-
International Journal of Molecular... Jun 2024Nicotinamide adenine dinucleotide (NAD) is involved in renal physiology and is synthesized by nicotinamide mononucleotide adenylyltransferase (NMNAT). NMNAT exists as...
Nicotinamide adenine dinucleotide (NAD) is involved in renal physiology and is synthesized by nicotinamide mononucleotide adenylyltransferase (NMNAT). NMNAT exists as three isoforms, namely, NMNAT1, NMNAT2, and NMNAT3, encoded by , , and , respectively. In diabetic nephropathy (DN), NAD levels decrease, aggravating renal fibrosis. Conversely, sodium-glucose cotransporter-2 inhibitors increase NAD levels, mitigating renal fibrosis. In this regard, renal NAD synthesis has recently gained attention. However, the renal role of in DN remains uncertain. Therefore, we investigated the role of by establishing genetically engineered mice. Among the three isoforms, NMNAT1 levels were markedly reduced in the proximal tubules (PTs) of db/db mice. We examined the phenotypic changes in PT-specific conditional knockout (CKO) mice. In CKO mice, expression in PTs was downregulated when the tubules exhibited albuminuria, peritubular type IV collagen deposition, and mitochondrial ribosome (mitoribosome) excess. In CKO mice, deficiency-induced mitoribosome excess hindered mitoribosomal translation of mitochondrial inner membrane-associated oxidative phosphorylation complex I (CI), CIII, CIV, and CV proteins and mitoribosomal dysfunction. Furthermore, the expression of hypermethylated in cancer 1, a transcription repressor, was downregulated in CKO mice, causing mitoribosome excess. overexpression preserved mitoribosomal function, suggesting its protective role in DN.
Topics: Animals; Diabetic Nephropathies; Mice; Nicotinamide-Nucleotide Adenylyltransferase; Mice, Knockout; Kidney Tubules, Proximal; Male; Mitochondria; Mice, Inbred C57BL
PubMed: 38928090
DOI: 10.3390/ijms25126384 -
International Journal of Molecular... Jun 2024SARS-CoV-2 S-protein-mediated fusion is thought to involve the interaction of the membrane-distal or N-terminal heptad repeat (NHR) ("HR1") of the cleaved S2 segment of...
SARS-CoV-2 S-protein-mediated fusion is thought to involve the interaction of the membrane-distal or N-terminal heptad repeat (NHR) ("HR1") of the cleaved S2 segment of the protein and the membrane-proximal or C-terminal heptad repeat (CHR) ("HR2") regions of the protein. We examined the fusion inhibitory activity of a PEGylated HR2-derived peptide and its palmitoylated derivative using a pseudovirus infection assay. The latter peptide caused a 76% reduction in fusion activity at 10 µM. Our results suggest that small variations in peptide derivatization and differences in the membrane composition of pseudovirus preparations may affect the inhibitory potency of HR2-derived peptides. We suggest that future studies on the inhibition of infectivity of SARS-CoV-2 in both in vitro and in vivo systems consider the need for higher concentrations of peptide inhibitors.
Topics: SARS-CoV-2; Humans; Spike Glycoprotein, Coronavirus; Peptides; Palmitic Acid; Virus Internalization; COVID-19; Antiviral Agents
PubMed: 38928089
DOI: 10.3390/ijms25126382 -
International Journal of Molecular... Jun 2024Mutations in the gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of...
Mutations in the gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify mutations in a Korean CMT cohort with cerebellar ataxia and spasticity by whole exome sequencing (WES). As a result, eight pathogenic mutations in four families were identified as the underlying causes of these complex phenotypes. The prevalence of CMT families with mutations was determined to be 0.3%. All the patients showed sensory, motor, and gait disturbances with increased deep tendon reflexes. Lower limb magnetic resonance imaging (MRI) was performed in four patients and all had fatty replacements. Of note, they all had similar fatty infiltrations between the proximal and distal lower limb muscles, different from the neuromuscular imaging feature in most CMT patients without mutations who had distal dominant fatty involvement. Therefore, these findings were considered a characteristic feature in CMT patients with mutations. Although further studies with more cases are needed, our results highlight lower extremity MRI findings in CMT patients with mutations and broaden the clinical spectrum. We suggest screening for in recessive CMT patients with complex phenotypes of ataxia and spasticity.
