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Introduction: The relationship between gut microbiota and peripheral artery disease (PAD) remains understudied. While traditional risk factors like smoking and hyperlipidemia are well-understood, our study aims to determine the potential causative association of gut microbiota with PAD using Mendelian Randomization. Methods: Data from the International MiBioGen Consortium and the FinnGen research project were used to study 211 bacterial taxa. Instrumental variables, comprising 2079 SNPs, were selected based on significance levels and linkage disequilibrium. Analyses were conducted utilizing the inverse-variance weighted (IVW) method and other statistical MR techniques to mitigate biases, processed in R (v4.3.1) with the TwosampleMR package. Results: Three bacterial taxa, namely genus Coprococcus2, RuminococcaceaeUCG004, and RuminococcaceaeUCG010, emerged as protective factors against PAD. In contrast, family. FamilyXI and the genus Lachnoclostridium and LachnospiraceaeUCG001 were identified as risk factors. Conclusion: Our findings hint at a causative association between certain gut microbiota and PAD, introducing new avenues for understanding PAD's etiology and developing effective treatments. The observed associations now warrant further validation in varied populations and detailed exploration at finer taxonomic levels. [ABSTRACT FROM AUTHOR]

Candidate drugs targeting the central nervous system (CNS) demonstrate extremely low clinical success rates, with more than 98% of potential treatments being discontinued due to poor blood-brain barrier (BBB) permeability. Neurological conditions were shown to be the second leading cause of death globally in 2016, with the number of people currently affected by neurological disorders increasing rapidly. This increasing trend, along with an inability to develop BBB permeating drugs, is presenting a major hurdle in the treatment of CNS-related disorders, like dementia. To overcome this, it is necessary to understand the structure and function of the BBB, including the transport of molecules across its interface in both healthy and pathological conditions. The use of CNS drug carriers is rapidly gaining popularity in CNS research due to their ability to target BBB transport systems. Further research and development of drug delivery vehicles could provide essential information that can be used to develop novel treatments for neurological conditions. This review discusses the BBB and its transport systems and evaluates the potential of using nanoparticle-based delivery systems as drug carriers for CNS disease with a focus on dementia., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Brain diseases, including neurodegenerative diseases, acute ischemic stroke and brain tumors, have become a major health problem and a huge burden on society with high morbidity and mortality. However, most of the current therapeutic drugs can only relieve the symptoms of brain diseases, and it is difficult to achieve satisfactory therapeutic effects fundamentally. Extensive studies have shown that the therapeutic effects of brain diseases are mainly affected by two factors: the conservation of the blood–brain barrier (BBB) and the complexity of the brain micro‐environment. Brain‐targeting drug delivery systems provide new possibilities for overcoming these barriers with versatility. In this review, it provides an overview of BBB alteration and discusses targeting delivery strategies for brain diseases therapy. Furthermore, delivery systems which are designed to modulate the brain micro‐environment with synergistic effects were also highlighted. This article is categorized under:Therapeutic Approaches and Drug Discovery > Emerging Technologies [ABSTRACT FROM AUTHOR]

The bioactive sphingolipid ceramide has many important roles in cell signaling processes, particularly in signaling programmed cell death in cancer. However, ceramide levels are often impaired in multi‐drug resistant and radiation resistant cancers due to the dysregulation of ceramide metabolism. Restoration of ceramide levels through external delivery therefore represents a potential therapeutic target for the treatment of resistant cancers. However, as a lipid, ceramide is extremely hydrophobic and requires a delivery system to enter cells. Here we report the development of a method to load significant amounts of the long chain C16 and C24 ceramides onto oxidized graphene nanoribbons (O‐GNRs) derived from carbon nanotubes. Using O‐GNRs as a delivery system for these ceramides, we were able to induce significant biological effects in HeLa cells in conjunction with C6 ceramide and ultraviolet radiation treatment. However, we found that O‐GNRs themselves exert significant biological effects and can interfere with the actions of these ceramides and ultraviolet treatment. Loading of ceramides onto O‐GNRs did not have a significant effect on the entry of the nanoparticles into cells. Despite the need for further improvement, these data represent an important first step in the development of O‐GNRs as a delivery system for long chain ceramides. [ABSTRACT FROM AUTHOR]

