A Review of Pharmacologic and Non-Pharmacologic Therapies in the Management of Irritable Bowel Syndrome: Current Recommendations and Evidence.

Irritable bowel syndrome (IBS) is a highly prevalent and debilitating disorder of gut-brain interaction (DGBI) affecting millions globally. It imposes a significant burden on healthcare systems and is a leading cause of workplace absenteeism. IBS is classified into several subtypes based on predominant presenting symptoms, including IBS with constipation (IBS-C) and IBS with diarrhea (IBS-D), with each requiring targeted approaches to treatment.

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration.

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Senescent cells accumulate in organisms over time because of tissue damage and impaired immune surveillance and contribute to age-related tissue decline. In agreement, genetic ablation studies reveal that elimination of senescent cells from aged tissues can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs capable of eliminating senescent cells (known as 'senolytics') partially replicate these phenotypes, many have undefined mechanisms of action and all require continuous administration to be effective.

Optogenetic stimulation of the brainstem dorsal motor nucleus ameliorates acute pancreatitis.

Introduction: Inflammation is an inherently self-amplifying process, resulting in progressive tissue damage when unresolved. A brake on this positive feedback system is provided by the nervous system which has evolved to detect inflammatory signals and respond by activating anti-inflammatory processes, including the cholinergic anti-inflammatory pathway mediated by the vagus nerve. Acute pancreatitis, a common and serious condition without effective therapy, develops when acinar cell injury activates intrapancreatic inflammation.

Does Chronic Use of High Dose Proton Pump Inhibitors Increase Risk for Pancreatic Cancer?

Objectives: To analyze whether use of proton pump inhibitors increase the risk for pancreatic cancer in a mouse model and human clinical cohorts.

Methods: p48-Cre/LSL-KrasG12D mice that develop precancerous pancreatic intraepithelial neoplasia (PanINs) were treated with low- or high-dose proton pump inhibitors (PPIs) orally for 1 and 4 months. The mechanism for the cholecystokinin receptor 2 (CCK-2R) activation was investigated in vitro.

Safety and Dosing Study of a Cholecystokinin Receptor Antagonist in Non-alcoholic Steatohepatitis.

High saturated fat diets have been shown to raise blood levels of cholecystokinin (CCK) and induce nonalcoholic steatohepatitis (NASH). CCK receptors are expressed on stellate cells and are responsible for hepatic fibrosis when activated. The purpose of this study was to test the safety and dose of a CCK receptor antagonist, proglumide, in human participants with NASH.

Minimal Change Patients Versus Obvious Chronic Pancreatitis: A Comparison of Classical Secretin Stimulation Testing Results.

Objectives: The objective was to assess if the peak bicarbonate level during secretin stimulation testing (SST) differs between patients with minimal change (or small duct) chronic pancreatitis (CP) versus those with obvious CP (or large duct) versus those without CP.

Methods: Two hundred nineteen patient records at the University of Florida who had been referred for SST were analyzed for peak bicarbonate, total volume of juice collected, age, sex, and clinical presentation.

Results: Fifty-one patients with minimal change CP were identified.

Oral famotidine versus placebo in non-hospitalised patients with COVID-19: a randomised, double-blind, data-intense, phase 2 clinical trial.

Objective: We assessed whether famotidine improved inflammation and symptomatic recovery in outpatients with mild to moderate COVID-19.

Design: Randomised, double-blind, placebo-controlled, fully remote, phase 2 clinical trial (NCT04724720) enrolling symptomatic unvaccinated adult outpatients with confirmed COVID-19 between January 2021 and April 2021 from two US centres. Patients self-administered 80 mg famotidine (n=28) or placebo (n=27) orally three times a day for 14 consecutive days.

Photosensitive Ru(II) Complexes as Inhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4.

