Corrigendum: Unveiling the therapeutic potential of exogenous ß-hydroxybutyrate for chronic colitis in rats: novel insights on autophagy, apoptosis, and pyroptosis.

[This corrects the article DOI: 10.3389/fphar.2023.1239025.].

Acute Kidney Injury Among COVID-19-Positive Patients Is Associated With Higher Mortality: A Single-Center Experience.

OBJECTIVES: Renal complications of COVID-19 are not yet well studied. We aimed to evaluate acute kidney injury prevalence among hospitalized patients with COVID-19 infection and explore its effect on patient outcomes. MATERIALS AND METHODS: We retrospectively evaluated 586 hospitalized patients with COVID-19. Of these patients, 267 (45.5%) developed acute kidney injury, as classified according to the Kidney Disease Improving Global Outcomes guidelines. We compared this group with 319 patients (54.5%) without acute kidney injury. RESULTS: Most patients in both study groups were men; mean age was 60.8 ± 14 versus 51.7 ± 16 years. Comorbid conditions that were substantially predominant among patients with acute kidney injury were diabetes mellitus (64% vs 42.9%), hypertension (72.6% vs 43.5%), and ischemic heart disease (25% vs 14.7%). Fever, cough, shortness of breath, and dehydration were the main presentations among patients with acute kidney injury, and patients in this group had greater prevalence of radiological findings concordant with COVID-19 (86.8% vs 59.8%). Sepsis, volume depletion, shock, arrhythmias, and acute respiratory distress syndrome were higher in patients with acute kidney injury. Anticoagulation (85% vs 59.2%), vasopressors, plasma infusions, antimicrobials, and steroids were more frequently used in patients with acute kidney injury. More patients with acute kidney injury had acute respiratory failure requiring mechanical ventilation (62.3% vs 32.9%), with higher overall mortality rate (63.2% vs 31.1%). CONCLUSIONS: We found more frequent prevalence of acute kidney injury associated with severe COVID-19 than shown in reports from Chinese, European, and North American cohorts. Patients with COVID-19 who developed acute kidney injury had risk factors such as hypertension and diabetes, greater need for mechanical ventilation, were males, and were older age. Mortality was high in this population, especially among older patients and those who developed Kidney Disease Improving Global Outcomes stage 3 disease.

Design and construction of novel pyridine-pyrimidine hybrids as selective COX-2 suppressors: anti-inflammatory potential, ulcerogenic profile, molecular modeling and ADME/Tox studies.

NSAIDs represent a mainstay in pain and inflammation suppression, and their actions are mainly based on inhibiting COX-1 and COX-2 enzymes.Due to the adverse effects of these drugs, especially on the stomach and heart, scientists efforts have been directed to manufacture selective COX-2 without cardiovascular side effects and with minimal effects on the stomach. The cardiovascular side effects are thought to be related to the chemical composition rather than mechanism of action of these drugs.Novel pyridopyrimidines, 9a-j, were prepared and their chemical structures were confirmed by NMR, mass and IR Spectra, and elemental analysis. The effect of the 9a-j compounds on COX-1 and COX-2 was assessed and it was found that 2-hydrazino-5-(4-methoxyphenyl)-7-phenyl-3H-pyrido[2,3-d)pyrimidin-4-one (9d) was the most potent COX-2 inhibitor (IC50 = 0.54 uM) compared to celecoxib (IC50 = 1.11 uM) with selectivity indices of 6.56 and 5.12, respectively.The in vivo inhibition of paw edema of novel compounds 9a-j was measured using carrageenan-induced paw edema method, and that 2-hydrazino-5-(4-methoxyphenyl)-7-phenyl-3H-pyrido[2,3-d)pyrimidin-4-one (9d) showed the best inhibitory activity in comparison with the other compounds and celecoxib.The gastroprotective effect of the potent derivatives 9d, 9e, 9f, 9 g and 9h was investigated. 2-Hydrazino-5-(4-methoxyphenyl)-7-phenyl-3H-pyrido[2,3-d)pyrimidin-4-one (9d) and 7-(chlorophenyl)-hydrazino-5-(4-methoxyphenyl)-3H-pyrido[2,3-d)pyrimidin-4-one (9e) showed ulcer indices comparable to celecoxib (1 and 0.5 vs 0.5, respectively). Docking studies were carried out and they confirmed the mechanistic action of the designed compoundsCommunicated by Ramaswamy H. Sarma.

