Cognitive performance in aged rats is associated with differences in distinctive neuronal populations in the ventral tegmental area and altered synaptic plasticity in the hippocampus.

Introduction: Deterioration of cognitive functions is commonly associated with aging, although there is wide variation in the onset and manifestation. Albeit heterogeneity in age-related cognitive decline has been studied at the cellular and molecular level, there is poor evidence for electrophysiological correlates. The aim of the current study was to address the electrophysiological basis of heterogeneity of cognitive functions in cognitively Inferior and Superior old (19-20 months) rats in the ventral tegmental area (VTA) and the hippocampus, having Young (12 weeks) rats as a control. The midbrain VTA operates as a hub amidst affective and cognitive facets, processing sensory inputs related to motivated behaviours and hippocampal memory. Increasing evidence shows direct dopaminergic and non-dopaminergic input from the VTA to the hippocampus. Methods: Aged Superior and Inferior male rats were selected from a cohort of 88 animals based on their performance in a spatial learning and memory task. Using in vivo single-cell recording in the VTA, we examined the electrical activity of different neuronal populations (putative dopaminergic, glutamatergic and GABAergic neurons). In the same animals, basal synaptic transmission and synaptic plasticity were examined in hippocampal slices. Results: Electrophysiological recordings from the VTA and hippocampus showed alterations associated with aging per se, together with differences specifically linked to the cognitive status of aged animals. In particular, the bursting activity of dopamine neurons was lower, while the firing frequency of glutamatergic neurons was higher in VTA of Inferior old rats. The response to high-frequency stimulation in hippocampal slices also discriminated between Superior and Inferior aged animals. Discussion: This study provides new insight into electrophysiological information underlying compromised cerebral ageing. Further understanding of brain senescence, possibly related to neurocognitive decline, will help develop new strategies towards the preservation of a high quality of life.

Generation and Characterization of a Human Neuronal In Vitro Model for Rett Syndrome Using a Direct Reprogramming Method.

Rett Syndrome (RTT) is a severe neurodevelopmental disorder, afflicting 1 in 10,000 female births. It is caused by mutations in the X-linked methyl-CpG-binding protein gene (MECP2), which encodes for the global transcriptional regulator methyl CpG binding protein 2 (MeCP2). As human brain samples of RTT patients are scarce and cannot be used for downstream studies, there is a pressing need for in vitro modeling of pathological neuronal changes. In this study, we use a direct reprogramming method for the generation of neuronal cells from MeCP2-deficient and wild-type human dermal fibroblasts using two episomal plasmids encoding the transcription factors SOX2 and PAX6. We demonstrated that the obtained neurons exhibit a typical neuronal morphology and express the appropriate marker proteins. RNA-sequencing confirmed neuronal identity of the obtained MeCP2-deficient and wild-type neurons. Furthermore, these MeCP2-deficient neurons reflect the pathophysiology of RTT in vitro, with diminished dendritic arborization and hyperacetylation of histone H3 and H4. Treatment with MeCP2, tethered to the cell penetrating peptide TAT, ameliorated hyperacetylation of H4K16 in MeCP2-deficient neurons, which strengthens the RTT relevance of this cell model. We generated a neuronal model based on direct reprogramming derived from patient fibroblasts, providing a powerful tool to study disease mechanisms and investigating novel treatment options for RTT.

Design, synthesis, and lead optimization of piperazinyl-pyrimidine analogues as potent small molecules targeting the viral capping machinery of Chikungunya virus.

