Intestinal Vessels Research Articles

Less Is More: Donor Engineering of a Stable Molecular Dye for Bioimaging in the NIR-IIb Window.

Fluorescence molecular imaging aims to enhance clarity in the region of interest, particularly in the near-infrared IIb window (NIR-IIb, 1500-1700 nm). To achieve this, we developed a novel small-molecule dye, named DA-5, based on classic cyanine dyes (heptamethine or pentamethine is essential for wavelengths beyond 1000 nm). By reducing excessive polymethine to a single methine and disrupting symmetry to form an asymmetric donor-π-acceptor (D-π-A) architecture, we enhanced the donor's electron-donating capability, yielding emission at 1088 nm. DA-5 exhibits superior properties, including excellent chemo- and photostability, resistance against solvatochromism-caused quenching, and antiaggregation in aqueous solution. With a large Stokes shift (241 nm) and high brightness (321 M-1 cm-1), DA-5 enables high-performance imaging of the lymphatic system, intestinal vessels, whole-body angiography, and cerebral and hindlimb microvasculature in NIR-IIb. This molecular design strategy offers a promising platform for advancing in vivo biophotonics.

Intraoperative evaluation of the intestinal wall viability

An analysis of data from national and foreign literature was carried out in terms of intraoperative determination of the intestinal viability in cases of developing the diseases in the abdominal cavity organs, associated with impaired intestinal blood supply. The basis of this work is the analysis of the modern literature on the methods of intraoperative evaluation of mesenteric ischemia. Impaired mesenteric blood supply is often the consequence of a number of reasons of developing critical conditions (mesenteric thrombosis, acute adhesive intestinal obstruction, incarcerated hernia etc.), also representing a high risk factor for lethal outcomes. Special attention is paid to the occlusion-related pathogenetic mechanism of developing mesenteric ischemia, which is accompanied by rapid development of irreversible morphological changes in the tissues and by significant disorders in the homeostasis systems of the organism. The generally available method for visual evaluation of the intestine viability is not always valid in terms of determining the degree of intensity of the ischemic changes in the intestinal wall. The algorithm of determining the intestine viability includes the determination of the intestine color, the peristaltic motions, the pulsation and the blood filling of mesenteric vessels with dynamic evaluation of these signs after the injecting the local anesthetic drug solution into the mesenterium and after “warming” the intestine with towels soaked in warm sodium chloride solution. In the current surgical conditions, a more precise method is required for intraoperative determination of the tissue viability. For the purpose of the objective evaluation of the intestinal blood supply, the recommendations include using intraoperative ultrasonic and laser Doppler flowmetry, as well as the regional transillumination angiotensometry of the intramural vessels in the small intestine. At the same time, a number of optical spectroscopy and visualization methods show high sensitivity to changes in blood microcirculation without using exogenous contrasting, which can also be successfully used when evaluating the intestinal circulation. According to data from modern literature, there is still controversy on the efficiency of various methods for intraoperative evaluation of disorders of the regional blood microcirculation and the intestine viability, which justifies the conduct of further research works.

Transport functions of intestinal lymphatic vessels.

Lymphatic vessels are crucial for fluid absorption and the transport of peripheral immune cells to lymph nodes. However, in the small intestine, the lymphatic fluid is rich in diet-derived lipids incorporated into chylomicrons and gut-specific immune cells. Thus, intestinal lymphatic vessels have evolved to handle these unique cargoes and are critical for systemic dietary lipid delivery and metabolism. This Review covers mechanisms of lipid absorption from epithelial cells to the lymphatics as well as unique features of the gut microenvironment that affect these functions. Moreover, we discuss details of the intestinal lymphatics in gut immune cell trafficking and insights into the role of inter-organ communication. Lastly, we highlight the particularities of fat absorption that can be harnessed for efficient lipid-soluble drug distribution for novel therapies, including the ability of chylomicron-associated drugs to bypass first-pass liver metabolism for systemic delivery. In all, this Review will help to promote an understanding of intestinal lymphatic-systemicinteractionsto guide future research directions.