Patients with peripheral arterial disease (PAD) have substantially impaired health-related quality of life (HR-QoL). Chronic lower limb ischaemia due to the atherosclerotic occlusion of infra-inguinal arteries is one of the most important causes of invalidity among smokers over the age of fifty. Historically, these lesions were treated by open bypass surgery. Less invasive endovascular revascularisation methods are available to treat short lesions, while treatment of long lesions are lacking. Fully endovascular trans-venous femoro-popliteal bypass (PQ Bypass, Inc., Sunnyvale, CA, USA) to treat long femoral lesions has been developed recently. The objective of the study was to evaluate duplex ultrasound (DUS) as a tool to follow up patients after PQ bypass procedure. A prospective clinical study was conducted at one clinical site. DUS of treated arteries and femoral vein was performed before the procedure, 30 days, 6 months, and 12 months in follow-up period by 2 independent radiologists. Ankle-brachial index (ABI) evaluation was performed at all visits. Thirty-five patients (35 limbs) treated with PQ bypass were enrolled in the study. Median age was 63.6 years (ranged 50 to 87 years). There was 100% successful evaluation of all patients at all clinical visits available. Deviation of the DUS results was found within the accepted standard limit between two radiologists. Twelve months after the PQ procedure, 28 (80.0%) PQ stent-grafts were still functioning without DUS signs of stenosis, while seven (20.0%) limbs experienced varying degrees of stent malfunction. PQ stent-graft occlusion was detected in five (14.3%) – 1 (2.9%) patients at one-month follow-up, 3 (8.6%) at six months and 1 (2.9%) at twelve months follow-up period, respectively. PQ stent-graft proximal junction stenosis was detected in one patient (2.9%) at six months and distal junction stenosis in one patient (2.9%) at twelve months follow-up, respectively. Despite of graft occlusion found with DUS, two patients had no severe worsening of post-operative ABI. DUS is a reliable method to evaluate patients after PQ bypass procedure and has higher sensitivity than ABI to follow-up patients after PQ procedure, especially in asymptomatic stent stenosis. Regular and timely use of DUS during the postoperative period may help to recognise potential complications and provide effective treatment.. [ABSTRACT FROM AUTHOR]

Stem cell therapies, although promising for treating peripheral arterial disease (PAD), often suffer from low engraftment rates and the inability to confirm the delivery success and track cell distribution and engraftment. Stem cell microencapsulation combined with imaging contrast agents may provide a means to simultaneously enhance cell survival and enable cell tracking with noninvasive imaging. Here, we have evaluated a novel MRI- and X-ray-visible microcapsule formulation for allogeneic mesenchymal stem cell (MSC) delivery and tracking in a large animal model. Bone marrow-derived MSCs from male New Zealand White rabbits were encapsulated using a modified cell encapsulation method to incorporate a dual-modality imaging contrast agent, perfluorooctyl bromide (PFOB). PFOB microcapsules (PFOBCaps) were then transplanted into the medial thigh of normal or PAD female rabbits. In vitro MSC viability remained high (79±5% at 4 weeks of postencapsulation), and as few as two and ten PFOBCaps could be detected in phantoms using clinical C-arm CT and 19F MRI, respectively. Successful injections of PFOBCaps in the medial thigh of normal (n=15) and PAD (n=16) rabbits were demonstrated on C-arm CT at 1-14 days of postinjection. Using 19F MRI, transplanted PFOBCaps were clearly identified as "hot spots" and showed one-to-one correspondence to the radiopacities on C-arm CT. Concordance of 19F MRI and C-arm CT locations of PFOBCaps with postmortem locations was high (95%). Immunohistological analysis revealed high MSC survival in PFOBCaps (>56%) two weeks after transplantation while naked MSCs were no longer viable beyond three days after delivery. These findings demonstrate that PFOBCaps could maintain cell viability even in the ischemic tissue and provide a means to monitor cell delivery and track engraftment using clinical noninvasive imaging systems. [ABSTRACT FROM AUTHOR]