The worldwide re-emerge of the Chikungunya virus (CHIKV), the high morbidity associated with it, and the lack of an available vaccine or antiviral treatment make the development of a potent CHIKV-inhibitor highly desirable. Therefore, an extensive lead optimization was performed based on the previously reported CHVB compound 1b and the reported synthesis route was optimized - improving the overall yield in remarkably shorter synthesis and work-up time. Hundred analogues were designed, synthesized, and investigated for their antiviral activity, physiochemistry, and toxicological profile. An extensive structure-activity relationship study (SAR) was performed, which focused mainly on the combination of scaffold changes and revealed the key chemical features for potent anti-CHIKV inhibition. Further, a thorough ADMET investigation of the compounds was carried out: the compounds were screened for their aqueous solubility, lipophilicity, their toxicity in CaCo-2 cells, and possible hERG channel interactions. Additionally, 55 analogues were assessed for their metabolic stability in human liver microsomes (HLMs), leading to a structure-metabolism relationship study (SMR). The compounds showed an excellent safety profile, favourable physicochemical characteristics, and the required metabolic stability. A cross-resistance study confirmed the viral capping machinery (nsP1) to be the viral target of these compounds. This study identified 31b and 34 as potent, safe, and stable lead compounds for further development as selective CHIKV inhibitors. Finally, the collected insight led to a successful scaffold hop (64b) for future antiviral research studies.

Enhancement of Radiation Sensitivity by Cathepsin L Suppression in Colon Carcinoma Cells.

Cancer is one of the main causes of death globally. Radiotherapy/Radiation therapy (RT) is one of the most common and effective cancer treatments. RT utilizes high-energy radiation to damage the DNA of cancer cells, leading to their death or impairing their proliferation. However, radiation resistance remains a significant challenge in cancer treatment, limiting its efficacy. Emerging evidence suggests that cathepsin L (cath L) contributes to radiation resistance through multiple mechanisms. In this study, we investigated the role of cath L, a member of the cysteine cathepsins (caths) in radiation sensitivity, and the potential reduction in radiation resistance by using the specific cath L inhibitor (Z-FY(tBu)DMK) or by knocking out cath L with CRISPR/Cas9 in colon carcinoma cells (caco-2). Cells were treated with different doses of radiation (2, 4, 6, 8, and 10), dose rate 3 Gy/min. In addition, the study conducted protein expression analysis by western blot and immunofluorescence assay, cytotoxicity MTT, and apoptosis assays. The results demonstrated that cath L was upregulated in response to radiation treatment, compared to non-irradiated cells. In addition, inhibiting or knocking out cath L led to increased radiosensitivity in contrast to the negative control group. This may indicate a reduced ability of cancer cells to recover from radiation-induced DNA damage, resulting in enhanced cell death. These findings highlight the possibility of targeting cath L as a therapeutic strategy to enhance the effectiveness of RT. Further studies are needed to elucidate the underlying molecular mechanisms and to assess the translational implications of cath L knockout in clinical settings. Ultimately, these findings may contribute to the development of novel treatment approaches for improving outcomes of RT in cancer patients.

Proteolytic Activation of the Epithelial Sodium Channel (ENaC): Its Mechanisms and Implications.

Epithelial sodium channel (ENaC) are integral to maintaining salt and water homeostasis in various biological tissues, including the kidney, lung, and colon. They enable the selective reabsorption of sodium ions, which is a process critical for controlling blood pressure, electrolyte balance, and overall fluid volume. ENaC activity is finely controlled through proteolytic activation, a process wherein specific enzymes, or proteases, cleave ENaC subunits, resulting in channel activation and increased sodium reabsorption. This regulatory mechanism plays a pivotal role in adapting sodium transport to different physiological conditions. In this review article, we provide an in-depth exploration of the role of proteolytic activation in regulating ENaC activity. We elucidate the involvement of various proteases, including furin-like convertases, cysteine, and serine proteases, and detail the precise cleavage sites and regulatory mechanisms underlying ENaC activation by these proteases. We also discuss the physiological implications of proteolytic ENaC activation, focusing on its involvement in blood pressure regulation, pulmonary function, and intestinal sodium absorption. Understanding the mechanisms and consequences of ENaC proteolytic activation provides valuable insights into the pathophysiology of various diseases, including hypertension, pulmonary disorders, and various gastrointestinal conditions. Moreover, we discuss the potential therapeutic avenues that emerge from understanding these mechanisms, offering new possibilities for managing diseases associated with ENaC dysfunction. In summary, this review provides a comprehensive discussion of the intricate interplay between proteases and ENaC, emphasizing the significance of proteolytic activation in maintaining sodium and fluid balance in both health and disease.