Intraoperative indocyanine green fluorescence for precise resection of nonocclusive mesenteric ischemia: a case report and diagnostic considerations based on pathology findings

BackgroundNonocclusive mesenteric ischemia (NOMI) is characterized by intestinal ischemia caused by spasms in the peripheral intestinal vessels without organic obstruction in the main mesenteric vessels. NOMI can be fatal in case of delayed diagnosis and treatment. Although the use of indocyanine green (ICG) fluorescence in assessing intestinal viability during NOMI surgery is well recognized, there is a paucity of reported cases using this technique. Herein, we present a case of NOMI that was successfully managed through accurate diagnosis and resection of the ischemic intestines guided by ICG fluorescence.Case presentationAn 81-year-old man presented with abdominal pain. Contrast-enhanced computed tomography revealed intrahepatic portal vein gas, superior mesenteric vein gas, and terminal ileal edema. Considering these findings, the patient was diagnosed with NOMI and emergency surgery was performed. Intestinal edema was observed 30 cm upstream of the terminal ileum without serosal discoloration. ICG fluorescence revealed areas of normal perfusion as well as mild and moderate hypoperfusion. The small bowel, including the hypoperfusion area, was resected. As no clinical signs of residual bowel ischemia were observed during the postoperative course, a second-look operation was deemed unnecessary. Intraoperative ICG fluorescence and histopathological findings indicated mucosal edema in the mildly hypoperfused area and mucosal necrosis in the moderately hypoperfused area.ConclusionsThis case highlights the use of intraoperative ICG fluorescence in the disease. ICG fluorescence is invaluable in assessing the extent of bowel ischemia and guiding precise resection. Thus, future efforts should focus on identifying accumulation of cases and quantification of ICG fluorescence intensity to further improve diagnostic performance.

Effects of Beraprost on Intestinal Microcirculation and Barrier Function in a Mouse Model of Renal Failure.

Endothelial dysfunction plays an important role in the pathogenesis of chronic kidney disease. Prostacyclin (PGI2), an endothelial cell-produced endogenous prostaglandin, plays a crucial role in maintaining endothelial function. However, its effects on intestinal microcirculation and barrier function are not fully understood. We hypothesized that PGI2 improves intestinal microcirculation and barrier function via endothelial protective effects. ICR and ICGN (a spontaneous nephrotic model) mice were used in this study. Intestinal microcirculation was visualized invivo to investigate PGI2 effects. Beraprost served as PGI2. PGI2 administration spanned 4 weeks, following which we assessed its influence on intestinal endothelial, intestinal barrier, and renal functions. We visualized intestinal microcirculation and endothelial glycocalyx in the intestinal blood vessels. Beraprost administration induced a 1.2-fold dilatation of the vascular diameter of the small intestine. Intestinal blood flow in ICGN mice was significantly reduced compared that in ICR mice but improved with beraprost administration. ICGN mice exhibited reduced serum albumin levels, decreased ambulation, an imbalance in intestinal reactive oxygen species (ROS)/nitric oxide (NO), and impaired tight junctions; all were ameliorated by beraprost administration. Beraprost improves intestinal microcirculation and barrier function by ameliorating ROS/NO imbalances, thereby reducing physical inactivity during renal failure.

Bile salt integrated cerasomes: A potential nanocarrier for enhancement of the oral bioavailability of idarubicin hydrochloride

Cerasomes are a modified form of liposomes containing both inorganic and organic parts and due to their strong polyorganosiloxane surface have remarkably high morphological stability and provide easier functionalization compared with conventional liposomes. To investigate the potential of these nanocarriers for oral delivery, bile salt integrated cerasomes (named bilocerasomes) encapsulating idarubicin hydrochloride (IDA) were prepared and characterized. The optimum formulation showed excellent stability in the simulated gastrointestinal fluids as well as under storage conditions. The oral pharmacokinetics of the IDA solution, empty nanocarrier + drug solution, and IDA-loaded bilocerasome were evaluated. The nanoformulation significantly increased the area under the drug concentration–time curve and the mean residence time (∼14.3- and 9-fold, respectively). The results obtained from cell uptake and chylomicron flow blocking approach revealed that bilocerasomes are absorbed into the intestinal cells via a clathrin/caveolin-independent endocytosis pathway and transported to the systemic circulation extensively via the intestinal lymphatic vessels. Considering the high stability of the prepared bilocerasome, noticeable participation of lymphatic transport in its systemic absorption and marked enhancement in the oral absorption of IDA, bilocerasomes can be introduced as a capable carrier for improving the oral bioavailability of drugs, particularly those that hepatic first-pass metabolism seriously limits their oral absorption.