We report the synthesis and photochemical and biological characterization of the first selective and potent metal-based inhibitors of cytochrome P450 3A4 (CYP3A4), the major human drug metabolizing enzyme. Five Ru(II)-based derivatives were prepared from two analogs of the CYP3A4 inhibitor ritonavir, and : [Ru(tpy)(L)()]Cl (tpy = 2,2':6',2″-terpyridine) with L = 6,6'-dimethyl-2,2'-bipyridine (Mebpy; ), dimethylbenzo[]dipyrido[3,2-:2',3'-]phenazine (Medppn; ) and 3,6-dimethyl-10,15-diphenylbenzo[]dipyrido[3,2-:2',3'-]phenazine (MePhdppn; ), [Ru(tpy)(Mebpy)()]Cl () and [Ru(tpy)(Medppn)()]Cl (). Photochemical release of or from - was demonstrated, and the spectrophotometric evaluation of showed that it behaves similarly to free (type II heme ligation) after irradiation with visible light but not in the dark.

Safety and efficacy of sofosbuvir/velpatasvir/voxilaprevir in post-liver transplant patients with previous direct-acting antiviral failure: Six case reports.

Background: Direct-acting antiviral (DAA) therapy regimens are highly effective at eliminating hepatitis C virus (HCV) infection but rates of sustained virologic response (SVR) are lower in patients with decompensated cirrhosis or hepatocellular carcinoma. Since many of these patients will be referred for liver transplant, they will require retreatment after transplantation. Sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) is recommended by guidelines as the preferred regimen to treat HCV in DAA-experienced patients following liver transplant however there is limited data.

Dual-Action Ru(II) Complexes with Bulky π-Expansive Ligands: Phototoxicity without DNA Intercalation.

We report the synthesis and photochemical and biological characterization of Ru(II) complexes containing π-expansive ligands derived from dimethylbenzo[]dipyrido[3,2-:2',3'-]phenazine (Medppn) adorned with flanking aryl substituents. Late-stage Suzuki couplings produced Medppn ligands substituted at the 10 and 15 positions with phenyl (), 2,4-dimethylphenyl (), and 2,4-dimethoxyphenyl () groups. Complexes of the general formula [Ru(tpy)(L)(py)](PF) (-), where L = -, were characterized and shown to have dual photochemotherapeutic (PCT) and photodynamic therapy (PDT) behavior.

Cholecystokinin Receptor Antagonist Therapy Decreases Inflammation and Fibrosis in Chronic Pancreatitis.

Background And Aims: Chronic pancreatitis is associated with recurrent inflammation, pain, fibrosis, and loss of exocrine and endocrine pancreatic function and risk of cancer. We hypothesized that activation of the CCK receptor contributes to pancreatitis and blockade of this pathway would improve chronic pancreatitis.

Methods: Two murine models were used to determine whether CCK receptor blockade with proglumide could prevent and reverse histologic and biochemical features of chronic pancreatitis: the 6-week repetitive chronic cerulein injection model and the modified 75% choline-deficient ethionine (CDE) diet.

Vaccine against gastrin, a polyclonal antibody stimulator, decreases pancreatic cancer metastases.

Growth of pancreatic cancer is stimulated by gastrin in both a paracrine and an autocrine fashion. Traditional therapies have not significantly improved survival, and recently pancreatic cancer has been deemed a "cold" tumor due to its poor response to immunotherapy. Strategies to improve survival of pancreatic cancer are desperately needed.

A Cholecystokinin Receptor Antagonist Halts Nonalcoholic Steatohepatitis and Prevents Hepatocellular Carcinoma.

Background And Aims: Nonalcoholic steatohepatitis (NASH) is a common inflammatory liver condition that may lead to cirrhosis and hepatocellular carcinoma (HCC). Risk factors for NASH include a saturated fat diet, altered lipid metabolism, and genetic and epigenetic factors, including microRNAs. Serum levels of cholecystokinin (CCK) are elevated in mice and humans that consume a high-saturated fat diet.

Endogenous Gastrin Collaborates With Mutant KRAS in Pancreatic Carcinogenesis.

