Polyethylene terephthalate (PET) micro- and nanoplastic particles affect the mitochondrial efficiency of human brain vascular pericytes without inducing oxidative stress.

The objective of this investigation was to evaluate the influence of micro- and nanoplastic particles composed of polyethylene terephthalate (PET), a significant contributor to plastic pollution, on human brain vascular pericytes. Specifically, we delved into their impact on mitochondrial functionality, oxidative stress, and the expression of genes associated with oxidative stress, ferroptosis and mitochondrial functions. Our findings demonstrate that the exposure of a monoculture of human brain vascular pericytes to PET particles in vitro at a concentration of 50 µg/ml for a duration of 3, 6 and 10 days did not elicit oxidative stress. Notably, we observed a reduction in various aspects of mitochondrial respiration, including maximal respiration, spare respiratory capacity, and ATP production in pericytes subjected to PET particles for 3 days, with a mitochondrial function recovery at 6 and 10 days. Furthermore, there were no statistically significant alterations in mitochondrial DNA copy number, or in the expression of genes linked to oxidative stress and ferroptosis, but an increase of the expression of the gene mitochondrial transcription factor A (TFAM) was noted at 3 days exposure. These outcomes suggest that, at a concentration of 50 µg/ml, PET particles do not induce oxidative stress in human brain vascular pericytes. Instead, at 3 days exposure, PET exposure impairs mitochondrial functions, but this is recovered at 6-day exposure. This seems to indicate a potential mitochondrial hormesis response (mitohormesis) is incited, involving the gene TFAM. Further investigations are warranted to explore the stages of mitohormesis and the potential consequences of plastics on the integrity of the blood-brain barrier and intercellular interactions. This research contributes to our comprehension of the potential repercussions of nanoplastic pollution on human health and underscores the imperative need for ongoing examinations into the exposure to plastic particles.

Dementia with Lewy Bodies: Genomics, Transcriptomics, and Its Future with Data Science.

Dementia with Lewy bodies (DLB) is a significant public health issue. It is the second most common neurodegenerative dementia and presents with severe neuropsychiatric symptoms. Genomic and transcriptomic analyses have provided some insight into disease pathology. Variants within SNCA, GBA, APOE, SNCB, and MAPT have been shown to be associated with DLB in repeated genomic studies. Transcriptomic analysis, conducted predominantly on candidate genes, has identified signatures of synuclein aggregation, protein degradation, amyloid deposition, neuroinflammation, mitochondrial dysfunction, and the upregulation of heat-shock proteins in DLB. Yet, the understanding of DLB molecular pathology is incomplete. This precipitates the current clinical position whereby there are no available disease-modifying treatments or blood-based diagnostic biomarkers. Data science methods have the potential to improve disease understanding, optimising therapeutic intervention and drug development, to reduce disease burden. Genomic prediction will facilitate the early identification of cases and the timely application of future disease-modifying treatments. Transcript-level analyses across the entire transcriptome and machine learning analysis of multi-omic data will uncover novel signatures that may provide clues to DLB pathology and improve drug development. This review will discuss the current genomic and transcriptomic understanding of DLB, highlight gaps in the literature, and describe data science methods that may advance the field.

Healing of Endosseous Implants Having Different Surface Characteristics in the Alveolar Bone: A Clinical Study.