Intestinal lymphangiectasia: Understanding the bigger picture

Intestinal lymphangiectasia (IL) is characterized by the dilation of intestinal lymphatic vessels, which can rupture and cause loss of lymph into the intestine. Due to the high content of proteins, lipoproteins, and lymphocytes in the intestinal lymph, loss of lymph might result in hypoproteinemia, hypoalbuminemia, hypogammaglobulinemia, and lymphocytopenia. In addition, there may be a depletion of minerals, lipids, and fat-soluble vitamins. IL can be primary due to inherent malfunctioning of the lymphatic system, or secondly, a result of various factors that may hinder lymphatic drainage either directly or indirectly. This condition has emerged as a subject of significant clinical interest. Given that the intestinal lymphatic system plays an important role in the body’s fluid homeostasis, adaptive immunity, nutrient and drug absorption, intestinal transport, and systemic metabolism, its dysfunction may have wider implications. Although primary IL is rare, with varied clinical features, complications, treatment response, and outcomes, secondary IL is more common than previously believed. The definitive diagnosis of IL requires endoscopic demonstration of whitish villi (which frequently resemble snowflakes) and histological confirmation of dilated lacteals in the small intestinal mucosa. Treatment of IL is challenging and involves dietary modifications, managing underlying medical conditions, and using medications such as sirolimus and octreotide. Recognizing its prevalence and diverse etiology is crucial for targeted management of this challenging medical condition. This article provides a comprehensive exploration of the clinical implications associated with IL. In addition, it offers valuable insights into critical knowledge gaps in the existing diagnostic and management landscape.

Distal Immunization and Systemic Cytokines Establish a Transient Immune Alert State in the Intestine.

Conventionally, immune responses are studied in the context of inflamed tissues and their corresponding draining lymph nodes (LNs). However, little is known about the effects of systemic inflammatory signals generated during local inflammation on distal tissues and nondraining LNs. Using a mouse model of cutaneous immunization, we found that systemic inflammatory stimuli triggered a rapid and selective distal response in the small intestine and the mesenteric LN (mesLN). This consisted of increased permeability of intestinal blood vessels and lymphatic drainage of bloodborne solutes into the mesLN, enhanced activation and migration of intestinal dendritic cells, as well as amplified T cell responses in the mesLNs to systemic but not orally derived Ags. Mechanistically, we found that the small intestine endothelial cells preferentially expressed molecules involved in TNF-α signaling and that TNF-α blockade markedly diminished distal intestinal responses to cutaneous immunization. Together, these findings reveal that the intestinal immune system is rapidly and selectively activated in response to inflammatory cues regardless of their origin, thus identifying an additional layer of defense and enhanced surveillance of a key barrier organ at constant risk of pathogen encounter.

A missed mummified twin abdominal pregnancy: A case report

Background: Abdominal pregnancies are rare pathologic ectopic pregnancies that occur in 1:10,000-30,000 pregnancies. Implantation sites include the pelvic and abdominal peritoneum, uterine surface, omentum, and abdominal organs, including the intestine, liver, spleen, diaphragm, and large blood vessels. They are frequently missed antenatally, especially because there are no specific clinical signs and symptoms for abdominal pregnancy making diagnosis difficult. Diagnosis is often made during cesarean delivery. Ultrasonography modalities have high diagnostic errors between 50 and 90%. Case presentation: A 41-year-old presented with copious purulent vaginal discharge that was mixed with blood and was foul-smelling for two months as a referral to the Kenyatta National Hospital. Abdominopelvic computed tomography revealed a heterogeneous lesion in the left hemi abdomen. Her last menstrual period was December 2022 with DMPA in the same month. Her PDT was negative. She was sick-looking and had a purulent vaginal discharge. Intraoperatively, 500 mls of serous fluid was observed, and abdominal pregnancy, approximately 24–28 weeks of gestation with mummified skull bone, brain tissue, ribs, and long bones of the lower and upper limbs in their multiples suggestive of twin gestation. The patient’s postoperative period was uneventful, and she was later discharged in good condition. Conclusion: Proper and timely diagnosis of abdominal pregnancy is required to improve outcomes, especially maternal outcomes. In this case, the pregnancy was fatal to the fetus, although maternal mortality have been reported. The diagnosis may come as a surprise finding intraoperatively theatre-like in this case and in some cases postemergency cesarean delivery for failed labor induction. The diagnostic modality of choice is ultrasonography, although our patient had ultrasound and computed tomography but ended up with a misdiagnosis because of the complexity of the diagnosis of abdominal pregnancy.

