MicroRNA-5010-5p ameliorates high-glucose induced inflammation in renal tubular epithelial cells by modulating the expression of PPP2R2D.

INTRODUCTION: We previously reported the significant upregulation of eight circulating exosomal microRNAs (miRNAs) in patients with diabetic kidney disease (DKD). However, their specific roles and molecular mechanisms in the kidney remain unknown. Among the eight miRNAs, we evaluated the effects of miR-5010-5p on renal tubular epithelial cells under diabetic conditions in this study. RESEARCH DESIGN AND METHODS: We transfected the renal tubular epithelial cell line, HK-2, with an miR-5010-5p mimic using recombinant plasmids. The target gene of hsa-miR-5010-5p was identified using a dual-luciferase assay. Cell viability was assessed via the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Moreover, mRNA and protein expression levels were determined via real-time PCR and western blotting, respectively. RESULTS: High glucose levels did not significantly affect the intracellular expression of miR-5010-5p in HK-2 cells. Transfection of the miR-5010-5p mimic caused no change in cell viability. However, miR-5010-5p-transfected HK-2 cells exhibited significantly decreased expression levels of inflammatory cytokines, such as the monocyte chemoattractant protein-1, interleukin-1ß, and tumor necrosis factor-ɑ, under high-glucose conditions. These changes were accompanied by the restored expression of phosphorylated AMP-activated protein kinase (AMPK) and decreased phosphorylation of nuclear factor-kappa B. Dual-luciferase assay revealed that miR-5010-5p targeted the gene, protein phosphatase 2 regulatory subunit B delta (PPP2R2D), a subunit of protein phosphatase 2A, which modulates AMPK phosphorylation. CONCLUSIONS: Our findings suggest that increased miR-5010-5p expression reduces high glucose-induced inflammatory responses in renal tubular epithelial cells via the regulation of the target gene, PPP2R2D, which modulates AMPK phosphorylation. Therefore, miR-5010-5p may be a promising therapeutic target for DKD.

Opportunities to sustain a multi-country quality of care network: Lessons on the actions of four countries Bangladesh, Ethiopia, Malawi, and Uganda.

The Quality of Care Network (QCN) is a global initiative that was established in 2017 under the leadership of WHO in 11 low-and- middle income countries to improve maternal, newborn, and child health. The vision was that the Quality of Care Network would be embedded within member countries and continued beyond the initial implementation period: that the Network would be sustained. This paper investigated the experience of actions taken to sustain QCN in four Network countries (Bangladesh, Ethiopia, Malawi, and Uganda) and reports on lessons learned. Multiple iterative rounds of data collection were conducted through qualitative interviews with global and national stakeholders, and non-participatory observation of health facilities and meetings. A total of 241 interviews, 42 facility and four meeting observations were carried out. We conducted a thematic analysis of all data using a framework approach that defined six critical actions that can be taken to promote sustainability. The analysis revealed that these critical actions were present with varying degrees in each of the four countries. Although vulnerabilities were observed, there was good evidence to support that actions were taken to institutionalize the innovation within the health system, to motivate micro-level actors, plan opportunities for reflection and adaptation from the outset, and to support strong government ownership. Two actions were largely absent and weakened confidence in future sustainability: managing financial uncertainties and fostering community ownership. Evidence from four countries suggested that the QCN model would not be sustained in its original format, largely because of financial vulnerability and insufficient time to embed the innovation at the sub-national level. But especially the efforts made to institutionalize the innovation in existing systems meant that some characteristics of QCN may be carried forward within broader government quality improvement initiatives.

Individual interactions in a multi-country implementation-focused quality of care network for maternal, newborn and child health: A social network analysis.