Background Total treatment time in implant placement can be significantly reduced by placing immediate implants into the freshly extracted sockets. Also, immediate implant placement can act as a guide for proper and accurate implant placement. Additionally, in immediate implant placement, the resorption of bone associated with the healing of the extraction socket is also reduced. This clinical study aimed to clinically and radiographically assess the healing of endosseous implants having different surface characteristics in nongrafted and grafted bone. Methodology In 68 subjects, 198 implants were placed, including 102 oxidized (TiUnite, Göteborg, Sweden) and 96 turned surface implants (Nobel Biocare Mark III, Göteborg) were placed. Survival was considered with clinical stability and acceptable function with no discomfort and no radiographic or clinical signs of pathology/infection. Rest cases that showed no healing and implant no osseointegration were considered failures. Clinical and radiographic examination was done by two experts after two years of loading based on bleeding on probing (BOP) mesially and distally, radiographic marginal bone levels, and probing depth (mesial and distal). Results Five implants failed in total where four implants were with the turned surface (Nobel Biocare Mark III) and one was from the oxidized surface (TiUnite). The one oxidized implant was in a 62-year-old female and was placed in the region of mandibular premolar (44) of length 13 mm and was lost within five months of placement before functional loading. Mean probing depth had a nonsignificant difference between oxidized and turned surfaces with the mean values of 1.6 ± 1.2 and 1.5 ± 1.0 mm, respectively, with P = 0.5984; mean BOP in oxidized and turned surfaces was 0.3 ± 0.7 and 0.4 ± 0.6, respectively (P = 0.3727). Marginal bone levels, respectively, were 2.0 ± 0.8 and 1.8 ± 0.7 mm (P = 0.1231). In marginal bone levels related to implant loading, a nonsignificant difference was seen in early loading and one-stage loading with P-values of 0.06 and 0.09, respectively. However, in two-stage placement, significantly higher values were seen for oxidized surfaces (2.4 ± 0.8 mm) compared to turned surfaces (1.9 ± 0.8 mm), with P = 0.0004. Conclusions This study concludes that nonsignificantly higher survival rates are associated with oxidized surfaces compared to turned surfaces after two years of follow-up. Higher marginal bone levels were seen in oxidized surfaces for single implants and implants placed in two stages.

In vitro study of ochratoxin A in the expression of genes associated with neuron survival and viability.

Ochratoxin A (OTA) is a common mycotoxin and known contaminant of crops, foods and drinks. As OTA crosses the blood-brain barrier, this study investigated the role of OTA, as an environmental hazard, on neuronal survival and viability. The impact of a range of OTA concentrations on the expression of MAPT, BAX, P53, BDNF and TPPP genes was investigated using human neuroblastoma (SH-SY5Y) cells. The absence of altered gene expression determined using reverse transcription quantitative PCR demonstrated that exposure to a typical daily dose of OTA delivered to the brain (2 fM), may not trigger neuronal dysfunction. However, a dose of OTA (2 pM) decreased BDNF expression. BDNF and TPPP expression were significantly reduced after 1 day and significantly increased after 2 days of exposure to 1 µM OTA. The expression of P53, MAPT, and BAX was reduced at both days. Thus, despite OTA cytotoxicity, SH-SY5Y cells entered a survival state following a strong toxic insult. A typical daily environmental OTA exposure does not appear to carry an increased risk of neurodegenerative disease. However, BDNF dysfunction may occur through prolonged exposure to a dose one thousand times higher than the typical daily consumed OTA dose potentially causing adverse effects on neuronal health.

iPS Cells-The Triumphs and Tribulations.

The year 2006 will be remembered monumentally in science, particularly in the stem cell biology field, for the first instance of generation of induced pluripotent stem cells (iPSCs) from mouse embryonic/adult fibroblasts being reported by Takahashi and Yamanaka. A year later, human iPSCs (hiPSCs) were generated from adult human skin fibroblasts by using quartet of genes, Oct4, Sox2, Klf4, and c-Myc. This revolutionary technology won Yamanaka Nobel Prize in Physiology and Medicine in 2012. Like human embryonic stem cells (hESCs), iPSCs are pluripotent and have the capability for self-renewal. Moreover, complications of immune rejection for therapeutic applications would be greatly eliminated by generating iPSCs from individual patients. This has enabled their use for drug screening/discovery and disease modelling in vitro; and for immunotherapy and regenerative cellular therapies in vivo, paving paths for new therapeutics. Although this breakthrough technology has a huge potential, generation of these unusual cells is still slow, ineffectual, fraught with pitfalls, and unsafe for human use. In this review, I describe how iPSCs are being triumphantly used to lay foundation for a fully functional discipline of regenerative dentistry and medicine, alongside discussing the challenges of translating therapies into clinics. I also discuss their future implications in regenerative dentistry field.

