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International Journal of Molecular... Jun 2024Berberine (BBR) is used to treat cancer, inflammatory conditions, and so on. But the side effects of BBR causing constipation should not be ignored. In clinical...
Berberine (BBR) is used to treat cancer, inflammatory conditions, and so on. But the side effects of BBR causing constipation should not be ignored. In clinical application, the combination of Lour. (AVL) and BBR can relieve it. However, the effective ingredients and molecular mechanism of AVL in relieving constipation are not clear. A small intestine propulsion experiment was conducted in constipated mice to screen active ingredients of AVL. We further confirmed the molecular mechanism of action of the active ingredient on BBR-induced constipation. Quercetin (QR) was found to be the effective ingredient of AVL in terms of relieving constipation. QR can efficiently regulate the microbiota in mice suffering from constipation. Moreover, QR significantly raised the levels of substance P and motilin while lowering those of 5-hydroxytryptamine and vasoactive intestinal peptide; furthermore, it also increased the protein expression levels of calmodulin, myosin light-chain kinase, and myosin light chain. The use of QR in combination with BBR has an adverse effect-reducing efficacy. The study provides new ideas and possibilities for the treatment of constipation induced by BBR.
Topics: Animals; Berberine; Quercetin; Constipation; Gastrointestinal Microbiome; Mice; Male; Disease Models, Animal; Motilin
PubMed: 38892414
DOI: 10.3390/ijms25116228 -
International Journal of Molecular... May 2024Sepsis-associated kidney injury is common in critically ill patients and significantly increases morbidity and mortality rates. Several complex pathophysiological... (Review)
Review
Sepsis-associated kidney injury is common in critically ill patients and significantly increases morbidity and mortality rates. Several complex pathophysiological factors contribute to its presentation and perpetuation, including macrocirculatory and microcirculatory changes, mitochondrial dysfunction, and metabolic reprogramming. Recovery from acute kidney injury (AKI) relies on the evolution towards adaptive mechanisms such as endothelial repair and tubular cell regeneration, while maladaptive repair increases the risk of progression to chronic kidney disease. Fundamental management strategies include early sepsis recognition and prompt treatment, through the administration of adequate antimicrobial agents, fluid resuscitation, and vasoactive agents as needed. In septic patients, organ-specific support is often required, particularly renal replacement therapy (RRT) in the setting of severe AKI, although ongoing debates persist regarding the ideal timing of initiation and dosing of RRT. A comprehensive approach integrating early recognition, targeted interventions, and close monitoring is essential to mitigate the burden of SA-AKI and improve patient outcomes in critical care settings.
Topics: Humans; Acute Kidney Injury; Sepsis; Renal Replacement Therapy; Critical Illness
PubMed: 38892111
DOI: 10.3390/ijms25115924 -
Animals : An Open Access Journal From... May 2024Crotalus snakebites induce various toxicological effects, encompassing neurological, myotoxic, and cytotoxic symptoms, with potentially fatal outcomes. Investigating...
A Comparative Analysis of the Cytotoxic and Vascular Activity Effects of Western Diamondback Rattlesnake () and Eastern Diamondback Rattlesnake () Venoms Using a Chick Embryo Model.
Crotalus snakebites induce various toxicological effects, encompassing neurological, myotoxic, and cytotoxic symptoms, with potentially fatal outcomes. Investigating venom toxicity is essential for public health, and developing new tools allows for these effects to be studied more comprehensively. The research goals include the elucidation of the physiological consequences of venom exposure and the assessment of toxicity using animal models. Chicken embryos serve as valuable models for assessing venom toxicity through the chick embryotoxicity screening test (CHEST) and the chick chorioallantoic membrane (CAM) assay, particularly useful for evaluating vascular impacts. venom application resulted in higher embryotoxicity and morphological abnormalities, such as Siamese twins. The CAM assay demonstrated the hemorrhagic effects of venom, varying with venom type and concentration. The irritant potential of both venom types was classified as slight or moderate depending on their concentration. Additionally, acetylcholinesterase (AChE) activity was performed to receive information about organ toxicity. The results show that both venoms induced changes in the whole embryo, heart, and liver weights, but the venom was identified as more toxic. Specific venom concentrations affected AChE activity in embryonic tissues. These findings underscore the embryotoxic and vasoactive properties of , providing valuable insights into their mechanisms of toxicity and potential applications in biomedicine.