Iatrogenic gas embolism in a juvenile loggerhead sea turtle (Caretta caretta)

A mild pneumocoelom was diagnosed by computed tomography in a stranded juvenile loggerhead sea turtle (Caretta caretta). After gas extraction by ultrasound-guided puncture, the animal did not improve and was subjected to hyperbaric oxygen therapy (HBOT). After HBOT, the turtle developed marked subcutaneous emphysema and was found dead the following morning. Gross lesions included a distended right atrium with numerous gas bubbles within the epicardium, gas bubbles in the hepatic, gastric and mesenteric veins, a small gas-filled bulla in the left lung and diffuse haemorrhages in the encephalon. Histological lesions included gas-like emboli in the lumen of the right atrium with myocardial necrosis, gas-like emboli in the lumina of intestinal, pulmonary and renal blood vessels and severe meningeal haemorrhages. From a forensic pathology perspective, the subcutaneous emphysema of immediate onset after HBOT and the greater severity of the histological lesions in blood vessels, heart, lung and brain differentiate this case from other cases of gas embolism in turtles due to incidental capture. Two factors contributed to this outcome: the existence of a probably unresolved pneumocoelom and the application of HBOT without an initial diagnosis that accurately indicated its use. Therefore, as in human medicine, the use of HBOT in sea turtles with lung lesions and pneumocoelom is discouraged. This is the first description of an iatrogenic gas embolism in a sea turtle.

Deletion of RAMP1 Signaling Enhances Diet-induced Obesity and Fat Absorption via Intestinal Lacteals in Mice.

Intestinal lymphatic vessels (lacteals) play a critical role in the absorption and transport of dietary lipids into the circulation. Calcitonin gene-related peptide and receptor activity-modifying protein 1 (RAMP1) are involved in lymphatic vessel growth. This study aimed to examine the role of RAMP1 signaling in lacteal morphology and function in response to a high-fat diet (HFD). RAMP1 deficient (RAMP1-/-) or wild-type (WT) mice were fed a normal diet (ND) or HFD for 8 weeks. RAMP1-/- mice fed a HFD had increased body weights compared to WT mice fed a HFD, which was associated with high levels of total cholesterol, triglycerides, and glucose. HFD-fed RAMP1-/- mice had shorter and wider lacteals than HFD-fed WT mice. HFD-fed RAMP1-/- mice had lower levels of lymphatic endothelial cell gene markers including vascular endothelial growth factor receptor 3 (VEGFR3) and lymphatic vascular growth factor VEGF-C than HFD-fed WT mice. The concentration of an absorbed lipid tracer in HFD-fed RAMP1-/- mice was higher than that in HFD-fed WT mice. The zipper-like continuous junctions were predominant in HFD-fed WT mice, while the button-like discontinuous junctions were predominant in HFD-fed RAMP1-/- mice. Deletion of RAMP1 signaling suppressed lacteal growth and VEGF-C/VEGFR3 expression but accelerated the uptake and transport of dietary fats through discontinuous junctions of lacteals, leading to excessive obesity. Specific activation of RAMP1 signaling may represent a target for the therapeutic management of diet-induced obesity.

Evaluation of imaging findings in gastrointestinal anisakiasis in emergency CT and ultrasound