The Significance of Cathepsin B in Mediating Radiation Resistance in Colon Carcinoma Cell Line (Caco-2).

Cathepsins (Caths) are lysosomal proteases that participate in various physiological and pathological processes. Accumulating evidence suggests that caths play a multifaceted role in cancer progression and radiotherapy resistance responses. Their proteolytic activity influences the tumor's response to radiation by affecting oxygenation, nutrient availability, and immune cell infiltration within the tumor microenvironment. Cathepsin-mediated DNA repair mechanisms can promote radioresistance in cancer cells, limiting the efficacy of radiotherapy. Additionally, caths have been associated with the activation of prosurvival signaling pathways, such as PI3K/Akt and NF-κB, which can confer resistance to radiation-induced cell death. However, the effectiveness of radiotherapy can be limited by intrinsic or acquired resistance mechanisms in cancer cells. In this study, the regulation and expression of cathepsin B (cath B) in the colon carcinoma cell line (caco-2) before and after exposure to radiation were investigated. Cells were exposed to escalating ionizing radiation doses (2 Gy, 4 Gy, 6 Gy, 8 Gy, and 10 Gy). Analysis of protein expression, in vitro labeling using activity-based probes DCG04, and cath B pull-down revealed a radiation-induced up-regulation of cathepsin B in a dose-independent manner. Proteolytic inhibition of cathepsin B by cathepsin B specific inhibitor CA074 has increased the cytotoxic effect and cell death due to ionizing irradiation treatment in caco-2 cells. Similar results were also obtained after cathepsin B knockout by CRISPR CAS9. Furthermore, upon exposure to radiation treatment, the inhibition of cath B led to a significant upregulation in the expression of the proapoptotic protein BAX, while it induced a significant reduction in the expression of the antiapoptotic protein BCL-2. These results showed that cathepsin B could contribute to ionizing radiation resistance, and the abolishment of cathepsin B, either by inhibition of its proteolytic activity or expression, has increased the caco-2 cells susceptibility to ionizing irradiation.

Dose-dependent anti-hyperglycemic & anti-dyslipidemic potential of aqueous leaves extract of Typha elephantina in-vivo and in-vitro.

Diabetes mellitus is among the fundamental causes of illness and millions of deaths around the globe are directly attributed to it each year. Current antidiabetic medications often lack sustained glycemic control and carry significant risks of side effects. As a result, the use of plant-based treatments has gained popularity. In this experimental study, we evaluated the aqueous extracts (LQE) of Typha elephantina (also known as Elephant grass) leaves collected from freshwater marshes, for their potential anti-hyperglycemic and anti-hyperlipidemic antioxidant effects in healthy streptozotocin caused diabetic-mice. We employed glucose adsorption tests at different glucose levels and glucose diffusion tests to assess the in-vitro antidiabetic action of plant extract. For the in-vivo trail, we measured fasting blood glucose (FBG), glucose tolerance (GTT), as well as long-term anti-diabetic, anti-hyperlipidemic, and antioxidant activities. Our results from the glucose diffusion test indicated that the extract was highly effective at both low glucose concentrations (5 mmol L) and high glucose concentrations (100 mmol L). However, the glucose-diffusion ability reached its peaked at an excessively high dosage of the aqueous extract, suggesting a dose-related effect. Similarly, we observed that high doses of TEL.AQ extracts (400 mg/kg body weight) significantly reduced blood glucose levels in healthy mice during the glucose tolerance test (GTT) at 3 h and fasting blood glucose studies (FBG) at 6 h. Furthermore, the high-dose TEL.AQ extract effectively reduced liver-related serum markers and blood-glucose concentration (BGC) in severely chronic diabetic rats. The extract dosage also influenced lipid profile, conjugate and unconjugated bilirubin levels, cholesterol, triglycerides, HDL, and total bilirubin levels. Additionally, after administering a high extract dose, we observed considerable improvement in the liver homogenate markers CAT, POD, and SOD. In contrast, the extract at a low dosage (100 mg/kg), showed minimal, while a moderate dose (200 mg/kg), yielded promising results.