Topics: Humans; Male; Charcot-Marie-Tooth Disease; Female; Mutation; Adult; Republic of Korea; Muscle Spasticity; Heterozygote; Cohort Studies; Middle Aged; Magnetic Resonance Imaging; Heat-Shock Proteins; Pedigree; Exome Sequencing; Cerebellar Ataxia; Phenotype; Adolescent; Young Adult
PubMed: 38928084
DOI: 10.3390/ijms25126378 -
Cancers Jun 2024This study introduces a free-style perforator based island flap (PBIF) for the reconstruction of skin defects. From March 2012 to December 2022, a retrospective...
This study introduces a free-style perforator based island flap (PBIF) for the reconstruction of skin defects. From March 2012 to December 2022, a retrospective investigation was conducted on patients who underwent reconstruction for facial defects due to skin cancer. Data on the patients' gender, age, anesthesia method, diagnosis, defect location, flap size, complications, and follow-up periods were collected. There are several principles for designing the PBIF: finger-pinching method, alignment with the direction of wrinkles, the smaller width and longer length of the flap, and proximal attachment to the muscle. A total of 32 patients were included, with an average age of 63.6 years. Surgeries were performed in various regions, such as the infraorbital area, nose, cheek, philtrum, and the anterior/posterior/inferior auricular regions, with an average flap size of 7.63 cm. There were no complications, such as venous congestion or vascular insufficiency in the skin flaps, although one case required revisional closure due to flap disruption. The PBIF is a useful and effective method for the restoration of facial defects. This method can provide simple yet aesthetically satisfying results, showing stable outcomes without complex surgeries or complications. This study indicates the potential for this method to be more widely employed in reconstructive surgeries in the future.
PubMed: 38927912
DOI: 10.3390/cancers16122206 -
Bioengineering (Basel, Switzerland) Jun 2024This study aimed to investigate the effect of the transverse sinus (TS) stenosis (TSS) position caused by arachnoid granulation on patients with venous pulsatile...
This study aimed to investigate the effect of the transverse sinus (TS) stenosis (TSS) position caused by arachnoid granulation on patients with venous pulsatile tinnitus (VPT) and to further identify the types of TSS that are of therapeutic significance for patients. Multiphysics interaction models of six patients with moderate TSS caused by arachnoid granulation and virtual stent placement in TSS were reconstructed, including three patients with TSS located in the middle segment of the TS (group 1) and three patients with TTS in the middle and proximal involvement segment of the TS (group 2). The transient multiphysics interaction simulation method was applied to elucidate the differences in biomechanical and acoustic parameters between the two groups. The results revealed that the blood flow pattern at the TS and sigmoid sinus junction was significantly changed depending on the stenosis position. Preoperative patients had increased blood flow in the TSS region and TSS downstream where the blood flow impacted the vessel wall. In group 1, the postoperative blood flow pattern, average wall pressure, vessel wall vibration, and sound pressure level of the three patients were comparable to the preoperative state. However, the postoperative blood flow velocity decreased in group 2. The postoperative average wall pressure, vessel wall vibration, and sound pressure level of the three patients were significantly improved compared with the preoperative state. Intravascular intervention therapy should be considered for patients with moderate TSS caused by arachnoid granulations in the middle and proximal involvement segment of the TS. TSS might not be considered the cause of VPT symptoms in patients with moderate TSS caused by arachnoid granulation in the middle segment of the TS.
PubMed: 38927848
DOI: 10.3390/bioengineering11060612 -
Genes May 2024To date, only 13 studies have described patients with large overlapping deletions of 10p11.2-p12. These individuals shared a common phenotype characterized by...