Objective: The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis.

Role of colonoscopy in diagnosis of capecitabine associated ileitis: Two case reports.

Background: Capecitabine is considered a first line agent in adjuvant therapy for breast and colorectal cancer. However, cases of severe diarrhea have been reported with increasing frequency in recent years. When diarrhea is severe and prolonged, capecitabine associated ileitis should be considered as a possible etiology.

Cholecystokinin Receptor-Targeted Polyplex Nanoparticle Inhibits Growth and Metastasis of Pancreatic Cancer.

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) remains the most aggressive malignancy with the lowest 5-year survival rate of all cancers in part owing to the lack of tumor-specific therapy and the rapid metastatic nature of this cancer. The gastrointestinal peptide gastrin is a trophic peptide that stimulates growth of PDAC in an autocrine fashion by interaction with the cholecystokinin receptor that is overexpressed in this malignancy.

Methods: We developed a therapeutic novel polyplex nanoparticle (NP) that selectively targets the cholecystokinin receptor on PDAC.

Dietary fat stimulates pancreatic cancer growth and promotes fibrosis of the tumor microenvironment through the cholecystokinin receptor.

The gastrointestinal peptide cholecystokinin (CCK) is released from the duodenum in response to dietary fat to aid in digestion, and plasma CCK levels are elevated with the consumption of high-fat diets. CCK is also a trophic peptide for the pancreas and has also been shown to stimulate growth of pancreatic cancer. In the current investigation, we studied the influence of a diet high in saturated fat on the growth of pancreatic cancer in syngeneic murine models before the mice became obese to exclude the confounding factors associated with obesity.

Cholecystokinin receptor antagonist alters pancreatic cancer microenvironment and increases efficacy of immune checkpoint antibody therapy in mice.

Advanced pancreatic ductal adenocarcinoma (PDAC) has typically been resistant to chemotherapy and immunotherapy; therefore, novel strategies are needed to enhance therapeutic response. Cholecystokinin (CCK) has been shown to stimulate growth of pancreatic cancer. CCK receptors (CCKRs) are present on pancreatic cancer cells, fibroblasts, and lymphocytes.

Gastrin and Gastric Cancer.

Gastric cancer is the third leading cause of cancer-related mortality worldwide. Despite progress in understanding its development, challenges with treatment remain. Gastrin, a peptide hormone, is trophic for normal gastrointestinal epithelium.

Sensing of phosphates by using luminescent Eu(III) and Tb(III) complexes: application to the microalgal cell Chlorella vulgaris.

Phenanthroline-based chiral ligands L(1) and L(2) as well as the corresponding Eu(III) and Tb(III) complexes were synthesized and characterized. The coordination compounds show red and green emission, which was explored for the sensing of a series of anions such as F(-), Cl(-), Br(-), I(-), NO3(-), NO2(-), HPO4(2-), HSO4(-), CH3COO(-), and HCO3(-). Among the anions, HPO4(2-) exhibited a strong response in the emission property of both europium(III) and terbium(III) complexes.

Lanthanide(III) complexes of bis-semicarbazone and bis-imine-substituted phenanthroline ligands: solid-state structures, photophysical properties, and anion sensing.

Phenanthroline-based hexadentate ligands L(1) and L(2) bearing two achiral semicarbazone or two chiral imine moieties as well as the respective mononuclear complexes incorporating various lanthanide ions, such as La(III), Eu(III), Tb(III), Lu(III), and Y(III) metal ions, were synthesized, and the crystal structures of [ML(1)Cl(3)] (M=La(III), Eu(III), Tb(III), Lu(III), or Y(III)) complexes were determined. Solvent or water molecules act as coligands for the rare-earth metals in addition to halide anions. The big Ln(III) ion exhibits a coordination number (CN) of 10, whereas the corresponding Eu(III), Tb(III), Lu(III), and Y(III) centers with smaller ionic radii show CN=9.