan

Abstract Present study was conducted to study seasonal abundance and distribution of dragonflies in upper Siran valley district Mansehra Pakistan. To collect data, eleven localities were visited for three consecutive years (2016-2018). Results come up with a sum of 300 specimens identified under three families, eight genera and twenty species. Highest seasonal abundance recorded during summer and spring were 80.67% and 13.33% respectively while minimum 6.00% was recorded during early autumn. Dominant species observed were, Orthetrum chrysis (14.00%), followed by O. gluacum (12.00%), Palpoleura sexmaculata sexmaculata (11.33%) and O. cancellatum cancellatum (8.00%). However the highest population of dragonflies was found in Munda Gucha with a percentage of 11.33 followed by Jabbar (11.00%) and Sachan (9.67%). The lowest populations were recorded in Suham (6.00%), Dadar (7.67%) and Jabori (7.67%). The surveyed valley showed diverse Anisopterous fauna and thus further extensive surveys are recommended that can come up with more important species from the area.

Resumo O presente estudo foi realizado para verificar a abundância sazonal e a distribuição de libélulas no vale superior de Siran, distrito de Mansehra, Paquistão. Para a coleta de dados, 11 localidades foram visitadas por três anos consecutivos (2016-2018). Os resultados apresentaram uma soma de 300 espécimes identificados em três famílias, 8 gêneros e 20 espécies. A maior abundância sazonal registrada durante o verão e a primavera foi de 80,67% e 13,33%, respectivamente, enquanto o mínimo de 6% foi registrado no início do outono. As espécies dominantes observadas foram Orthetrum chrysis (14%), seguido por O. gluacum (12%), Palpoleura sexmaculata sexmaculata (11,33%) e O. cancellatum cancellatum (8%). No entanto, a maior população de libélulas foi encontrada em Munda Gucha (11,33%), seguida por Jabbar (11%) e Sachan (9,67%). As populações mais baixas foram registradas em Suham (6%), Dadar (7,67%) e Jabori (7,67%). O vale pesquisado mostrou fauna Anisopterous diversificada, e, portanto, recomenda-se a realização de mais pesquisas que possam apresentar mais espécies importantes da área.

Developing a multidisciplinary Young Women's Blood Disorders Program: a single-centre approach with guidance for other centres.

INTRODUCTION: Bleeding from the reproductive tract in women is a natural event, generally occurring with menstruation and childbirth. Women with an underlying bleeding disorder may experience heavy menstrual bleeding (HMB) and thereby, unacceptable blood loss. Up to 20% of US women with abnormal uterine bleeding and a normal gynaecological exam may have an underlying bleeding disorder corresponding to almost 2-3 million American women. These females face many obstacles in achieving optimum medical care for their problems. A haematologist may not evaluate these women as they are treated symptomatically. Recognition of an underlying bleeding disorder is not straightforward and many come to attention after serious bleeding events. Although mortality from HMB is uncommon, the true burden of HMB is its impact on health-related quality of life. To address these issues, women with HMB require a comprehensive approach to their care. METHODS: These reasons compelled us to institute a multidisciplinary Young Women's Blood Disorders (YWBD) Program at our institution. RESULTS: Herein, we describe the process of developing this program involving paediatric haematology, adolescent medicine and paediatric/adolescent gynaecology, and the expertise of a laboratory coagulationist, a nutritionist and nursing professionals. We also describe our experience with patient selection, the role of each specialty in the program, our approach to testing, the coordination of care and overall management of this patient population. Lastly, we propose metrics that could be followed in justifying the support of such a program. CONCLUSIONS: There is a growing need to offer comprehensive care to women with HMB and blood disorders. The YWBD program at our institution appears to be successful in delivering optimal care to young women affected with HMB.