Characterizing the oncogenic importance and exploring gene-immune cells correlation of ACTB in human cancers.

After cardiovascular diseases, cancer is the second deadliest malignancy in the world. The current study was launched to investigate the diagnostic and prognostic landscape of Beta-actin (ACTB) via a multi-layered bioinformatics approach. ACTB expression was analyzed and validated via UALCAN, TIMER, GENT2, GEPIA, and HPA. ACTB promoter methylation was evaluated via MREXPRES. Furthermore, ACTB prognostic values and their correlation with cancer metastasis were explored through the KM plotter and TNMplot, respectively. Then, cBioPortal, CancerSEA, Enrichr, TIMER, MuTarget, and CDT were used to analyze ACTB-related genetic alterations, transcription factors (TFS), MicroRNAs (miRNAs), chemotherapeutic drugs, and the correlation between its expression, immune cells, and different other parameters. We found that ACTB expression was remarkably higher in 24 major human cancer tissues than the normal samples. Additionally, elevated ACTB expression was associated with poorer survival and metastasis in only liver hepatocellular carcinoma (LIHC), head and neck squamous cancer (HNSC), and lung adenocarcinoma (LUAD). This implies that ACTB plays a significant role in the development and progression of LIHC, HNSC, and LUAD. Furthermore, enrichment analysis showed that ACTB-associated genes regulate different Biological Processes (BP), Molecular Functions (MF), and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms. Moreover, ACTB up-regulation had interesting correlations with immune infiltration of CD4+ T, and CD8+ T, tumor purity, mutant genes, and a few other important parameters. At last, via this study, we also explored ACTB-associated clinically important expression regulators, including TFS, miRNAs, and different chemotherapeutic drugs. The results of the present study suggested that ACTB might be a potential candidate biomarker in LIHC, HNSC, and LUAD.

A pan-cancer analysis of HAVCR1 with a focus on diagnostic, prognostic and immunological roles in human cancers.

OBJECTIVES: Cancer is one of the most prominent causes of death world wide. Identification of novel cancer biomarkers woud help with cancer diagnosis and possible treatment. METHODS: In this study, we comprehensively studied the diagnostic, prognostic, and therapeutic values of the hepatitis A virus cellular receptor 1 (HAVCR1) gene across multiple cancers from a pan-cancer point of view via a detailed in silico approach. RESULTS: HAVCR1 expression was up-regulated in a variety of malignancies. The up-regulated HAVCR1 was closely related to the poor prognosis in patients with esophageal carcinoma (ESCA), lung adenocarcinoma (LUAD), and stomach adenocarcinoma (STAD). Moreover, DAVID analysis showed that HAVCR1, along with different other associated genes, was involved in numerous cancer-associated signaling pathways across ESCA, STAD, and LUAD. Furthermore, in these cancers, HAVCR1 was also found closely associated with some other parameters such as promoter methylation, tumor purity, level of CD8+ T immune cells, genomic alterations, and chemotherapeutic drugs. CONCLUSION: HAVCR1 was overexpressed in multiple tumors. However, the up-regulated HAVCR1 is a valuable diagnostic and prognostic biomarker as well as a therapeutic target in only ESCA, STAD, and LUAD patients.

Impact of Enniatin B and Beauvericin on Lysosomal Cathepsin B Secretion and Apoptosis Induction.