Piperidine: A Versatile Heterocyclic Ring for Developing Monoamine Oxidase Inhibitors.

The monoamine oxidase enzyme (MAO), which is bound on the membrane of mitochondria, catalyzes the oxidative deamination of endogenous and exogenous monoamines, including monoamine neurotransmitters such as serotonin, adrenaline, and dopamine. These enzymes have been proven to play a significant role in neurodegeneration; thus, they have recently been researched as prospective therapeutic targets for neurodegenerative illness treatment and management. MAO inhibitors have already been marketed as neurodegeneration illness treatments despite their substantial side effects. Hence, researchers are concentrating on developing novel molecules with selective and reversible inhibitory properties. Piperine, which is a phytochemical component present in black pepper, has been established as a potent MAO inhibitor. Piperine encompasses a piperidine nucleus with antibacterial, anti-inflammatory, antihypertensive, anticonvulsant, antimalarial, antiviral, and anticancer properties. The current Review focuses on the structural changes and structure-activity relationships of piperidine derivatives as MAO inhibitors.

Unveiling the therapeutic potential of exogenous ß-hydroxybutyrate for chronic colitis in rats: novel insights on autophagy, apoptosis, and pyroptosis.

Ulcerative colitis (UC) is a chronic relapsing inflammatory disease of the colorectal area that demonstrates a dramatically increasing incidence worldwide. This study provides novel insights into the capacity of the exogenous ß-hydroxybutyrate and ketogenic diet (KD) consumption to alleviate dextran sodium sulfate (DSS)-induced UC in rats. Remarkably, both interventions attenuated disease activity and colon weight-to-length ratio, and improved macro and microstructures of the damaged colon. Importantly, both ß-hydroxybutyrate and KD curbed the DSS-induced aberrant NLRP3 inflammasome activation as observed in mRNA and protein expression analysis. Additionally, inhibition of the NLRP3/NGSDMD-mediated pyroptosis was detected in response to both regimens. In parallel, these modalities attenuated caspase-1 and its associated consequences of IL-1ß and IL-18 overproduction. They also mitigated apoptosis as indicated by the inactivation of caspase-3. The anti-inflammatory effects of BHB and KD were confirmed by the reported decline in the levels of inflammatory markers including MPO, NFκB, IL-6, and TNF-α. Moreover, these interventions exhibited antioxidative properties by reducing ROS production and improving antioxidative enzymes. Their effectiveness in mitigating UC was also evident in the renovation of normal intestinal epithelial barrier function, as shown by correcting the discrepancies in the levels of tight junction proteins ZO-1, OCLN, and CLDN5. Furthermore, their effects on the intestinal microbiota homeostasis were investigated. In terms of autophagy, exogenous ß-hydroxybutyrate upregulated BECN-1 and downregulated p62, which may account for its superiority over KD in attenuating colonic damage. In conclusion, this study provides experimental evidence supporting the potential therapeutic use of ß-hydroxybutyrate or ß-hydroxybutyrate-boosting regimens in UC.

Geraniol Suppresses Oxidative Stress, Inflammation, and Interstitial Collagenase to Protect against Inflammatory Arthritis.