BackgroundTo assess the frequency of appearance of various signs (isolated and grouped) in emergency imaging tests in patients with anisakiasis, according to the location of gastrointestinal tract involvement.MethodsRetrospective review by two experienced radiologists of emergency ultrasounds and CTs performed on patients admitted in the Emergency Department of our hospital with later confirmed anisakiasis (2010–2021), assessing the presence of signs suggesting anisakiasis. Calculation of the frequency of appearance according to the gastric or intestinal location, as well as the most common grouped signs.ResultsOut of 231 total patients with anisakiasis, imaging studies were performed in 144: abdominopelvic ultrasound in 43 cases and CT in 111 (both techniques in 31). In cases with gastric occurrence (34), in CT the wall stratification (100%), wall thickening (97%), fat stranding (91%) and ascitic fluid (82%) were predominant. In the intestinal cases (105), in CT (95) the wall thickening (100%), fat stranding (92%) and mesenteric vessel engorgement (83%) were usual; in ultrasound (40), ascitic fluid and wall thickening (70% in both cases) were frequently observed. The frequency of grouped appearance of the mentioned signs was 82% in gastric cases, 80% in intestinal cases and 50% in ultrasounds. Multisegment involvement in CT reached 28% (gastric + intestinal) and 11% (only intestinal) of cases.ConclusionsThe most frequent CT findings in patients with gastric anisakiasis are wall stratification and thickening, fat stranding and ascitic fluid. In the intestinal cases, wall thickening, fat oedema and vessel engorgement are the most often observed findings.Critical relevance statementThe presence of different radiological signs makes it advisable to include anisakiasis in the differential diagnosis of acute abdomen. Intestinal and multifocal involvement rates are greater than previously reported.Key points• In gastric anisakiasis, CT frequently shows wall stratification and thickening, fat stranding and ascitic fluid.• In intestinal anisakiasis, CT often presents wall thickening, fat stranding and vessel engorgement.• In intestinal anisakiasis, ultrasounds most frequently show ascitic fluid and wall thickening.Graphical

Para- and Transcellular Transport Kinetics of Nanoparticles across Lymphatic Endothelial Cells.

Lymphatic vessels have received significant attention as drug delivery targets, as they shuttle materials from peripheral tissues to the lymph nodes, where adaptive immunity is formed. Delivery of immune modulatory materials to the lymph nodes via lymphatic vessels has been shown to enhance their efficacy and also improve the bioavailability of drugs when delivered to intestinal lymphatic vessels. In this study, we generated a three-compartment model of a lymphatic vessel with a set of kinematic differential equations to describe the transport of nanoparticles from the surrounding tissues into lymphatic vessels. We used previously published data and collected additional experimental parameters, including the transport efficiency of nanoparticles over time, and also examined how nanoparticle formulation affected the cellular transport mechanisms using small molecule inhibitors. These experimental data were incorporated into a system of kinematic differential equations, and nonlinear, least-squares curve fitting algorithms were employed to extrapolate transport coefficients within our model. The subsequent computational framework produced some of the first parameters to describe transport kinetics across lymphatic endothelial cells and allowed for the quantitative analysis of the driving mechanisms of transport into lymphatic vessels. Our model indicates that transcellular mechanisms, such as micro- and macropinocytosis, drive transport into lymphatics. This information is crucial to further design strategies that will modulate lymphatic transport for drug delivery, particularly in diseases like lymphedema, where normal lymphatic functions are impaired.

Vedolizumab Efficacy Is Associated With Decreased Intracolonic Dendritic Cells, Not Memory T Cells.

Vedolizumab, an antibody blocking integrin α4β7, is a safe and effective therapy for Crohn's disease and ulcerative colitis. Blocking α4β7 from binding its cognate addressin MAdCAM-1 on intestinal blood vessel endothelial cells prevents T cells from migrating to the gut mucosa in animal models. However, data supporting this mechanism of action in humans is limited. We conducted a cross-sectional case-control study to evaluate the effect of vedolizumab on intestinal immune cell populations while avoiding the confounding effect of resolving inflammation on the cellularity of the colonic mucosa in treatment-responsive patients. Colon biopsies from 65 case subjects receiving vedolizumab were matched with biopsies from 65 control individuals, similar in disease type, medications, anatomic location, and inflammation. Biopsies were analyzed by flow cytometry and full messenger RNA transcriptome sequencing of sorted T cells. No difference was seen between vedolizumab recipients and control individuals in the quantity of any antigen-experienced T lymphocyte subset or in the quality of the transcriptome in any experienced T cell subset. Fewer naïve colonic B and T cells were seen in vedolizumab recipients than control individuals, regardless of response. However, the most striking finding was a marked reduction in CD1c+ (BDCA1+) dendritic cells exclusively in vedolizumab-responsive patients. In blood, these dendritic cells ubiquitously express high levels of α4β7, which is rapidly downregulated upon vedolizumab exposure. The clinical effects of vedolizumab reveal integrin α4β7-dependent dendritic cell migration to the intestinal mucosa to be central to inflammatory bowel disease pathogenesis.