Enniatin B (ENN B) and Beauvericin (BEA) are cyclohexadepsipeptides that can be isolated from Fusarium and Beauveria bassiana, respectively. Both compounds are cytotoxic and ionophoric. In the present study, the mechanism of cell death induced by these compounds was investigated. Epidermal carcinoma-derived cell line KB-3-1 cells were treated with different concentrations of these compounds. The extracellular secretion of cathepsin B increased in a concentration-dependent manner, and the lysosomal staining by lysotracker red was reduced upon the treatment with any of the compounds. However, the extracellular secretion of cathepsin L and cathepsin D were not affected. Inhibition of cathepsin B with specific inhibitor CA074 significantly reduced the cytotoxic effect of both compounds, while inhibition of cathepsin D or cathepsin L did not influence the cytotoxic activities of both compounds. In vitro labelling of lysosomal cysteine cathepsins with Ethyl (2S, 3S)-epoxysuccinate-Leu-Tyr-Acp-Lys (Biotin)-NH2 (DCG04) was not affected in case of cathepsin L upon the treatment with both compounds, while it was significantly reduced in case of cathepsin B. In conclusion, ENN B and BEA increase lysosomal Ph, which inhibits delivery of cathepsin B from Golgi to lysosomes, thereby inducing cathepsin B release in cytosol, which activates caspases and hence the apoptotic pathway.

Novel insight on chemo-specific detection of toxic environmental chromium residues existing as recalcitrant Cr(III)-carboxyl complexes using plasmonic silver nanoplatform bi-functionalized with citrate and PVP.

Chromium (Cr) is a toxic environmental pollutant that majorly exists in trivalent and hexavalent forms. Though Cr(VI) is more dangerous than Cr(III), the trivalent Cr forms complexes with environmentally-available organic molecules. This makes them potentially harmful and difficult to detect. In this study, we have designed an ultrasensitive plasmonic nanosensor using citrate and PVP functionalized Ag nanoparticles (Ag-citrate-PVPNPs) for the detection of trivalent chromium organic complexes such as Cr(III)-EDTA (Cr-E), Cr(III)-acetate (Cr-A), Cr(III)-citrate (Cr-C) and Cr(III)-tartrate (Cr-T). The nanoparticles (NPs) were structurally characterized by XRD, SEM, HRTEM, SAED, EDX and elemental mapping. The citrate and PVP molecules played a vital role in the detection mechanism and stability of the sensor. Upon detection, the yellow-colored Ag-citrate-PVP NPs turned into different shades of brown depending on the type of the Cr complex and concentration. It was accompanied by diminishing and/or shifting UV-Visible absorbance peaks due to the aggregation of Ag-citrate-PVP NPs. Further, a linear relationship was observed between absorbance reduction and analyte concentration. The selectivity tests showed that the sensor was non-functional to other metal ions and inorganic anions. The sensor was optimized using pH and temperature studies. The mechanism of detection was elucidated with the help of characterization techniques such as Raman spectroscopy, FTIR, XPS and UV-visible spectrophotometer. The limit of detection (LOD) was found to be 3.29, 4.87, 1.76 and 1.79 nM for Cr-E, Cr-A, Cr-C and Cr-T complexes respectively. This study provides a rapid and sensitive approach for the detection of multiple Cr(III)-organic complexes present in an aqueous solution.

Evidence of Guanidines Potential against Leishmania (Viannia) braziliensis: Exploring In Vitro Effectiveness, Toxicities and of Innate Immunity Response Effects.

Leishmaniasis is a complex group of infectious and parasitic diseases that afflict many thousands of individuals across five continents. Leishmaniasis treatment remains a challenge because it relies on drugsknown for their high toxicity and limited efficacy, making itimperative to identify new molecules that offer greater effectiveness and safety. This study sought to explore the impact of seven synthetic guanidine derivatives (LQOF-G1, LQOF-G2, LQOF-G6, LQOF-G7, LQOF-G32, LQOF-G35 and LQOF-G36) onthe parasite Leishmania (Viannia) braziliensis and in vitro macrophage infection by this parasite, as well as cytotoxic approaches in vitro models of mammalian host cells and tissues. The synthesized compounds showed purity ≥ 99.65% and effectively inhibited parasite growth. LQOF-G1 proved the most potent, yielding the best half-maximal inhibitory concentration (IC50) values against promastigotes (4.62 µmol/L), axenic amastigotes (4.27 µmol/L), and intracellular amastigotes (3.65 µmol/L). Notably, the antileishmanial activity of LQOF-G1, LQOF-G2, and LQOF-G6 was related to immunomodulatory effects, evidenced by alterations in TNF-α, IL-12, IL-10, nitric oxide (NO), and reactive oxygen species (ROS) levels in the supernatant of culture macrophages infected with L. (V.) braziliensis and coincubated with these compounds. LQOF-G2 and LQOF-G36 compounds exhibited vasodilator and spasmolytic effects at higher concentrations (≥100 µmol/L). Generally, LQOF-G1, LQOF-G2, and LQOF-G32 compounds were found to be nontoxic to assessed organs and cells. No toxic effects were observed in human cell lines, such as HEK-293, CaCo-2 and A549, at concentrations ≥ 500 µmol/L. Collectively, data have shown unequivocal evidence of the effectiveness of these compounds against L. (V.) braziliensis parasite, one of the causative agents of Tegumentary Leishmaniasis and Mucocutaneous Leishmaniasis in America.