The bioactive sphingolipid ceramide has many important roles in cell signaling processes, particularly in signaling programmed cell death in cancer. However, ceramide levels are often impaired in multi-drug resistant and radiation resistant cancers due to the dysregulation of ceramide metabolism. Restoration of ceramide levels through external delivery therefore represents a potential therapeutic target for the treatment of resistant cancers. However, as a lipid, ceramide is extremely hydrophobic and requires a delivery system to enter cells. Here we report the development of a method to load significant amounts of the long chain C 16 and C 24 ceramides onto oxidized graphene nanoribbons (O-GNRs) derived from carbon nanotubes. Using O-GNRs as a delivery system for these ceramides, we were able to induce significant biological effects in HeLa cells in conjunction with C 6 ceramide and ultraviolet radiation treatment. However, we found that O-GNRs themselves exert significant biological effects and can interfere with the actions of these ceramides and ultraviolet treatment. Loading of ceramides onto O-GNRs did not have a significant effect on the entry of the nanoparticles into cells. Despite the need for further improvement, these data represent an important first step in the development of O-GNRs as a delivery system for long chain ceramides., (© 2019 Wiley Periodicals, Inc.)

Despite the therapeutic potential of sphingolipids, the ability to develop this class of compounds as active pharmaceutical ingredients has been hampered by issues of solubility and delivery. Beyond these technical hurdles, significant challenges in completing the necessary preclinical studies to support regulatory review are necessary for commercialization. This review seeks to identify the obstacles and potential solutions in the translation of a novel liposomal technology from the academic bench to investigational new drug (IND) stage by discussing the preclinical development of the Ceramide NanoLiposome (CNL), which is currently being developed as an anticancer drug for the initial indication of hepatocellular carcinoma (HCC). [ABSTRACT FROM AUTHOR]

Coronary angiography is the gold standard for the diagnosis of coronary artery disease. Coronary artery Gensini scoring systems measure both the extent and the degree of stenosis of coronary artery and therefore, give clinicians a more accurate, objective, and comprehensive assessment of the severity of coronary artery disease. Using Gensini scoring systems in combination with statistical analysis, we found that five variables, namely, Brachial-ankle pulse wave velocity (PWV), ankle-brachial index (ABI), carotid artery intima-media thickness (IMT), blood sugar, and high density lipoprotein cholesterol (HDL-C), were all significantly different among groups of patients with different Gensini scores. All five variables can be used for early screening and assessment of coronary artery disease as independent prognostic factors for the morbidity and mortality from cardiovascular conditions. With the progression of coronary artery disease, the levels of PWV, IMT, and blood glucose are gradually increasing whereas the levels of ABI and HDL-C are gradually decreasing. These changes can be treated as warning signs and can also be helpful in evaluating the severity of coronary artery diseases. It is highly recommended to perform these five non-invasive tests as early as possible in order to identify high-risk patients at their subclinical stages. This would allow timely intervention and thereby lead to reduced morbidity and mortality from cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: In patients with peripheral artery disease (PAD), the impact of diabetes mellitus (DM) on patient-profile and adverse in-hospital events is not well investigated. Methods: The German nationwide inpatient sample 2005–2019 was used for this analysis. Hospitalized PAD patients were stratified for DM and the influence of DM on patient-profile and adverse in-hospital events was investigated. Results: Our study comprised 2,654,871 hospitalizations (54.3% aged ≥70 years, 36.7% females) of patients with PAD in Germany 2005–2019. Among these, 864,691 (32.6%) patients had DM and 76,716 (2.9%) died during hospitalization. Diabetic PAD patients revealed an aggravated cardiovascular profile (Charlson Comorbidity Index: 6.0 (5.0–8.0) vs. 4.0 (3.0–5.0), p < 0.001). PAD patients with DM showed a higher rate of in-hospital mortality (3.5% vs. 2.6%, p < 0.001), as well as major adverse cardiovascular and cerebrovascular events (MACCE, 4.7% vs. 3.3%, p < 0.001) and had more often operated with amputation surgery (16.4% vs. 9.1%, p < 0.001). DM was an independent predictor of in-hospital mortality (OR 1.077 (95%CI 1.060–1.093), p < 0.001) and MACCE (OR 1.118 (95%CI 1.103–1.133), p < 0.001). In addition, amputations were also associated with DM (OR 1.804 (95%CI 1.790–1.818)), p < 0.001). Conclusions: DM is associated with an unfavorable clinical patient-profile and higher risk for adverse events in PAD patients, including substantially increased in-hospital mortality as well as MACCE rate, and were more often associated with amputation surgeries. [ABSTRACT FROM AUTHOR]