To date, only 13 studies have described patients with large overlapping deletions of 10p11.2-p12. These individuals shared a common phenotype characterized by intellectual disability, developmental delay, distinct facial dysmorphic features, abnormal behaviour, visual impairment, cardiac malformation, and cryptorchidism in males. Molecular cytogenetic analysis revealed that the deletion in this chromosomal region shares a common smallest region of overlap (SRO) of 80 kb, which contains only the gene (WW-domain-containing adaptor with coiled coil). In this clinical case report, we report a 5-year-old girl, born from non-consanguineous parents, with a 10p11.22p11.21 microdeletion. She presents clinical features that overlap with other patients described in the literature, such as dysmorphic traits, speech delay, and behavioural abnormalities (hyperactivity), even though the gene is not involved in the microdeletion. Our results are the first to highlight that the deletion described here represents a contiguous gene syndrome that is enough to explain the distinct phenotype but partially overlaps with the previous cases reported in the literature, even though the same genes are not involved. In particular, in this study, we speculate about the role of the gene that seems to be associated with normal motor development. In fact, we found that our patient is the only one described in the literature with a large deletion in the 10p11.22p11.21 region without the involvement of the gene deletion, and, interestingly, the patient did not have motor delay.
Topics: Humans; Female; Child, Preschool; Chromosome Deletion; Intellectual Disability; Abnormalities, Multiple; Syndrome; Phenotype; Developmental Disabilities
PubMed: 38927586
DOI: 10.3390/genes15060650 -
Biomedicines Jun 2024Autologous vein grafts are widely used for bypass procedures in cardiovascular surgery. However, these grafts are susceptible to failure due to vein graft disease. Our...
BACKGROUND
Autologous vein grafts are widely used for bypass procedures in cardiovascular surgery. However, these grafts are susceptible to failure due to vein graft disease. Our study aimed to evaluate the impact of the latest-generation FRAME external support on vein graft remodeling in a preclinical model.
METHODS
We performed autologous internal jugular vein interposition grafting in porcine carotid arteries for one month. Four grafts were supported with a FRAME mesh, while seven unsupported grafts served as controls. The conduits were examined through flowmetry, angiography, macroscopy, and microscopy.
RESULTS
The one-month patency rate of FRAME-supported grafts was 100% (4/4), whereas that of unsupported controls was 43% (3/7, Log-rank = 0.071). On explant angiography, FRAME grafts exhibited significantly more areas with no or mild stenosis (9/12) compared to control grafts (3/21, = 0.0009). Blood flow at explantation was higher in the FRAME grafts (145 ± 51 mL/min) than in the controls (46 ± 85 mL/min, = 0.066). Area and thickness of neo-intimal hyperplasia (NIH) at proximal anastomoses were similar for the FRAME and the control groups: 5.79 ± 1.38 versus 6.94 ± 1.10 mm, respectively ( = 0.558) and 480 ± 95 vs. 587 ± 52 μm/μm, respectively ( = 0.401). However, in the midgraft portions, the NIH area and thickness were significantly lower in the FRAME group than in the control group: 3.73 ± 0.64 vs. 6.27 ± 0.64 mm, respectively ( = 0.022) and 258 ± 49 vs. 518 ± 36 μm/μm, respectively ( = 0.0002).
CONCLUSIONS
In our porcine model, the external mesh FRAME improved the patency of vein-to-carotid artery grafts and protected them from stenosis, particularly in the mid regions. The midgraft neo-intimal hyperplasia was two-fold thinner in the meshed grafts than in the controls.
PubMed: 38927542
DOI: 10.3390/biomedicines12061335 -
Antibiotics (Basel, Switzerland) Jun 2024In this study, we assessed the impact of commercially available polymyxin B against VRP-034 (novel formulation of polymyxin B) using a validated in vitro human renal...
In this study, we assessed the impact of commercially available polymyxin B against VRP-034 (novel formulation of polymyxin B) using a validated in vitro human renal model, aProximate. Freshly isolated primary proximal tubule cells (PTCs) were cultured in Transwell plates and treated with various concentrations of the formulations for up to 48 h. The functional expression of megalin-cubilin receptors in PTC monolayers was validated using FITC-conjugated albumin uptake assays. Polymyxin B and VRP-034 were evaluated at six concentrations (0.3, 1, 3, 10, 30, and 60 µM), and nephrotoxicity was assessed through measurements of transepithelial electrical resistance (TEER), intracellular adenosine triphosphate (ATP) levels, lactate dehydrogenase (LDH) release, and novel injury biomarkers [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and clusterin]. Additionally, histological analysis using annexin V apoptosis staining was performed. Our results indicated a significant decrease in TEER with polymyxin B at concentrations ≥10 μM compared to VRP-034. Toxic effects were observed from ATP and LDH release only at concentrations ≥30 μM for both formulations. Furthermore, injury biomarker release was higher with polymyxin B compared to VRP-034, particularly at concentrations ≥10 µM. Histologically, polymyxin B-treated PTCs showed increased apoptosis compared to VRP-034-treated cells. Overall, VRP-034 demonstrated improved tolerance in the aProximate model compared to polymyxin B, suggesting its potential as a safer alternative for renal protection.