Novel Selective and Low-Toxic Inhibitor of LmCPB2.8ΔCTE (CPB) One Important Cysteine Protease for Leishmania Virulence.

Leishmaniasis is a highly prevalent, yet neglected disease caused by protozoan parasites of the genus Leishmania. In the search for newer, safer, and more effective antileishmanial compounds, we herein present a study of the mode of action in addition to a detailed structural and biological characterization of LQOF-G6 [N-benzoyl-N'-benzyl-N″-(4-tertbutylphenyl)guanidine]. X-ray crystallography and extensive NMR experiments revealed that LQOF-G6 nearly exclusively adopts the Z conformation stabilized by an intramolecular hydrogen bond. The investigated guanidine showed selective inhibitory activity on Leishmania major cysteine protease LmCPB2.8ΔCTE (CPB) with ~73% inhibition and an IC50-CPB of 6.0 µM. This compound did not show any activity against the mammalian homologues cathepsin L and B. LQOF-G6 has been found to be nontoxic toward both organs and several cell lines, and no signs of hepatotoxicity or nephrotoxicity were observed from the analysis of biochemical clinical plasma markers in the treated mice. Docking simulations and experimental NMR measurements showed a clear contribution of the conformational parameters to the strength of the binding in the active site of the enzyme, and thus fit the differences in the inhibition values of LQOF-G6 compared to the other guanidines. Furthermore, the resulting data render LQOF-G6 suitable for further development as an antileishmanial drug.

Decoding signal transducer and activator of transcription 1 across various cancers through data mining and integrative analysis.

OBJECTIVES: Using different online available databases and Bioinformatics tools, we extensively studied the role STAT1 across different cancers. METHODS: STAT1 mRNA, protein expression, and promoter methylation were analyzed and validated using UALCAN, GENT2, Human Protein Atlas (HPA), and MEXPRESS. Furthermore, the potential prognostic values were evaluated through KM plotter. Then, cBioPortal was utilized to examine the STAT1-related genetic mutations, while pathway enrichment analysis was performed using DAVID. To identify STAT1 targeted microRNAs (miRNAs) and transcription factors (TFs) we used Enricher. Moreover, a correlational analysis between STAT1 expression tumor purity and CD8+ T immune cells and a gene-drug interaction network analysis was performed using TIMER, CTD, and Cytoscape. RESULTS: In 23 major human cancers, STAT1 expression was notably up-regulated relative to corresponding controls. As well, the elevated expression of STAT1 was exclusively found to be associated with the reduced overall survival (OS) of Esophageal Carcinoma (ESCA), Kidney Renal Clear Cell Carcinoma (KIRC), and Lung adenocarcinoma (LUAD) patients. This implies that STAT1 plays a significant role in the development and progression of these three cancers. Further pathway analysis indicated that STAT1 enriched genes were involved in six critical pathways, while a few interesting correlations were also documented between STAT1 expression and promoter methylation level, tumor purity, CD8+ T immune cells infiltration, and genetic alteration. In addition, we have also predicted a few miRNAs, TFs, and chemotherapeutic drugs that could regulate the STAT1 expression. CONCLUSION: The current study revealed the shared oncogenic, diagnostic, and prognostic role of STAT1 in ESCA, KIRC, and LUAD.

