Development Of Apoptosis Research Articles

The regulatory role of microRNAs in common eye diseases: A brief review.

MicroRNAs (miRNAs) are highly conserved, small non-coding RNA molecules (∼21 nucleotides) that regulate numerous biological processes, including developmental timing, hematopoiesis, organogenesis, apoptosis, cell differentiation, and proliferation either by mRNA degradation or translation repression. Since eye physiology requires a perfect orchestration of complex regulatory networks, an altered expression of key regulatory molecules such as miRNAs potentially leads to numerous eye disorders. In recent years, comprehensive progress has been made in demonstrating the precise roles of miRNAs, emphasizing their potential use in diagnostic and therapeutic purposes of chronic human diseases. Thus, this review explicitly illustrates the regulatory roles of miRNAs in four common eye disorders, such as cataract, glaucoma, macular degeneration, and uveitis, and their application in disease management.

Repressive ZINC FINGER OF ARABIDOPSIS THALIANA proteins promote programmed cell death in the Arabidopsis columella root cap.

Developmental programmed cell death (dPCD) controls a plethora of functions in plant growth and reproduction. In the root cap of Arabidopsis (Arabidopsis thaliana), dPCD functions to control organ size in balance with the continuous stem cell activity in the root meristem. Key regulators of root cap dPCD including SOMBRERO/ANAC033 (SMB) belong to the NAC family of transcription factors. Here, we identify the C2H2 zinc finger protein ZINC FINGER OF ARABIDOPSIS THALIANA 14 ZAT14 as part of the gene regulatory network of root cap dPCD acting downstream of SMB. Similar to SMB, ZAT14-inducible misexpression leads to extensive ectopic cell death. Both the canonical EAR motif and a conserved L-box motif of ZAT14 act as transcriptional repression motifs and are required to trigger cell death. While a single zat14 mutant does not show a cell death-related phenotype, a quintuple mutant knocking out 5 related ZAT paralogs shows a delayed onset of dPCD execution in the columella and the adjacent lateral root cap. While ZAT14 is co-expressed with established dPCD-associated genes, it does not activate their expression. Our results suggest that ZAT14 acts as a transcriptional repressor controlling a so far uncharacterized subsection of the dPCD gene regulatory network active in specific root cap tissues.

Developmental toxicity and inflammatory response induced by Botrytis cinerea in zebrafish (Danio rerio) larvae

Botrytis cinerea can reduce the yield of fruits and vegetables by infecting plants. The conidia produced by Botrytis cinerea can be transmitted to the aquatic environment via air and water, but the effects of Botrytis cinerea on aquatic animals is unknown. In this research, the influence of Botrytis cinerea on the development, inflammation, and apoptosis of zebrafish larvae and the underlying mechanism was evaluated. Results indicated that, compared with the control group, the larvae exposed to 101–103 CFU/mL of Botrytis cinerea spore suspension had a delayed hatching rate, lower head and eye area, shorter body length, and larger yolk sac at 72 h post-fertilization. In addition, the quantitative fluorescence intensity of treated larvae displayed a dose-dependent increase in apoptosis sign, revealing that Botrytis cinerea could generate apoptosis. Subsequently, zebrafish larvae were inflamed after exposure to Botrytis cinerea spore suspension, which was characterized as inflammatory infiltration and macrophage aggregation in the intestine. The enrichment of the pro-inflammatory factor TNF-α activated the NF-κB signaling pathway, generating the increase of the transcription level of target genes (jak3, pi3k, pdk1, akt, and ikk2) and the high expression of major proteins NF-κB (P65) in this pathway. Likewise, elevated content of TNF-α could activate JNK, which turned on the P53 apoptotic pathway, leading to a significant increase in the bax, caspase3, and caspase9 transcript abundances. This study demonstrated that Botrytis cinerea could cause developmental toxicity, morphological malformation, inflammation, and cell apoptosis in zebrafish larvae, which provided data support and a theoretical basis for ecological health risk assessment and filled the gap in biological research of Botrytis cinerea.