PubMed: 38891681
DOI: 10.3390/ani14111634 -
Annals of Clinical and Translational... Jun 2024Migraine is a complex and disabling neurological disorder. Recent years have witnessed the development and emergence of novel treatments for the condition, namely those... (Review)
Review
OBJECTIVE
Migraine is a complex and disabling neurological disorder. Recent years have witnessed the development and emergence of novel treatments for the condition, namely those targeting calcitonin gene-related peptide (CGRP). However, there remains a substantial need for further treatments for those unresponsive to current therapies. Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) as a possible therapeutic strategy in the primary headache disorders has gained interest over recent years.
METHODS
This review will summarize what we know about PACAP to date: its expression, receptors, roles in migraine and cluster headache biology, insights gained from preclinical and clinical models of migraine, and therapeutic scope.
RESULTS
PACAP shares homology with vasoactive intestinal polypeptide (VIP) and is one of several vasoactive neuropeptides along with CGRP and VIP, which has been implicated in migraine neurobiology. PACAP is widely expressed in areas of interest in migraine pathophysiology, such as the thalamus, trigeminal nucleus caudalis, and sphenopalatine ganglion. Preclinical evidence suggests a role for PACAP in trigeminovascular sensitization, while clinical evidence shows ictal release of PACAP in migraine and intravenous infusion of PACAP triggering attacks in susceptible individuals. PACAP leads to dural vasodilatation and secondary central phenomena via its binding to different G-protein-coupled receptors, and intracellular downstream effects through cyclic adenosine monophosphate (cAMP) and phosphokinase C (PKC). Targeting PACAP as a therapeutic strategy in headache has been explored using monoclonal antibodies developed against PACAP and against the PAC1 receptor, with initial positive results.
INTERPRETATION
Future clinical trials hold considerable promise for a new therapeutic approach using PACAP-targeted therapies in both migraine and cluster headache.
PubMed: 38887982
DOI: 10.1002/acn3.52119 -
Frontiers in Pediatrics 2024The primary aim of this study was to compare non-invasive blood pressure (NIBP) measurement using the automated oscillometric method with invasive blood pressure (IBP)...
Comparison of invasive blood pressure monitoring vs. non-invasive blood pressure monitoring in critically ill children receiving vasoactive agents-a prospective observational study.
OBJECTIVE
The primary aim of this study was to compare non-invasive blood pressure (NIBP) measurement using the automated oscillometric method with invasive blood pressure (IBP) measurement using peripheral arterial line insertion in critically ill children receiving vasoactive agents.
DESIGN
Single-centre, prospective cohort study.
SETTING
Tertiary care 15 bedded Pediatric ICU in Urban Indian city.
SUBJECTS
All critically ill children between the ages of 1 month to 16 years with shock on vasoactive medications and with IBP monitoring.
RESULTS
Forty children with 1,072 paired BP measurements were incorporated in the final analysis. Among all normotensive children (Total number of paired measurements = 623) receiving vasoactive agents, Bland-Altman analysis revealed an acceptable agreement between Invasive mean blood pressure (MBP) and non-invasive MBP with a bias of -2.10 mmHg (SD 11.35). The 95% limits of agreement were from -24.34 to 20.14 mmHg. In children with hypotension (Total number of paired measurements = 449), Bland-Altman analysis showed disagreement between Invasive MBP and non-invasive MBP i.e., a bias of -8.44 mmHg (SD 9.62). The 95% limits of agreement were from -27.29 to 10.41 mmHg.
CONCLUSION
A limited agreement exists between invasive blood pressure (IBP) and non-invasive blood pressure (NIBP) measurements in critically ill children requiring vasoactive agents. This discrepancy can lead to either an underestimation or an overestimation of blood pressure. While NIBP can serve as a screening tool for hemodynamically stable children, those who are hemodynamically unstable and necessitate the initiation of vasoactive agents should undergo IBP monitoring.
PubMed: 38887566
DOI: 10.3389/fped.2024.1376327 -
Infection Jun 2024In this retrospective observational multicenter study, we aimed to assess efficacy and mortality between ceftazidime/avibactam (CAZ/AVI) or polymyxin B (PMB)-based...