Geraniol (GER) is a plant-derived acyclic isoprenoid monoterpene that has displayed anti-inflammatory effects in numerous in vivo and in vitro models. This study was therefore designed to evaluate the antiarthritic potential of GER in complete Freund's adjuvant (CFA)-induced inflammatory arthritis (IA) model in rats. IA was induced by intraplantar injection of CFA (0.1 mL), and a week after CFA administration, rats were treated with various doses of methotrexate (MTX; 1 mg/kg) or GER (25, 50, and 100 mg/kg). Treatments were given on every alternate day, and animals were sacrificed on the 35th day. Paw volume, histopathological, hematological, radiographic, and qPCR analyses were performed to analyze the severity of the disease. GER significantly reduced paw edema after 35 days of treatment, and these results were comparable to the MTX-treated group. GER-treated animals displayed a perfect joint structure with minimal inflammation and no signs of cartilage or bone damage. Moreover, GER restored red blood cell and hemoglobin levels, normalized erythrocyte sedimentation rate, platelet, and c-reactive protein values, and also attenuated the levels of rheumatoid factor. RT-qPCR analysis demonstrated that GER decreased mRNA expression of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta. GER also down-regulated the transcript levels of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1, prostaglandin D2 synthase, and interstitial collagenase (MMP-1). Molecular docking of GER with COX-2, TNF-α, and MMP-1 also revealed that the antiarthritic effects of GER could be due to its direct interactions with these mediators. Based on our findings, it is conceivable that the antiarthritic effects of GER could be attributed to downregulation of pro-inflammatory mediators and protease like MMP-1.

Egyptian Society of Liver Cancer Recommendation Guidelines for the Management of Hepatocellular Carcinoma.

Globally, hepatocellular carcinoma (HCC) is the fourth most common cause of death from cancer. The prevalence of this pathology, which has been on the rise in the last 30 years, has been predicted to continue increasing. HCC is the most common cause of cancer-related morbidity and mortality in Egypt and is also the most common cancer in males. Chronic liver diseases, including chronic hepatitis C, which is a primary health concern in Egypt, are considered major risk factors for HCC. However, HCC surveillance is recommended for patients with chronic hepatitis B virus (HBV) and liver cirrhosis; those above 40 with HBV but without cirrhosis; individuals with hepatitis D co-infection or a family history of HCC; and Nonalcoholic fatty liver disease (NAFLD) patients exhibiting significant fibrosis or cirrhosis. Several international guidelines aid physicians in the management of HCC. However, the availability and cost of diagnostic modalities and treatment options vary from one country to another. Therefore, the current guidelines aim to standardize the management of HCC in Egypt. The recommendations presented in this report represent the current management strategy at HCC treatment centers in Egypt. Recommendations were developed by an expert panel consisting of hepatologists, oncologists, gastroenterologists, surgeons, pathologists, and radiologists working under the umbrella of the Egyptian Society of Liver Cancer. The recommendations, which are based on the currently available local diagnostic aids and treatments in the country, include recommendations for future prospects.

Corrigendum: Mitigation of acetaminophen-induced liver toxicity by the novel phosphatidylinositol 3-kinase inhibitor alpelisib.

[This corrects the article DOI: 10.3389/fphar.2023.1212771.].

Assembling a Cinnamyl Pharmacophore in the C3-Position of Substituted Isatins via Microwave-Assisted Synthesis: Development of a New Class of Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson's Disease.

Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, IHC, IHMC, and IHNC, and were developed and examined for their ability to inhibit MAO. Among them, compound IHC3 showed a strong MAO-B inhibitory effect with an IC50 (half-maximal inhibitory concentration) value of 1.672 µM, followed by IHC2 (IC50 = 16.934 µM). Additionally, IHC3 showed the highest selectivity index (SI) value of >23.92. The effectiveness of IHC3 was lower than the reference pargyline (0.14 µM); however, the SI value was higher than pargyline (17.16). Structurally, the IHC (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the IHC series, IHC3 (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH3, -CH3, and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, IHC3 was a reversible inhibitor with a Ki value of 0.51 ± 0.15 µM for MAO-B. Further, it was observed that IHC3 greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that IHC3 is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases.

Mitigation of acetaminophen-induced liver toxicity by the novel phosphatidylinositol 3-kinase inhibitor alpelisib.