Green synthesis of two-electron centre based ZnO/NiCo2S4 QDs-OVs using Punica granatum fruit peel extract for an exceptional visible light photocatalytic degradation of doxycycline and ciprofloxacin.

Biosynthesis of nanomaterials using plant extract makes them attractive in the field of photocatalysis as they are environmental friendly. The current study focused on the biosynthesis of ZnO/NiCo2S4 QDs (NCs) using Punica granatum fruit peel extract as the reducing agent. The nanomaterials were characterized with XRD, FTIR, Raman, SEM, TEM, UV-vis DRS, BET, PL, EIS, and ESR analysis and were used for photocatalytic degradation of doxycycline (DOX) and ciprofloxacin (CIP). The bandgap of ZnO is 3.2 eV, and the decoration of NiCo2S4 QDs aids in narrowing the bandgap (2.8 eV), making the NCs visible light active. The fabricated NCs achieved 99 and 89% degradation of DOX and CIP respectively. The photocatalytic efficiency of ZnO/NiCo2S4 QDs was much higher compared to individual ZnO and NiCo2S4 QDs. The half-life period of DOX and CIP were evaluated to be 58 and 152 min respectively. The percentage of TOC removal in the photodegraded product of DOX and CIP was estimated to be 99 and 89% respectively, indicating the mineralization of the compounds. The enhanced photocatalytic efficiency of the NCs was attributed to the narrowed visible light active bandgap, synergistic charge transfer across the interface, and lower charge recombination. The intermediates formed during the photocatalytic degradation of DOX and CIP were analyzed using GC-MS/MS analysis, and the photodegradation pathway was elucidated. Also, the toxicity of the intermediates was computationally analyzed using ECOSAR software. The fabricated ZnO/NiCo2S4 QDs have excellent stability and reusability, confirmed by XRD and XPS analysis. The reusable efficiency of the NCs for the photocatalytic degradation of DOX and CIP were 98.93, and 99.4% respectively. Thus, the biologically fabricated NCs are shown to be an excellent photocatalyst and have wide applications in environmental remediation.

Exercise Increases Adiponectin and Reduces Leptin Levels in Prediabetic and Diabetic Individuals: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

It is speculated that lifestyle interventions known to improve diabetic metabolic state may exert their effects via adipokines. The aim of this systematic review and meta-analysis was to evaluate the chronic effects of physical exercise on adiponectin and leptin levels in adult prediabetic and diabetic individuals. PubMed, Embase, Scopus, The Cochrane Library, clinicaltrials.gov, and WHO Clinical Trials Registry were searched for randomized controlled trials. Pooled effects of interventions were assessed as mean difference (MD) with random effects model. Sensitivity analysis was conducted to test data robustness and subgroup analysis for study heterogeneity. Twenty-two trials with 2996 individuals were included in the meta-analysis. Physical exercise increased levels of adiponectin (MD: 0.42 µg/mL; 95% confidence interval (CI), 0.23, 0.60, p < 0.00001, n = 19 trials) and reduced leptin levels (MD: -1.89 ng/mL; 95% CI, -2.64, -1.14, p < 0.00001, n = 14 trials). These results were robust and remained significant after sensitivity analysis. Study heterogeneity was generally high. As for physical exercise modalities, aerobic exercise, but not other modalities, increased adiponectin and reduced leptin levels. In conclusion, physical exercise and, specifically, aerobic exercise, leads to higher adiponectin and lower leptin levels in prediabetic and diabetic adults. However, cautious interpretation of current findings is warranted.

Erratum: Type of Manuscript Correction. Effects of Omega-3 Supplementation on Adipocytokines in Prediabetes and Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

This corrects the article on p. 101 in vol. 42, PMID: 29676540.