The Network for Improving Quality of Care for Maternal, Newborn and Child Health (QCN) was established to build a cross-country platform for joint-learning around quality improvement implementation approaches to reduce mortality. This paper describes and explores the structure of the QCN in four countries and at global level. Using Social Network Analysis (SNA), this cross-sectional study maps the QCN networks at global level and in four countries (Bangladesh, Ethiopia, Malawi and Uganda) and assesses the interactions among actors involved. A pre-tested closed-ended structured questionnaire was completed by 303 key actors in early 2022 following purposeful and snowballing sampling. Data were entered into an online survey tool, and exported into Microsoft Excel for data management and analysis. This study received ethical approval as part of a broader evaluation. The SNA identified 566 actors across the four countries and at global level. Bangladesh, Malawi and Uganda had multiple-hub networks signifying multiple clusters of actors reflecting facility or district networks, whereas the network in Ethiopia and at global level had more centralized networks. There were some common features across the country networks, such as low overall density of the network, engagement of actors at all levels of the system, membership of related committees identified as the primary role of actors, and interactions spanning all types (learning, action and information sharing). The most connected actors were facility level actors in all countries except Ethiopia, which had mostly national level actors. The results reveal the uniqueness and complexity of each network assessed in the evaluation. They also affirm the broader qualitative evaluation assessing the nature of these networks, including composition and leadership. Gaps in communication between members of the network and limited interactions of actors between countries and with global level actors signal opportunities to strengthen QCN.

Improving access to diabetes care for children: An evaluation of the changing diabetes in children project in Kenya and Bangladesh.

BACKGROUND: The changing diabetes in children (CDiC) project is a public-private partnership implemented by Novo Nordisk, to improve access to diabetes care for children with type 1 diabetes. This paper outlines the findings from an evaluation of CDiC in Bangladesh and Kenya, assessing whether CDiC has achieved its objectives in each of six core program components. RESEARCH DESIGN AND METHODS: The Rapid Assessment Protocol for Insulin Access (RAPIA) framework was used to analyze the path of insulin provision and the healthcare infrastructure in place for diagnosis and treatment of diabetes. The RAPIA facilitates a mixed-methods approach to multiple levels of data collection and systems analysis. Information is collected through questionnaires, in-depth interviews and focus group discussions, site visits, and document reviews, engaging a wide range of stakeholders (N = 127). All transcripts were analyzed thematically. RESULTS: The CDiC scheme provides a stable supply of free insulin to children in implementing facilities in Kenya and Bangladesh, and offers a comprehensive package of pediatric diabetes care. However, some elements of the CDiC program were not functioning as originally intended. Transitions away from donor funding and toward government ownership are a particular concern, as patients may incur additional treatment costs, while services offered may be reduced. Additionally, despite subsidized treatment costs, indirect costs remain a substantial barrier to care. CONCLUSION: Public-private partnerships such as the CDiC program can improve access to life-saving medicines. However, our analysis found several limitations, including concerns over the sustainability of the project in both countries. Any program reliant on external funding and delivered in a high-turnover staffing environment will be vulnerable to sustainability concerns.

Attenuation of diabetic kidney injury in DPP4-deficient rats; role of GLP-1 on the suppression of AGE formation by inducing glyoxalase 1.

Dipeptidyl peptidase 4 (DPP4) inactivates incretin hormone glucagon-like peptide-1. DPP4 inhibitors may exert beneficial effects on diabetic nephropathy (DN) independently of glycemic control; however, the mechanisms underlying are not fully understood. Here, we investigated the mechanisms of the beneficial effects of DPP4 inhibition on DN using DPP4-deficient (DPP4-def) rats and rat mesangial cells.Blood glucose and HbA1c significantly increased by streptozotocin (STZ) and no differences were between WT-STZ and DPP4-def-STZ. The albumin level in urine decreased significantly and the albumin/creatinine ratio decreased slightly in DPP4-def-STZ. The glomerular volume in DPP4-def-STZ significantly decreased compared with that of WT-STZ. Advanced glycation end products formation, receptor for AGE (RAGE) protein expression, and its downstream inflammatory cytokines and fibrotic factors in kidney tissue, were significantly suppressed in the DPP4-def-STZ compared to the WT-STZ with increasing glyoxalase-1 (GLO-1) expression responsible for the detoxification of methylglyoxal (MGO). In vitro, exendin-4 suppressed MGO-induced AGEs production by enhancing the expression of GLO-1 and nuclear factor-erythroid 2 p45 subunit-related factor 2, resulting in decreasing pro-inflammatory cytokine levels. This effect was abolished by GLO-1 siRNA.Our data suggest that endogenously increased GLP-1 in DPP4-deficient rats contributes to the attenuation of DN partially by regulating AGEs formation via upregulation of GLO-1 expression.