PubMed: 38927196
DOI: 10.3390/antibiotics13060530 -
Biomolecules May 2024Renal interstitial fibrosis (RIF) is a classic pathophysiological process of chronic kidney disease (CKD). However, the mechanisms underlying RIF remain unclear. The...
Renal interstitial fibrosis (RIF) is a classic pathophysiological process of chronic kidney disease (CKD). However, the mechanisms underlying RIF remain unclear. The present study found that a novel circular RNA, cirInpp5b, might be involved in RIF by high-throughput sequencing. Subsequent experiments revealed that circInpp5b was reduced in UUO mouse kidney tissues and TGF-β1-treated proximal tubular cells. The overexpression of circInpp5b inhibited RIF in UUO mice and prevented extracellular matrix (ECM) deposition in TGF-β1-treated proximal tubular cells. Furthermore, overexpression of circInpp5b down-regulated the protein level of DDX1. Mechanistically, circInpp5b bound to the DDX1 protein and promoted its lysosomal degradation. Collectively, the findings of our study demonstrate that circInpp5b ameliorates RIF by binding to the DDX1 protein and promoting its lysosomal degradation.
Topics: DEAD-box RNA Helicases; Animals; Mice; Lysosomes; Fibrosis; RNA, Circular; Proteolysis; Male; Mice, Inbred C57BL; Humans; Kidney; Kidney Diseases
PubMed: 38927017
DOI: 10.3390/biom14060613 -
BMC Public Health Jun 2024To analyze the vulnerability factors of snakebite patients in China.
OBJECTIVE
To analyze the vulnerability factors of snakebite patients in China.
METHODS
Multi-stage random sampling was used as the main sampling method and snowball sampling as the auxiliary sampling method. The knowledge, attitude and behavior of snakebite among Chinese residents were investigated. Non-parametric test was used to compare the percentage differences in residents' knowledge, attitude and behavior of snakebite, and generalized linear regression analysis was used to analyze the influencing factors, and the vulnerability factors of snakebite patients were comprehensively analyzed.
RESULTS
A total of 6338 subjects were included in this study, of which 68.4% were males, and 58.6% were farmers, workers and service personnel. The median total score of knowledge, attitude, and behavior was 26 (22,36). The patients who were improperly treated after injury were ligation proximal to the affected area (23.43%), squeezing (21.82%), and oral and suction wounds (8.74%). Did not go to hospital due to poverty (1351 cases) and did not receive antivenom (2068 cases). There were 21.32% and 32.63%, respectively. Among 4270 patients injected with antivenom 30.7% were vaccinated within 2 h. Among the patients who went to the hospital for treatment (4987), 75.0% arrived at the hospital within 6 h; Among the 4,761 patients who made emergency calls, 37.4% were treated within 0.5 h.
CONCLUSIONS
Snakebite patients in China have weak knowledge about snakebite, low awareness of medical treatment, lack of correct prevention and emergency treatment measures, dependence on folk remedies, poor housing and so on. In addition, there are low availability of antivenoms and unreasonable distribution of medical resources in some areas of China. Multisectoral and multidisciplinary cooperation should be developed to prevent and control snakebites in order to reduce the burden caused by snakebites.
Topics: Snake Bites; Humans; China; Male; Female; Adult; Health Knowledge, Attitudes, Practice; Middle Aged; Young Adult; Adolescent; Antivenins; Risk Factors; Surveys and Questionnaires; Aged
PubMed: 38926898
DOI: 10.1186/s12889-024-19169-3