In Vivo Delivery of Tinospora cordifolia Root Extract Preventing Radiation-Induced Dystrophies in Mice Ovaries.

Unconscious and unplanned radiation exposures are a severe threat to gonads particularly ovaries. The present study aims at finding radioprotective effect of Tinospora cordifolia (Willd.) Miers root extract (TCRE) in ovaries. Swiss albino mice were divided into four groups: Group 1 served as "normal" and is administered double distilled water and Group 2 is given TCRE with optimum dosage selected as 75 mg/mice. Group 3 serving the purpose of "irradiated control" were exposed to 2.5 Gy gamma radiation. Group 4 (experimental) were administered optimum dosage of TCRE with prior exposure to 2.5 Gy gamma radiation. Follicle cell counts were scored at autopsy intervals of 24 hrs, 3 days, 7 days, 15 days, and 30 days after gamma irradiation. To understand the mechanism of radioprotection, lipid peroxidation (LPO) and glutathione (GSH) levels were also measured in all groups. TCRE supplementation rendered significant protection to ovaries by restoring follicle counts; it also reduced LPO levels and increased GSH levels in ovaries. It implies that TCRE administration protects ovaries against radiation exposure.

Multiple unfolding pathways of leucine binding protein (LBP) probed by single-molecule force spectroscopy (SMFS).

Experimental studies on the folding and unfolding of large multi-domain proteins are challenging, given the proteins' complex energy landscapes with multiple intermediates. Here, we report a mechanical unfolding study of a 346-residue, two-domain leucine binding protein (LBP) from the bacterial periplasm. Forced unfolding of LBP is a prerequisite for its translocation across the cytoplasmic membrane into the bacterial periplasm. During the mechanical stretching of LBP, we observe that 38% of the unfolding flux followed a two-state pathway, giving rise to a single unfolding force peak at ~70 pN with an unfolding contour length of 120 nm in constant-velocity single-molecule pulling experiments. The remaining 62% of the unfolding flux followed multiple three-state pathways, with intermediates having unfolding contour lengths in the range ~20-85 nm. These results suggest that the energy landscape of LBP is complex, with multiple intermediate states, and a large fraction of molecules go through intermediate states during the unfolding process. Furthermore, the presence of the ligand leucine increased the unfolding flux through the two-state pathway from 38% to 65%, indicating the influence of ligand binding on the energy landscape. This study suggests that unfolding through parallel pathways might be a general mechanism for the large two-domain proteins that are translocated to the bacterial periplasmic space.

Single-molecule studies on PolySUMO proteins reveal their mechanical flexibility.

Proteins with ß-sandwich and ß-grasp topologies are resistant to mechanical unfolding as shown by single-molecule force spectroscopy studies. Their high mechanical stability has generally been associated with the mechanical clamp geometry present at the termini. However, there is also evidence for the importance of interactions other than the mechanical clamp in providing mechanical stability, which needs to be tested thoroughly. Here, we report the mechanical unfolding properties of ubiquitin-like proteins (SUMO1 and SUMO2) and their comparison with those of ubiquitin. Although ubiquitin and SUMOs have similar size and structural topology, they differ in their sequences and structural contacts, making them ideal candidates to understand the variations in the mechanical stability of a given protein topology. We observe a two-state unfolding pathway for SUMO1 and SUMO2, similar to that of ubiquitin. Nevertheless, the unfolding forces of SUMO1 (∼130 pN) and SUMO2 (∼120 pN) are lower than that of ubiquitin (∼190 pN) at a pulling speed of 400 nm/s, indicating their lower mechanical stability. The mechanical stabilities of SUMO proteins and ubiquitin are well correlated with the number of interresidue contacts present in their structures. From pulling speed-dependent mechanical unfolding experiments and Monte Carlo simulations, we find that the unfolding potential widths of SUMO1 (∼0.51 nm) and SUMO2 (∼0.33 nm) are much larger than that of ubiquitin (∼0.19 nm), indicating that SUMO1 is six times and SUMO2 is three times mechanically more flexible than ubiquitin. These findings might also be important in understanding the functional differences between ubiquitin and SUMOs.