Synthesis and Functionalization of Porous Zr-Diaminostilbenedicarboxylate Metal-Organic Framework for Storage and Stable Delivery of Ibuprofen.

A stable porous metal-organic framework (MOF), Zr-diaminostilbenedicarboxylate (Zr-DASDCA), was synthesized and modified with oxalyl chloride (OC) or terephthaloyl chloride (TC) to introduce various functional groups onto the Zr-DASDCA. Both pristine and functionalized Zr-DASDCAs, together with activated carbon, were used as a potential carrier for ibuprofen (IBU) storage and delivery. Zr-DASDCAs, especially the modified ones (OC-Zr-DASDCA and TC-Zr-DASDCA), showed competitive results in IBU delivery. Specifically, the release rate in phosphate-buffered saline solution at pH 7.4 was nearly constant (R 2 ≈ 0.98) for up to 10 days, which would be very effective in IBU dosing to the human body. Moreover, the release rate could be controlled by changing the pH of the releasing solution. The rate of IBU release from both pristine and modified Zr-DASDCAs at pH 7.4 and 3.0 was also explained with a few interactions such as H-bonding and electrostatic repulsion, together with the relative pore size of the Zr-DASDCAs. Therefore, the results suggested that functionalization of MOFs via postsynthetic modification, especially with OC and TC, to introduce various functional groups onto MOFs is an effective approach to not only reducing the release rate of IBU but also inducing a constant release of IBU for as long as 10 days.

Adsorptive removal of nitroimidazole antibiotics from water using porous carbons derived from melamine-loaded MAF-6.

Nitrogen-containing carbons were obtained via pyrolysis of melamine-loaded metal azolate frameworks (named mela@MAF-6), a sub-class of metal organic frameworks. The porosity and defect concentration of the obtained carbons (named as CDM@M-6) were dependent on the quantity of melamine loaded in the mela@MAF-6. The CDM@M-6 s were applied for the adsorptive removal of nitroimidazole antibiotics (NIABs) from water; the performance of CDM@M-6, particularly CDM(0.25)@M-6, was outstanding for the elimination of NIABs such as dimetridazole (DMZ), metronidazole (MNZ), and menidazole (MZ)) from water. The adsorption capacity of CDM(0.25)@M-6 for DMZ, MNZ, and MZ was higher than that of any adsorbent reported so far. The highest adsorptive performance of CDM(0.25)@M-6 for DMZ (Q0: 621 mg/g) and MNZ (Q0: 702 mg/g) was explained by hydrogen bonding, where CDM@M-6 and DMZ/MNZ acted as a H-donor and H-acceptor, respectively. In addition, CDM(0.25)@M-6 could be regenerated via ethanol washing and reused for next cycles without any severe decrease in performance. Therefore, CDM@M-6 is recommended as a suitable adsorbent for the elimination of NIABs from water.

Lysophosphatidic acid receptor 1 inhibitor, AM095, attenuates diabetic nephropathy in mice by downregulation of TLR4/NF-κB signaling and NADPH oxidase.