The sterile inflammatory response mediated by Toll-like receptors (TLRs) 4 and 9 is implicated in the massive hepatic damage caused by acetaminophen (APAP)-overdose. There is a crosstalk between TLR-dependent signaling with other intracellular kinases like phosphatidylinositol 3-kinases (PI3Ks). Nevertheless, the detailed role of PI3Kα is still unknown in hepatic sterile inflammation. Accordingly, the effect of the novel PI3Kα inhibitor alpelisib was investigated in the setting of APAP-driven sterile inflammation in the liver. This was examined by pretreating mice with alpelisib (5 and 10 mg/kg, oral) 2 h before APAP (500 mg/kg, i.p.)-intoxication. The results indicated that alpelisib dose-dependently lowered APAP-induced escalation in serum liver function biomarkers and hepatic necroinflammation score. Alpelisib also attenuated APAP-induced rise in cleaved caspase 3 and proliferating cell nuclear antigen (PCNA) in the liver hepatocytes, as indices for apoptosis and proliferation. Mechanistically, inhibition of PI3Kα by alpelisib limited APAP-induced overproduction of the pro-inflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6 in the blood circulation via switching off the activation of several signal transduction proteins, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription-3 (Stat-3), glycogen Synthase Kinase (GSK)-3ß and nuclear factor (NF)-κB. Alpelisib also impaired APAP-instigated immune cell infiltration in the liver via reducing systemic granulocyte/macrophage-colony stimulating factor (GM-CSF) release and reversed APAP-induced abnormalities in the systemic and hepatic levels of the anti-inflammatory IL-10 and IL-22. In conclusion, selective modulation of the PI3Kα activity by alpelisib can hinder the inflammatory response and infiltration of immune cells occurring by APAP-hepatotoxicity.

WITHDRAWN: Vinpocetine and Lactobacillus improve fatty liver in rats via modulating the oxidative stress, inflammation, adiponectin and gut microbiome.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

Emerging roles of tyrosine kinases in hepatic inflammatory diseases and therapeutic opportunities.

Inflammation has been convicted of causing and worsening many liver diseases like acute liver failure, fibrosis, cirrhosis, fatty liver and liver cancer. Pattern recognition receptors (PRRs) like TLRs 4 and 9 localized on resident or recruited immune cells are well known cellular detectors of pathogen and damage-associated molecular patterns (PAMPs/DAMPs). Stimulation of these receptors generates the sterile and non-sterile inflammatory responses in the liver. When these responses are repeated, there will be a sustained liver injury that may progress to fibrosis and its outcomes. Crosstalk between inflammatory/fibrogenic-dependent streams and certain tyrosine kinases (TKs) has recently evolved in the context of hepatic diseases. Because of TKs increasing importance, their role should be elucidated to highlight effective approaches to manage the diverse liver disorders. This review will give a brief overview of types and functions of some TKs like BTK, JAKs, Syk, PI3K, Src and c-Abl, as well as receptors for TAM, PDGF, EGF, VEGF and HGF. It will then move to discuss the roles of these TKs in the regulation of the proinflammatory, fibrogenic and tumorigenic responses in the liver. Lastly, the therapeutic opportunities for targeting TKs in hepatic inflammatory disorders will be addressed. Overall, this review sheds light on the diverse TKs that have substantial roles in hepatic disorders and potential therapeutics modulating their activity.

Engineering S-scheme Ag2CO3/g-c3N4 heterojunctions sonochemically to eradicate Rhodamine B dye under solar irradiation.

The use of natural solar radiation is a low-cost significant technology for water pollution remediation and production of clean energy. In this work, S-scheme Ag2CO3/g-C3N4 heterojunctions were engineered for carefully eradicating Rhodamine B dye under natural sunlight irradiation. Solid thermal decomposition reactions generate g-C3N4 sheets by annealing urea at 520 °C. Ag2CO3 nanoparticles are directed and localized sonochemically to the active centers of g-C3N4 sheets. The physicochemical properties of the solid specimen were determined by PL, DRS, XRD, HRTEM, mapping, EDX, N2-adsorption-desorption isotherm and XPS analyses. As elucidated by HRTEM, PL and DRS analyses, 5 wt% of spherical Ag2CO3 nanoparticles deposited on the g-C3N4 sheet surface and nearly equidistant from each other elevate the electron-hole separation efficiency and broaden the absorption capacity of photocatalysts. Rhodamine B dye was degraded at a rate of 0.0141 min-1 by heterojunctions containing 5 wt% Ag2CO3 and 95 wt% g-C3N4, which is three-fold higher than that on pristine g-C3N4 nanosheets. Free radical scrubber experiments revealed the contribution of charge carriers and reactive oxygen species to the decomposition of RhB dye with a preferential role of positive holes and superoxide species. PL measurements of terephthalic acid and scrubber trapping experiments provide confirmatory evidence for charge diffusion via the S-scheme mechanism that accounts for the production of electron-hole pairs with strong redox power. This novel research work is contributory to manipulate the S-scheme heterojunction for efficient and low-cost wastewater treatment under natural solar irradiation.