Cortical Parvalbumin-Positive Interneuron Development and Function Are Altered in the APC Conditional Knockout Mouse Model of Infantile and Epileptic Spasms Syndrome.

Infantile and epileptic spasms syndrome (IESS) is a childhood epilepsy syndrome characterized by infantile or late-onset spasms, abnormal neonatal EEG, and epilepsy. Few treatments exist for IESS, clinical outcomes are poor, and the molecular and circuit-level etiologies of IESS are not well understood. Multiple human IESS risk genes are linked to Wnt/β-catenin signaling, a pathway that controls developmental transcriptional programs and promotes glutamatergic excitation via β-catenin's role as a synaptic scaffold. We previously showed that deleting adenomatous polyposis coli (APC), a component of the β-catenin destruction complex, in excitatory neurons (APC cKO mice, APCfl/fl x CaMKIIαCre) increased β-catenin levels in developing glutamatergic neurons and led to infantile behavioral spasms, abnormal neonatal EEG, and adult epilepsy. Here, we tested the hypothesis that the development of GABAergic interneurons (INs) is disrupted in APC cKO male and female mice. IN dysfunction is implicated in human IESS, is a feature of other rodent models of IESS, and may contribute to the manifestation of spasms and seizures. We found that parvalbumin-positive INs (PV+ INs), an important source of cortical inhibition, were decreased in number, underwent disproportionate developmental apoptosis, and had altered dendrite morphology at P9, the peak of behavioral spasms. PV+ INs received excessive excitatory input, and their intrinsic ability to fire action potentials was reduced at all time points examined (P9, P14, P60). Subsequently, GABAergic transmission onto pyramidal neurons was uniquely altered in the somatosensory cortex of APC cKO mice at all ages, with both decreased IPSC input at P14 and enhanced IPSC input at P9 and P60. These results indicate that inhibitory circuit dysfunction occurs in APC cKOs and, along with known changes in excitation, may contribute to IESS-related phenotypes.SIGNIFICANCE STATEMENT Infantile and epileptic spasms syndrome (IESS) is a devastating epilepsy with limited treatment options and poor clinical outcomes. The molecular, cellular, and circuit disruptions that cause infantile spasms and seizures are largely unknown, but inhibitory GABAergic interneuron dysfunction has been implicated in rodent models of IESS and may contribute to human IESS. Here, we use a rodent model of IESS, the APC cKO mouse, in which β-catenin signaling is increased in excitatory neurons. This results in altered parvalbumin-positive GABAergic interneuron development and GABAergic synaptic dysfunction throughout life, showing that pathology arising in excitatory neurons can initiate long-term interneuron dysfunction. Our findings further implicate GABAergic dysfunction in IESS, even when pathology is initiated in other neuronal types.

Developmental Programmed Cell Death Involved in Ontogenesis of Dictamnus dasycarpus Capitate Glandular Hairs.

Plant glandular trichomes have received much attention due to their commercial and biological value. Recent studies have focused on the development of various glands in plants, suggesting that programmed cell death (PCD) may play an important role during the development of plant secretory structures. However, the development processes and cytological characteristics in different types of plant secretory structures differed significantly. This study aims to provide new data on the developmental PCD of the capitate glandular hairs in Dictamnus dasycarpus. Light, scanning, immunofluorescence labeling, and transmission electron microscopy were used to determine the different developmental processes of the capitate glandular hairs from a cytological perspective. Morphologically, the capitate glandular hair originates from one initial epidermal cell and differentiates into a multicellular trichome characterized by two basal cells, two lines of stalk cells, and a multicellular head. It is also histochemically detected by essential oils. TUNEL-positive reactions identified nuclei with diffused fluorescence or an irregular figure by DAPI, and Evans blue staining showed that the head and stalk cells lost their viability. Ultrastructural evidence revealed the developmental process by two possible modes of PCD. Non-autolytic PCD was characterized by buckling cell walls and degenerated nuclei, mitochondria, plastids, multivesicular body (MVB), and end-expanded endoplasmic reticulum in the condensed cytoplasm, which were mainly observed in the head cells. The MVB was detected in the degraded vacuole, a degraded nucleus with condensed chromatin and diffused membrane, and eventual loss of the vacuole membrane integrity exhibited typical evidence of vacuole-mediated autolytic PCD in the stalk cells. Furthermore, protoplasm degeneration coupled with dark oil droplets and numerous micro-dark osmiophilic substances was observed during late stages. The secretion mode of essential oils is also described in this paper.