OBJECTIVES
In this retrospective observational multicenter study, we aimed to assess efficacy and mortality between ceftazidime/avibactam (CAZ/AVI) or polymyxin B (PMB)-based regimens for the treatment of Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, as well as identify potential risk factors.
METHODS
A total of 276 CRKP-infected patients were enrolled in our study. Binary logistic and Cox regression analysis with a propensity score-matched (PSM) model were performed to identify risk factors for efficacy and mortality.
RESULTS
The patient cohort was divided into PMB-based regimen group (n = 98, 35.5%) and CAZ/AVI-based regimen group (n = 178, 64.5%). Compared to the PMB group, the CAZ/AVI group exhibited significantly higher rates of clinical efficacy (71.3% vs. 56.1%; p = 0.011), microbiological clearance (74.7% vs. 41.4%; p < 0.001), and a lower incidence of acute kidney injury (AKI) (13.5% vs. 33.7%; p < 0.001). Binary logistic regression revealed that the treatment duration independently influenced both clinical efficacy and microbiological clearance. Vasoactive drugs, sepsis/septic shock, APACHE II score, and treatment duration were identified as risk factors associated with 30-day all-cause mortality. The CAZ/AVI-based regimen was an independent factor for good clinical efficacy, microbiological clearance, and lower AKI incidence.
CONCLUSIONS
For patients with CRKP infection, the CAZ/AVI-based regimen was superior to the PMB-based regimen.
PubMed: 38884857
DOI: 10.1007/s15010-024-02324-8 -
MedRxiv : the Preprint Server For... Jun 2024Cerebrovascular reactivity (CVR) reflects the ability of blood vessels to dilate or constrict in response to a vasoactive stimulus, and allows researchers to assess the...
Cerebrovascular reactivity (CVR) reflects the ability of blood vessels to dilate or constrict in response to a vasoactive stimulus, and allows researchers to assess the brain's vascular health. Individuals with spinal cord injury (SCI) are at an increased risk for autonomic dysfunction in addition to cognitive impairments, which have been linked to a decline in CVR; however, there is currently a lack of brain-imaging studies that investigate how CVR is altered after SCI. In this study, we used a breath-holding hypercapnic stimulus and functional near-infrared spectroscopy (fNIRS) to investigate CVR alterations in individuals with SCI (n = 20, 14M, 6F, mean age = 46.3 ± 10.2 years) as compared to age- and sex-matched able-bodied (AB) controls (n = 25, 19M, 6F, mean age = 43.2 ± 12.28 years). CVR was evaluated by its amplitude and delay components separately by using principal component analysis and cross-correlation analysis, respectively. We observed significantly delayed CVR in the right inferior parietal lobe in individuals with SCI compared to AB controls (linear mixed-effects model, fixed-effects estimate = 6.565, Satterthwaite's t-test, t = 2.663, p = 0.008), while the amplitude of CVR was not significantly different. The average CVR delay in the SCI group in the right inferior parietal lobe was 14.21 s (sd: 6.60 s), and for the AB group, the average delay in the right inferior parietal lobe was 7.08 s (sd: 7.39 s). CVR delays were also associated with the duration since injury in individuals with SCI, in which a longer duration since injury was associated with a shortened delay in CVR in the right inferior parietal region (Pearson's r-correlation, r = -0.59, p = 0.04). This study shows that fNIRS can be used to quantify changes in CVR in individuals with SCI, and may be further used in rehabilitative settings to monitor the cerebrovascular health of individuals with SCI.
PubMed: 38883754
DOI: 10.1101/2024.06.03.24307819 -
MedComm Jul 2024Neuropeptide Y (NPY), a 36-amino-acid peptide, functions as a neurotransmitter in both the central and peripheral nervous systems by activating the NPY receptor...