Contrast-induced Nephropathy in Kidney Transplant Recipients: A Single-center Experience.

INTRODUCTION: Data regarding contrast-induced nephropathy (CIN) in kidney transplant (KT) recipients are scarce despite the distinct risk factors such as the use of immunosuppressive agents, sympathetic denervation, glomerular hyperfiltration, and high prevalence of the cardiovascular disease. This study aimed to determine the prevalence of CIN in KT recipients who received low-osmolality iodine-based contrast material (CM) for radiological assessment. METHODS: Between 2010 and 2020, 79 of the 3180 KT recipients followed at Hamed Al-Essa organ transplant center received low-osmolality iodine-based contrast for radiological assessment for various indications. Preventive measures including holding metformin, intravenous hydration, sodium bicarbonate and N-acetylcysteine were given before contrast administration. CIN was defined as an increase in serum creatinine of 25% from the baseline within 72 hours. RESULTS: The enrolled patients were divided into two groups: those who developed CIN (n = 7) and those with no increase in serum creatinine level (n = 72). The mean age of the patients was 52.1 ± 12.3 years; 44 of them were males, and the cause of end-stage kidney disease was mostly diabetic nephropathy. The pre-transplant demographics were comparable between the two groups. Fortyseven cases received contrast for coronary angiography, and 32 received it for a CT scan. The graft function deteriorated in group 1, but no significant difference was found between the two groups at the end of the study. CONCLUSION: CIN is not uncommon in KT recipients receiving CM, especially with ischemic heart disease. Risk stratification, optimizing hemodynamics, and avoiding potential nephrotoxins are essential before performing CM-enhanced studies in KT recipients.  DOI: 10.52547/ijkd.7165.

The anticancer and EGFR-TK/CDK-9 dual inhibitory potentials of new synthetic pyranopyrazole and pyrazolone derivatives: X-ray crystallography, in vitro, and in silico mechanistic investigations.

Treatment options for the management of breast cancer are still inadequate. This inadequacy is attributed to the lack of effective targeted medications, often resulting in the recurrence of metastatic disorders. Cumulative evidence suggests that epidermal growth factor receptor (EGFR-TK) and cyclin-dependent kinases-9 (CDK-9) overexpression correlates with worse overall survival in breast cancer patients. Pyranopyrazole and pyrazolone are privileged options for the development of anticancer agents. Inspired by this proven scientific fact, we report here the synthesis of two new series of suggested anticancer molecules incorporating both heterocycles together with their characterization by IR, 1H NMR, 13C NMR, 13C NMR-DEPT, and X-ray diffraction methods. An attempt to get the pyranopyrazole-gold complexes was conducted but unexpectedly yielded benzylidene-2,4-dihydro-3H-pyrazol-3-one instead. This unexpected result was confirmed by X-ray crystallographic analysis. All newly synthesized compounds were assessed for their anti-proliferative activity against two different human breast cancer cells, and the obtained results were compared with the reference drug Staurosporine. The target compounds revealed variable cytotoxicity with IC50 at a low micromolar range with superior selectivity indices. Target enzyme EGFR-TK and CDK-9 assays showed that compounds 22 and 23 effectively inhibited both biological targets with IC50 values of 0.143 and 0.121 µM, respectively. Molecular docking experiments and molecular dynamics simulation were also conducted to further rationalize the in vitro obtained results.Communicated by Ramaswamy H. Sarma.

Screening and Molecular Docking of Bioactive Metabolites of the Red Sea Sponge Callyspongia siphonella as Potential Antimicrobial Agents.