DUOX2-Induced Oxidative Stress Inhibits Intestinal Angiogenesis through MMP3 in a Low-Birth-Weight Piglet Model.

Intestinal vessels play a critical role in nutrient absorption, whereas the effect and mechanism of low birth weight (LBW) on its formation remain unclear. Here, twenty newborn piglets were assigned to the control (CON) group (1162 ± 98 g) and LBW group (724 ± 31 g) according to their birth weight. Results showed that the villus height and the activity of maltase in the jejunum were lower in the LBW group than in the CON group. LBW group exhibited a higher oxidative stress level and impaired mitochondrial function in the jejunum and was lower than the CON group in the intestinal vascular density. To investigate the role of oxidative stress in intestinal angiogenesis, H2O2 was employed to induce oxidative stress in porcine intestinal epithelial cells (IPEC-J2). The results showed that the conditioned media from IPEC-J2 with H2O2 treatment decreased the angiogenesis of porcine vascular endothelial cells (PVEC). Transcriptome analysis revealed that a higher expression level of dual oxidase 2 (DUOX2) was found in the intestine of LBW piglets. Knockdown of DUOX2 in IPEC-J2 increased the proliferation and decreased the oxidative stress level. In addition, conditioned media from IPEC-J2 with DUOX2-knockdown was demonstrated to promote the angiogenesis of PVEC. Mechanistically, the knockdown of DUOX2 decreased the reactive oxygen species (ROS) level, thus increasing the angiogenesis in a matrix metalloproteinase 3 (MMP3) dependent manner. Conclusively, our results indicated that DUOX2-induced oxidative stress inhibited intestinal angiogenesis through MMP3 in a LBW piglet model.

Primary Intestinal Lymphangiectasia Diagnosed by Capsule Endoscopy

Primary intestinal lymphangiectasia (PIL) is a rare disorder in children and it is more exceptional in adults. PIL is caused by a diffuse or localized dilatation and/or rupture of intestinal lymphatic vessels in the mucosa, submucosa, or subserosa due to high pressure in lymphatic vessels. The diagnosis is made on clinical grounds with the support of small bowel biopsies. The following report present a case of intestinal lymphangiectasia revealed by capsule endoscopy examination. This work shows that standard EGD and colonoscopy may miss characteristic lesions of PIL, and capsule endoscopy (or enteroscopy) may be required for the diagnosis because lesions are typically located in distal duodenum/jejunoileum.

Minimization of lumbar interbody fusion by percutaneous full-endoscopic lumbar interbody fusion (PELIF), and its minimally invasiveness comparison with minimally invasive surgery-transforaminal lumbar interbody fusion (MIS-TLIF)

ObjectiveIn fusion surgery, minimization of muscle damage and bone resection is important. To achieve these, we have developed a percutaneous full endoscopic lumbar interbody fusion (PELIF). We report the detailed operation procedure, and moreover a comparison of its minimally invasiveness with that of the minimally invasive surgery-transforminal lumbar interbody fusion (MIS-TLIF). Methods52 patients were treated with PELIF. Total discectomy and cartilage endplate removal were performed using an 8 mm rotate-cutter. A cage was sandwiched between two L-retract sliders, which protected the exiting root. The cancellous bone chips were harvested from the pelvis with a 5 mm trephine.On the other hand, 74 patients were treated with MIS-TLIF. ResultsIn PELIF, bleeding volume, VAS (back pain), ODI, JOA score, and Macnab’s criteria were significantly superior to MIS-TLIF except for VAS (leg symptom).The MRI cross-sectional area of degenerative spondylolisthesis was significantly improved after PELIF, but that of MIS-TLIF was significantly broader.PELIF was superior to MIS-TLIF in fat degeneration of multifidus muscle in the cross-sectional MRI under 50 years old.CT recognized insufficient fusion in one case of PELIF and seven cases of MIS-TLIF, with a tendancy to have more insufficient fusion in MIS-TLIF. ConclusionsPELIF provides clear visualization under continuous water irrigation. PELIF is an indirect decompression without canal invasion. The dura mater, intestine, and large blood vessels don’t appear in the surgical field. It is understood that PELIF is a less invasive surgery than MIS-TLIF.