Diabetic nephropathy (DN) is one of the major long-term complications of diabetes. Lysophosphatidic acid (LPA) signaling has been implicated in renal fibrosis. In our previous study, we found that the LPA receptor 1/3 (LPAR1/3) antagonist, ki16425, protected against DN in diabetic db/db mice. Here, we investigated the effects of a specific pharmacological inhibitor of LPA receptor 1 (LPA1), AM095, on DN in streptozotocin (STZ)-induced diabetic mice to exclude a possible contribution of LPAR3 inhibition. AM095 treatment significantly reduced albuminuria and the albumin to creatinine ratio and significantly decreased the glomerular volume and tuft area in the treated group compared with the STZ-vehicle group. In the kidney of STZ-induced diabetic mice, the expression of LPAR1 mRNA and protein was positively correlated with oxidative stress. AM095 treatment inhibited LPA-induced reactive oxygen species production and NADPH oxidase expression as well as LPA-induced toll like receptor 4 (TLR4) expression in mesangial cells and in the kidney of STZ-induced diabetic mice. In addition, AM095 treatment suppressed LPA-induced pro-inflammatory cytokines and fibrotic factors expression through downregulation of phosphorylated NFκBp65 and c-Jun N-terminal kinases (JNK) in vitro and in the kidney of STZ-induced diabetic mice. Pharmacological or siRNA inhibition of TLR4 and NADPH oxidase mimicked the effects of AM095 in vitro. In conclusion, AM095 is effective in preventing the pathogenesis of DN by inhibiting TLR4/NF-κB and the NADPH oxidase system, consequently inhibiting the inflammatory signaling cascade in renal tissue of diabetic mice, suggesting that LPAR1 antagonism might provide a potential therapeutic target for DN.

Screening of Baccaurea ramiflora (Lour.) extracts for cytotoxic, analgesic, anti-inflammatory, neuropharmacological and antidiarrheal activities.

BACKGROUND: It has been observed that the various part of Baccaurea ramiflora plant is used in rheumatoid arthritis, cellulitis, abscesses, constipation and injuries. This plant also has anticholinergic, hypolipidemic, hypoglycemic, antiviral, antioxidant, diuretic and cytotoxic activities. The present studyaimed to assess the cytotoxic, analgesic, anti-inflammatory, CNS depressant and antidiarrheal activities of methanol extract of Baccaurea ramiflora pulp and seeds in mice model. METHODS: The cytotoxic activity was determined by brine shrimp lethality bioassay; anti-nociceptive activity was determined by acetic acid-induced writhing, formalin- induced licking and biting, and tail immersion methods. The anti-inflammatory, CNS depressant and anti-diarrheal activities were assessed by carrageenan-induced hind paw edema, the open field and hole cross tests, and castor oil-induced diarrheal methods, respectively. The data were analyzed by one way ANOVA (analysis of variance) followed by Dunnett's test. RESULTS: In brine shrimp lethality bioassay, the LC50 values of the methanol extracts of Baccaurea ramiflora pulp and seed were 40 µg/mL and 10 µg/mL, respectively. Our investigation showed that Baccaurea ramiflora pulp and seed extracts (200 mg/kg) inhibited acetic acid induced pain 67.51 and 66.08%, respectively (p < 0.05) that was strongly comparable with that of Ibuprofen (72%) (p < 0.05). The Baccaurea ramiflora pulp and seed extracts (200 mg/kg) significantly (p < 0.05) reduced 58.5 and 53.4 in early and 80.8%, 76.61% in late phase of formalin-induced licking and biting. At 60 and 90 min pulp and seed extracts (200 mg/kg) inhibited nociception of thermal stimulus 50.16 and 62.4%, respectively (p < 0.05) which was comparable with the standard (morphine, 75.9% inhibition). The pulp and seed extracts (200 mg/kg) significantly (p < 0.05) reduced inflammation (42.00 and 55.22%, respectively) in carrageenan-induced hind paw edema and defecations (59.7 and 63.03%, respectively) in castor oil induced diarrhea. Both the extracts showed high sedative activity at 30, 60, 90, and 120 min. CONCLUSION: Our investigation demonstrated significant cytotoxic, analgesic, anti-inflammatory, CNS depressant and antidiarrheal activities of methanol extract of Baccaurea ramiflora pulp and seeds (200 mg/kg).

Adsorptive removal of indole and quinoline from model fuel using adenine-grafted metal-organic frameworks.