Neuropeptide Y (NPY), a 36-amino-acid peptide, functions as a neurotransmitter in both the central and peripheral nervous systems by activating the NPY receptor subfamily. Notably, NPY analogs display varying selectivity and exert diverse physiological effects through their interactions with this receptor family. [Pro]-NPY and [Leu, Pro]-NPY, mainly acting on YR, reportedly increases blood pressure and postsynaptically potentiates the effect of other vasoactive substances above all, while N-terminal cleaved NPY variants in human body primary mediates angiogenesis and neurotransmitter release inhibition through YR. However, the recognition mechanisms of YR and YR with specific agonists remain elusive, thereby hindering subtype receptor-selective drug development. In this study, we report three cryo-electron microscopy (cryo-EM) structures of Gi2-coupled YR and YR in complexes with NPY, as well as YR bound to a selective agonist [Leu, Pro]-NPY. Combined with cell-based assays, our study not only reveals the conserved peptide-binding mode of NPY receptors but also identifies an additional sub-pocket that confers ligand selectivity. Moreover, our analysis of YR evolutionary dynamics suggests that this sub-pocket has undergone functional adaptive evolution across different species. Collectively, our findings shed light on the molecular underpinnings of neuropeptide recognition and receptor activation, and they present a promising avenue for the design of selective drugs targeting the NPY receptor family.
PubMed: 38882210
DOI: 10.1002/mco2.565 -
Journal of Nanobiotechnology Jun 2024Oxygen is necessary for life and plays a key pivotal in maintaining normal physiological functions and treat of diseases. Hemoglobin-based oxygen carriers (HBOCs) have... (Review)
Review
Oxygen is necessary for life and plays a key pivotal in maintaining normal physiological functions and treat of diseases. Hemoglobin-based oxygen carriers (HBOCs) have been studied and developed as a replacement for red blood cells (RBCs) in oxygen transport due to their similar oxygen-carrying capacities. However, applications of HBOCs are hindered by vasoactivity, oxidative toxicity, and a relatively short circulatory half-life. With advancements in nanotechnology, Hb encapsulation, absorption, bioconjugation, entrapment, and attachment to nanomaterials have been used to prepare nanomaterial-related HBOCs to address these challenges and pend their application in several biomedical and therapeutic contexts. This review focuses on the progress of this class of nanomaterial-related HBOCs in the fields of hemorrhagic shock, ischemic stroke, cancer, and wound healing, and speculates on future research directions. The advancements in nanomaterial-related HBOCs are expected to lead significant breakthroughs in blood substitutes, enabling their widespread use in the treatment of clinical diseases.
Topics: Humans; Hemoglobins; Blood Substitutes; Oxygen; Animals; Nanostructures; Liposomes; Nanocapsules; Wound Healing; Neoplasms; Shock, Hemorrhagic
PubMed: 38880905
DOI: 10.1186/s12951-024-02606-1 -
The Journal of Rheumatology Jun 2024Raynaud's phenomenon (RP) and digital ulcers (DUs) are the main signs of digital vasculopathy in systemic sclerosis (SSc). Selexipag is an oral prostacyclin agonist...
OBJECTIVE
Raynaud's phenomenon (RP) and digital ulcers (DUs) are the main signs of digital vasculopathy in systemic sclerosis (SSc). Selexipag is an oral prostacyclin agonist approved for SSc-related pulmonary arterial hypertension. Following our previous preliminary short-course report, we herein present long-term data on selexipag safety and efficacy in the treatment of SSc digital vasculopathy.
METHODS
Selexipag was administered to SSc patients with severe digital vasculopathy refractory or with contraindication to all other vasoactive therapies. Each subject was assessed at baseline and after 3, 6 and 12 months. Clinical outcomes related to RP and DUs were evaluated along with fingers skin score. Digital perfusion was assessed by laser speckle contrast analysis (LASCA). Nailfold videocapillaroscopy (NVC) was also performed.
RESULTS
Eight SSc patients (63% female, mean age 50.1 years) received selexipag. After 12 months of treatment, RP was reported to significantly decrease in the number of daily episodes and mean duration (p<0.001 and p=0.01, respectively). All patients achieved a complete healing of their DUs (p=0.03) within six months. A progressive reduction of fingers skin score was observed (p=0.03). No structural changes of capillaries were noted at NVC. Conversely, LASCA revealed an important increase in total digital perfusion (p=0.004) despite seasonal variability. The safety profile was consistent with that reported in the literature.
CONCLUSION
We observed a sustained efficacy of selexipag on SSc digital vasculopathy during one year of administration. Our promising results encourage the design of a new randomized controlled trial to evaluate the effect of selexipag on SSc digital vasculopathy.
PubMed: 38879188
DOI: 10.3899/jrheum.2024-0103