Effects of Omega-3 Supplementation on Adipocytokines in Prediabetes and Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The objective of this systematic review and meta-analysis was to determine the effects of omega-3 supplementation on adipocytokine levels in adult prediabetic and diabetic individuals. METHODS: We searched PubMed, Medline, EMBASE, Scopus, Web of Science, Google Scholar, Cochrane Trial Register, World Health Organization Clinical Trial Registry Platform, and Clinicaltrial.gov Registry from inception to August 1, 2017 for randomized controlled trials. Pooled effects of interventions were assessed as mean difference using random effects model. We conducted a sensitivity, publication bias and subgroup analysis. RESULTS: Fourteen studies individuals (n=685) were included in the meta-analysis. Omega-3 supplementation increased levels of adiponectin (0.48 µg/mL; 95% confidence interval [CI], 0.27 to 0.68; P<0.00001, n=10 trials), but effects disappeared after sensitivity analysis. Tumor necrosis factor α (TNF-α) levels were reduced (-1.71; 95% CI, -3.38 to -0.14; P=0.03, n=8 trials). Treatment duration shorter than 12 weeks was associated with greater reduction than longer treatment duration. Levels of other adipocytokines were not significantly affected. Publication bias could generally not be excluded. CONCLUSION: Eicosapentaenoic acid and docosahexaenoic acid supplementation may increase adiponectin and reduce TNF-α levels in this population group. However, due to overall study heterogeneity and potential publication bias, a cautious interpretation is needed.

Discovery of small molecules with vasodilating characteristics and adjustable hydrolytic behavior.

In this contribution the development of a new class of vasodilating compounds obtained by lead structure optimization is described. Three groups of compounds were synthesized and tested for their activity on various smooth muscle preparations of the guinea pig. Beside the lead compound 3a, the most interesting derivative was 1H-imidazole-1-carbothioic acid O-cyclohexyl ester hydrochloride (5b) with a good selective vasodilating potential on aorta and pulmonary artery rings (EC50 14 µM and 24 µM, respectively). Due to the properties of small molecules the hydrolysis behavior of the compounds can be easily adapted hence opening a new route in terms of duration of the agent's effect. With the aid of structure-activity relationship studies, structural motifs influencing the biological activity on isolated smooth muscle cell preparations of the synthesized compounds were proposed. The presented compounds offer good tools in identifying promising molecules as emergency therapy in myocardial infarction.

Determination of the glycosylation-pattern of the middle ear mucosa in guinea pigs.

In the present study the glycosylation pattern of the middle ear mucosa (MEM) of guinea pigs, an approved model for middle ear research, was characterized with the purpose to identify bioadhesive ligands which might prolong the contact time of drug delivery systems with the middle ear mucosa (MEM). To assess the utility of five fluorescein labeled plant lectins with different carbohydrate specificities as bioadhesive ligands, viable MEM specimens were incubated at 4°C and the lectin binding capacities were calculated from the MEM-associated relative fluorescence intensities. Among all lectins under investigation, fluorescein-labeled wheat germ agglutinin (F-WGA) emerged as the highest bioadhesive lectin. In general, the accessibility of carbohydrate moieties of the MEM followed the order: sialic acid and N-acetyl-d-glucosamine (WGA)>>mannose and galactosamine (Lensculinaris agglutinin)>N-acetyl-d-glucosamine (Solanumtuberosum agglutinin)>fucose (Ulexeuropaeus isoagglutinin I)>>terminal mannose α-(1,3)-mannose (Galanthusnivalis agglutinin). Competitive inhibition studies with the corresponding carbohydrate revealed that F-WGA-binding was inhibited up to 90% confirming specificity of the F-WGA-MEM interaction. The cilia of the MEM were identified as F-WGA binding sites by fluorescence imaging as well as a z-stack of overlays of transmission, F-WGA- and nuclei-stained images of the MEM. Additionally, co-localisation experiments revealed that F-WGA bound to acidic mucopolysaccharides of the MEM. All in all, lectin-mediated bioadhesion to the MEM is proposed as a new concept for drug delivery to prolong the residence time of the drug in the tympanic cavity especially for successful therapy for difficult-to-treat diseases such as otitis media.