Marine sponges create a wide range of bioactive secondary metabolites, as documented throughout the year. Several bioactive secondary metabolites were isolated from different members of Callyspongia siphonella species. This study aimed for isolation and structural elucidation of major metabolites in order to investigate their diverse bioactivities such as antimicrobial and anti-biofilm activities. Afterwards, a molecular docking study was conducted, searching for the possible mechanistic pathway of the most bioactive metabolites. Extraction, fractionation, and metabolomics analysis of different fractions was performed in order to obtain complete chemical profile. Moreover, in vitro assessment of different bioactivities was performed, using recent techniques. Additionally, purification, structural elucidation of high features using recent chromatographic and spectroscopic techniques was established. Finally, AutoDock Vina software was used for the Pharmacophore-based docking-based analysis. As a result, DCM (dichloromethane) fraction exerted the best antibacterial activity using disc diffusion method; particularly against S. aureus with an inhibition zone of 6.6 mm. Compound 11 displayed a considerable activity against both MRSA (Methicillin-resistant Staphyllococcus aureus) and Staphyllococcus aureus with inhibition ratios of 50.37 and 60.90%, respectively. Concerning anti-biofilm activity, compounds 1 and 2 displayed powerful activity with inhibition ratios ranging from 39.37% to 70.98%. Pharmacophore-based docking-based analysis suggested elongation factor G (EF-G) to be a probable target for compound 11 (siphonellinol C) that showed the best in vitro antibacterial activity, offering unexplored potential for new drugs and treatment candidates.

New Sulfamethoxazole Derivatives as Selective Carbonic Anhydrase IX and XII Inhibitors: Design, Synthesis, Cytotoxic Activity and Molecular Modeling.

In this study new sulphamethoxazole derivatives (S1-S4, S6-S12, and S14-S22) were designed and synthesized and their structures were fully characterized and validated using NMR, mass, and IR spectroscopy, as well as elemental analyses. All new derivatives (S1-S22) were assayed against human carbonic anhydrase (hCAs IX and XII) for their inhibitory activities. hCAs IX and XII were chosen due to the fact that CAIX expression is recognized as a hypoxia marker with a poor prognosis in breast cancer. When compared to Dorzolamide HCl as a standard reference, derivatives S2, S3, S8, S9, and S15 had the most effective inhibition with low IC50 values. The active compounds were further evaluated against hCAs I and II inhibitory activity and compounds S8, S9 and S15 showed the least inhibitory effect compared to the reference standard, acetazolamide, indicating that their effect in normal cells is the lowest. Cell viability tests for the selected compounds were carried out on MCF7 (normoxia and hypoxia) and on the normal breast cell line (MCF10a) with Staurosporine as a standard. The results showed that compound S15 had a highly potent cytotoxic effect. Furthermore, cell cycle analysis results showed that compound S15 triggered cell cycle arrest and apoptosis in G1/S of MCF7 cancer cells. Finally, molecular docking was performed to point out the possible explanation for the vital structural features and key-interactions exerted by our ligands with hCAs IX and XII that might share additional designs and highlight possible leads for a hopeful anticancer agent. Consequently, sulphamethoxazole Derivative S15 could be the potential lead for emerging selective cytotoxic compounds directing h CAs IX and XII.

Combining the HSP90 inhibitor TAS-116 with metformin effectively degrades the NLRP3 and attenuates inflammasome activation in rats: A new management paradigm for ulcerative colitis.