Effects of Topical or Intravitreal Application of Anti-Vascular Endothelial Growth Factor on Density of Intestinal Blood Vessels of Mice.

Background and Objectives: Anti-vascular endothelial growth factor (anti-VEGF) therapy has become the first-line treatment for diabetic macular edema. However, it is still not clear whether anti-VEGF agents act on systemic blood vessels. The aim of this study is to determine whether a direct topical application or intravitreal injection of anti-VEGF will change the intestinal blood vessels of mice. Materials and Methods: C57BL/6 mice were laparotomied under deep anesthesia, and the blood vessels on the surface of the intestines were exposed, examined, and photographed through a dissecting microscope. Vascular changes were evaluated before and at 1, 5, and 15 min after the topical application of 50 µL of the different anti-VEGF agents onto the surface of the intestine (group S) or after the intravitreal injection (group V). The vascular density (VD) was determined for five mice in each group before and after 40 μg/μL of aflibercept (Af), or 25 μg/μL of bevacizumab (Be), or 10 μg/μL of ranibizumab (Ra) were applied. Endothelin-1 (ET1), a potent vasoconstrictor, was used as a positive control, and phosphate-buffered saline (PBS) was used as a control. Results: For group S, no significant changes were observed after PBS (baseline, 1, 5, and 15 min: 46.3, 44.5, 44.8, and 43.2%), Be (46.1, 46.7, 46.7, and 46.3%), Ra (44.7, 45.0, 44.7, and 45.6%), and Af (46.5, 46.2, 45.9, and 46.1%, repeated ANOVA) were applied topically. Significant decreases in the VD were observed after ET1 (46.7, 28.1, 32.1, and 34.0%, p < 0.05) was topically applied. For group V, no significant differences were observed for all anti-VEGF agents. Conclusions: The topical application or intravitreal injections of anti-VEGF agents do not cause a change in the VD of the intestinal vessels, which may be related to its safety.

Intestinal Damage, Inflammation and Microbiota Alteration during COVID-19 Infection.

The virus SARS-CoV-2 is responsible for respiratory disorders due to the fact that it mainly infects the respiratory tract using the Angiotensin-converting enzyme 2 (ACE2) receptors. ACE2 receptors are also highly expressed on intestinal cells, representing an important site of entry for the virus in the gut. Literature studies underlined that the virus infects and replicates in the gut epithelial cells, causing gastrointestinal symptoms such as diarrhea, abdominal pain, nausea/vomiting and anorexia. Moreover, the SARS-CoV-2 virus settles into the bloodstream, hyperactivating the platelets and cytokine storms and causing gut-blood barrier damage with an alteration of the gut microbiota, intestinal cell injury, intestinal vessel thrombosis leading to malabsorption, malnutrition, an increasing disease severity and mortality with short and long-period sequelae. This review summarizes the data on how SARS-CoV-2 effects on the gastrointestinal systems, including the mechanisms of inflammation, relationship with the gut microbiota, endoscopic patterns, and the role of fecal calprotectin, confirming the importance of the digestive system in clinical practice for the diagnosis and follow-up of SARS-CoV-2 infection.

Development and Application of a Dissolution-Transfer-Partitioning System (DTPS) for Biopharmaceutical Drug Characterization.

A variety of in vitro dissolution and gastrointestinal transfer models have been developed aiming to predict drug supersaturation and precipitation. Further, biphasic, one-vessel in vitro systems are increasingly applied to simulate drug absorption in vitro. However, to date, there is a lack of combining the two approaches. Therefore, the first aim of this study was to develop a dissolution-transfer-partitioning system (DTPS) and, secondly, to assess its biopredictive power. In the DTPS, simulated gastric and intestinal dissolution vessels are connected via a peristaltic pump. An organic layer is added on top of the intestinal phase, serving as an absorptive compartment. The predictive power of the novel DTPS was assessed to a classical USP II transfer model using a BCS class II weak base with poor aqueous solubility, MSC-A. The classical USP II transfer model overestimated simulated intestinal drug precipitation, especially at higher doses. By applying the DTPS, a clearly improved estimation of drug supersaturation and precipitation and an accurate prediction of the in vivo dose linearity of MSC-A were observed. The DTPS provides a useful tool taking both dissolution and absorption into account. This advanced in vitro tool offers the advantage of streamlining the development process of challenging compounds.