A highly porous metal-organic framework (MOF), MIL-101, was modified for the first time with the nucleobase adenine (Ade) by grafting onto the MOF. The Ade-grafted MOF, Ade-MIL-101, was further protonated to obtain P-Ade-MIL-101, and these MOFs were utilized to remove nitrogen-containing compounds (NCCs) (such as indole (IND) and quinoline (QUI)) from a model fuel by adsorption. These functionalized MOFs exhibited remarkable adsorption performance for NCCs compared with that shown by commercial activated carbon (AC) and pristine MIL-101, even though the porosities of the functionalized-MOFs were lower than that of pristine MIL-101. P-Ade-MIL-101 has 12.0 and 10.8 times capacity to that of AC for IND and QUI adsorption, respectively; its adsorption performance was competitive with that of other reported adsorbents. The remarkable adsorption of IND and QUI by Ade-MIL-101 was attributed to H-bonding. H-bonding combined with cation-π interactions was proposed as the mechanism for the removal of IND by P-Ade-MIL-101, whereas acid-base interactions were thought to be responsible for QUI adsorption by P-Ade-MIL-101. Moreover, P-Ade-MIL-101 can be regenerated without any severe degradation and used for successive adsorptions. Therefore, P-Ade-MIL-101 was recommended as an effective adsorbent for fuel purification by adsorptive removal of NCCs.

Adsorption of organic arsenic acids from water over functionalized metal-organic frameworks.

Organic arsenic acids (OAAs) are regarded as water pollutants because of their toxicity and considerable solubility in water. Adsorption of OAAs such as phenylarsonic acid (PAA) and p-arsanilic acid (ASA) from water was investigated over functionalized (with OH groups) metal-organic framework (MOF, MIL-101), as well as over pristine MIL-101 and commercial activated carbon. The highly porous MIL-101 bearing three hydroxyl groups (MIL-101(OH)3) exhibited remarkable PAA and ASA adsorption capacities. Based on the effects of pH on PAA and ASA adsorption, hydrogen bonding was suggested as a plausible mechanism of OAA adsorption. Importantly, OAAs and MIL-101(OH)3 can be viewed as hydrogen-bond acceptors and donors, respectively. Moreover, MIL-101(OH)3 could be regenerated by acidic ethanol treatment, being a promising adsorbent for the removal of PAA and ASA from water.

Nitrogen-Doped Porous Carbons from Ionic Liquids@MOF: Remarkable Adsorbents for Both Aqueous and Nonaqueous Media.

Porous carbons were prepared from a metal-organic framework (MOF, named ZIF-8), with or without modification, via high-temperature pyrolysis. Porous carbons with high nitrogen content were obtained from the calcination of MOF after introducing an ionic liquid (IL) (IL@MOF) via the ship-in-bottle method. The MOF-derived carbons (MDCs) and IL@MOF-derived carbons (IMDCs) were characterized using various techniques and used for liquid-phase adsorptions in both water and hydrocarbon to understand the possible applications in purification of water and fuel, respectively. Adsorptive performances for the removal of organic contaminants, atrazine (ATZ), diuron, and diclofenac, were remarkably enhanced with the modification/conversion of MOFs to MDC and IMDC. For example, in the case of ATZ adsorption, the maximum adsorption capacity of IMDC (Q0 = 208 m2/g) was much higher than that of activated carbon (AC, Q0 = 60 m2/g) and MDC (Q0 = 168 m2/g) and was found to be the highest among the reported results so far. The results of adsorptive denitrogenation and desulfurization of fuel were similar to that of water purification. The IMDCs are very useful in the adsorptions since these new carbons showed remarkable performances in both the aqueous and nonaqueous phases. These results are very meaningful because hydrophobic and hydrophilic adsorbents are usually required for the adsorptions in the water and fuel phases, respectively. Moreover, a plausible mechanism, H-bonding, was also suggested to explain the remarkable performance of the IMDCs in the adsorptions. Therefore, the IMDCs derived from IL@MOF might have various applications, especially in adsorptions, based on high porosity, mesoporosity, doped nitrogen, and functional groups.

Adsorption of benzotriazole and benzimidazole from water over a Co-based metal azolate framework MAF-5(Co).