Ulcerative colitis (UC) is a prevalent type of inflammatory bowel diseases that may predispose patients to acquire colitis-related cancer if treatment was not effective. Despite the presence of an array of established treatment options, current modalities are not successful for a substanial number of patients. The activation of the NLRP3 inflammasome is critical in the development of inflammatory processes in the colon. Additionally, the regulation of NLRP3 via HSP90 inhibition is a potential target to treat UC. Moreover, during inflammation, autophagy allows the turnover of malfunctioning proteins and therefore stands as a viable strategy for inactivating NLRP3 inflammasomes and halting hyperinflammation. Herein, we evaluated the effect of autophagy induction using metformin in the context of HSP90 inhibition by TAS-116 in the dextran sodium sulfate (DSS)-induced UC in rats. We revealed that TAS-116-induced interruption of the protein complex containing HSP90 and NLRP3 might hamper and delay the start of the inflammatory cascade ensued by the NLRP3 inflammasome oligomerization. In such circumstances, the unprotected NLRP3 is subjected to autophagic degradation in an environment of metformin-promoted autophagic signaling. As a result, such dynamic synergy was efficient in combating colon damage and immune-cell infiltration. This was confirmed by the macroscopic and microscopic investigations. Further, biochemical analysis revealed subdued inflammation cascade and oxidative injury. Therefore, simultaneous administration of TAS-116 and metformin is a new management paradigm aimed at inducing malfunction in the NLRP3 followed by augmenting its autophagic degradation, respectively. However, further studies should be conducted to assess the reliability and consistency of this novel approach.

Digoxin mitigates diethylnitrosamine-induced acute liver injury in mice via limiting production of inflammatory mediators.

The cardiotonic digoxin has been recently shown to possess an anti-inflammatory potential in numerous metabolic and inflammatory disorders. However, data about digoxin's impact in the setting of acute liver injury and sterile inflammation are still limited. Here, we investigated the potential effect of digoxin pretreatments (0.25 and 0.5 mg/kg, oral) on the severity of acute hepatotoxicity in mice challenged with a single dose of diethylnitrosamine (DN; 150 mg/kg, intraperitoneal) for 24 h. Our results indicated that digoxin pretreatments dose-dependently mitigated DN-induced rise of hepatocellular injury parameters and necroinflammation scores. Digoxin, particularly at dose of 0.5 mg/kg, boosted the number of PCNA positive hepatocytes, leading to improvement of the reparative potential in hepatocytes of DN-intoxicated livers. Digoxin's ameliorative effect on DN-hepatotoxicity coincided with (i) lowering the increased hepatic production and release of the proinflammatory mediators IL-17A, IL-1ß and TNF-α, and (ii) impeding the attraction and infiltration of monocytes to the liver, as denoted by decreasing serum MCP-1 and F4/80 immunohistochemical expression. These effects were attributed to reducing DN-induced activation of NF-κB and overexpression of CD98 in the liver. Meanwhile, DN elicited a decline in the hepatic production and release of the anti-inflammatory cytokines IL-22 and IL-6, which was intensified by digoxin, especially at a dose 0.5 mg/kg. In conclusion, digoxin conferred liver protection against DN-insult by impairing the overproduction of proinflammatory cytokines and infiltration of inflammatory cells to the liver.

Incremental Concentrations of Tacrolimus Eye Drops as a Strategy for the Management of Severe Vernal Keratoconjunctivitis.

Purpose: To assess the effect of different concentrations of tacrolimus eye suspension on the epithelium and stromal keratocytes of human corneas and investigate whether it can be safely used for severe cases of vernal keratoconjunctivitis (VKC). Methods: Tacrolimus eye suspension was prepared in a range of concentrations of 0.005%, 0.01%, 0.05%, 0.1%, and 0.2%. Molecular analysis was performed ex vivo on human corneas (n = 18), obtained from the eye bank. Transparency and thickness of each cornea were measured while live/dead staining was performed using a triple labeling assay. An incremental concentration approach was then tested on three severe cases of VKC. Results: All tested tacrolimus concentrations showed no significant changes in corneal thickness or transparency. In corneas treated with 0.1%, rare scattered dead cells were observed, while the folds of corneal surfaces were mostly viable, unlike concentrations higher than 0.1% and lower than 0.05%. Stromal cell densities were highest in the 0.1% tacrolimus treatment condition. Incremental concentrations of tacrolimus suspension were shown to significantly improve VKC cases, where the concentration used for each case depended on the severity of the case. Conclusions: Topical administration of tacrolimus was not toxic to human corneal cells at all tested concentrations, and the 0.1% concentration has shown the best viability of the corneal tissue. Tacrolimus eye suspension was shown to be safe and effective for use in severe VKC and is proposed as a topical ocular immunosuppressant drug enabling clinicians to incrementally increase the drug concentration according to the clinical severity of the disease to achieve the optimal therapeutic response.