Comparisons of known primary structures of polygalacturonases show that extent and localization of potential N-glycosylation sites differ. Some sites are similar in position and adjacent to strictly conserved residues at the potential active site. The presence of N-acetylglucosamine and mannose in the molecules of two homogeneous, major Aspergillus sp. polygalacturonase forms was confirmed by IR spectroscopy. The purification method, based on interaction of the carbohydrate part with concanavalin A immobilized on chlorotriazine bead cellulose, was optimized. Deglycosylation with N-glycosidase F under denaturating and nondenaturating conditions led to molecular mass decreases followed by complete inactivation of the polygalacturonase enzyme activity. These results show the importance of glycosylation in these protein forms, while the comparative patterns establish both variability and some similarities in overall glycosylation architectures. [ABSTRACT FROM AUTHOR]

In the present study, the molecular and basic biochemical characterization of endopolygalacturonase E, the fourth Aspergillus niger N400 endopolygalacturonase, is reported. The entire endopolygalacturonase E gene consists of 1293 bp interrupted by three short introns (50, 50, and 59 bp, respectively) as concluded from the cDNA sequence. The deduced amino acid sequence comprises 378 residues that include 39 N-terminal amino acids of the prepropeptide. The calculated Mr and pI of the mature protein are 35 584 and 3.6, respectively. Compared with other endopolygalacturonases from A. niger N400, the mature protein endopolygalacturonase E has the highest sequence identity with endopolygalacturonase C (77.6 %) followed by endopolygalacturonase I (57.6 %) and endopolygalacturonase II (54.3 %). For overproduction of endopolygalacturonase E, an A. niger multicopy strain was used that was transformed with a promoter gene fusion construct that directs expression from the glycolytic A. niger pyruvate kinase promoter. The enzyme was purified and characterized as an endopolygalacturonase based on product analysis after polygalacturonate hydrolysis and on bond cleavage frequencies of oligogalacturonates of different degree of polymerisation (n = 2-7). The pH optimum was 3.8. The Km and Vmax for polygalacturonate hydrolysis were 2.5 ± 0.4 mg &timesd; ml-1 and 1.3 ± 0.2 μkat &timesd; mg-1, respectively. A subsite map was calculated by the combination of the methods of Suganuma et al. [Suganuma, T., Matsuno, R., Ohnishi, M. & Hiromi, K. (1978) J. Biochem. (Tokyo) 84, 293-316] and Nitta et al. [Nitta, Y., Mizushima, M., Hiromi, K. & Ono, S. (1971) J. Biochem. (Tokyo) 69, 567-576]. This indicated that the enzyme was composed of at least five subsites. [ABSTRACT FROM AUTHOR]