Benzotriazole (BTA) and benzimidazole (BZI) are regarded as water pollutants because of their extensive uses in industry and appreciable water solubility. The adsorption of both BTA and BZI from water over a newly synthesized metal-organic framework, MAF-5(Co), was investigated and compared with zeolitic imidazole frameworks (ZIFs), such as ZIF-8(Zn) and ZIF-67(Co), as well as commercial activated carbon. MAF-5(Co) had the highest adsorption capacities for both BTA and BZI. The maximum adsorption capacities of MAF-5(Co) for BTA and BZI were 389 and 175mgg-1, respectively. Hydrophobic and π-π interactions between the aromatic adsorbate BTA and MAF-5(Co) were suggested as a plausible mechanism. Based on the zeta potential of MAF-5(Co) and effects of pH on the BTA adsorption, electrostatic interactions between the MAF-5(Co) and BTA species might also affect the adsorption of BTA over MAF-5(Co). MAF-5(Co) can be recycled for adsorptive removal of BTA by simple ethanol washing. Therefore, MAF-5(Co) is suggested as a promising adsorbent for the removal of BTA and BZI from water.

Evaluation of analgesic, anti-inflammatory, thrombolytic and hepatoprotective activities of roots of Premna esculenta (Roxb).

BACKGROUND: The objective of this study was to investigate the antinociceptive, anti-inflammatory, thrombolytic and hepatoprotective activities of root extracts of Premna esculenta (family: Verbenaceae). METHODS: The analgesic activity was evaluated using the acetic-acid-induced writhing test in mice and radiant heat tail-flick method in rats. The anti-inflammatory activity was investigated by carrageenan-induced rat's paw edema, while the thrombolytic activity was evaluated by in vitro clot lysis model. The hepatoprotective activity was investigated against carbon-tetrachloride-induced liver damage in rats. RESULTS: In acetic-acid-induced writhing test, chloroform and ethyl acetate fraction of ethanolic extract at a dose of 200 mg/kg showed a significant (p<0.001) reduction in the number of writhes with 85.96% and 61.98% of inhibition, respectively. In radiant heat tail-flick method, the ethanolic extract produced 88.49% (p<0.001) elongation of tail-flicking time at 90 min after oral administration at same dose level. In the carrageenan-induced edema test, the ethanolic extract at a dose of 200 mg/kg showed a significant inhibition of paw edema with 22.68% and 17.24% inhibition after the first and third hours of the study period, respectively. In clot lysis model, the ethanolic extract at 5 mg/mL induced a significant clot lysis activity (37.69%, p<0.001). Oral administration of ethanolic extract at the dose of 400 mg/kg/day for 7 days significantly (p<0.001) reduced the elevated levels of serum glutamic pyruvic transaminase, serum glutamyl oxaloacetate transaminase and alkaline phosphatase compared to the CCl4-treated control group. CONCLUSIONS: The results of the study demonstrated the antinociceptive, anti-inflammatory, thrombolytic and hepatoprotective activities of roots of P. esculenta.

Biochemical alterations and liver toxicity analysis with pioglitazone in healthy subjects.

Pioglitazone, a member of the thiazolidinediones, is a potent, highly selective agonist for peroxisome proliferator-activated receptor gamma and is an excellent insulin sensitizer used in treating type 2 diabetes mellitus. The present study investigated the effect of pioglitazone on glucose, total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol and high density lipoprotein (HDL) cholesterol, total proteins, albumin (ALB), alanine transaminase (ALT), and aspartate transaminase (AST) levels in 20 healthy Bengali male volunteers in a randomized, placebo-controlled study. Blood samples were collected before and 0.5-24.0 hours after a single oral dose of a 30 mg pioglitazone tablet. Plasma pioglitazone level was determined using a validated method of reverse-phase binary high-performance liquid chromatography. Blood lipid profile and levels of glucose, ALT, and AST were estimated using enzyme assay kits, plasma protein level was estimated by the biuret method, and plasma ALB level was determined colorimetrically. No significant change in blood glucose, total proteins, total cholesterol, triglyceride, HDL, and LDL levels was observed over the 24-hour assessment period, indicating no plasma biochemical alterations. There were no significant differences between baseline and 24-hour values of ALB, ALT, and AST levels, indicating a lack of liver toxicity. Our results indicate that a single dose of 30 mg of pioglitazone has no hypoglycemic or hypolipidemic effect or liver toxicity within 24 hours of treatment among healthy Bengali males.