Neurodevelopmental toxicity of organophosphate flame retardant triphenyl phosphate (TPhP) on zebrafish (Danio rerio) at different life stages

As a substitute for polybrominated diphenyl ethers (PBDEs), organophosphate flame retardant triphenyl phosphate (TPhP) is widely used in our daily products and diffusely exists in our living surroundings, but there is a paucity of information concerning its neurodevelopmental toxicity. Herein, we investigated the effects of TPhP exposure on developmental parameters, locomotor behavior, oxidative stress, apoptosis and transcriptional levels in zebrafish at different developmental stages, so as to explore the effects of TPhP exposure on zebrafish neural development and the underlying molecular mechanisms. TPhP concentration gradient exposure reduced the survival rate, hatchability, heart rate, body length and eye distance of zebrafish embryos/larvae, and caused malformations of zebrafish larvae. TPhP also leads to abnormal locomotor behaviors, such as reduced swimming distance and swimming speed, and impaired panic avoidance reflex to high light stimulation. TPhP caused ROS accumulation in 96 hpf larvae and induced Nrf2-antioxidant response in zebrafish. In addition, TPhP further activated mitochondrial signaling pathways, which affected apoptosis in the zebrafish eye region, resulting in visual impairment. Neurodevelopmental (mbpa, syn2a, foxo3a and pax6a), Retinoid acid metabolism (cyp26a1, raraa, rbp5, rdh1, crabp1a and rbp2a) and apoptosis-related genes (bcl2a, baxa and casp9) revealed the molecular mechanism of abnormal behavior and phenotypic symptoms, and also indicated that 96 hpf larvae are more sensitive than 7 dpf larvae. Thus, in the present study, we revealed the neurotoxic effects of TPhP at different early life stages in zebrafish, and zebrafish locomotor behavior impairments induced by TPhP exposure are attributed to co-regulation of visuomotor dysfunction and neuro-related genes. These results suggest that the safety of TPhP in organisms and even in humans needs to be further studied.

Neonatal ketamine exposure impairs infrapyramidal bundle pruning and causes lasting increase in excitatory synaptic transmission in hippocampal CA3 neurons

Preclinical models demonstrate that nearly all anesthetics cause widespread neuroapoptosis in the developing brains of infant rodents and non-human primates. Anesthesia-induced developmental apoptosis is succeeded by prolonged neuropathology in the surviving neurons and lasting cognitive impairments, suggesting that anesthetics interfere with the normal developmental trajectory of the brain. However, little is known about effects of anesthetics on stereotyped axonal pruning, an important developmental algorithm that sculpts neural circuits for proper function. Here, we proposed that neonatal ketamine exposure may interfere with stereotyped axonal pruning of the infrapyramidal bundle (IPB) of the hippocampal mossy fiber system and that impaired pruning may be associated with alterations in the synaptic transmission of CA3 neurons. To test this hypothesis, we injected postnatal day 7 (PND7) mouse pups with ketamine or vehicle over 6 h and then studied them at different developmental stages corresponding to IPB pruning (PND20–40). Immunohistochemistry with synaptoporin (a marker of mossy fibers) revealed that in juvenile mice treated with ketamine at PND7, but not in vehicle-treated controls, positive IPB fibers extended farther into the stratum pyramidale of CA3 region. Furthermore, immunofluorescent double labeling for synaptoporin and PSD-95 strongly suggested that the unpruned IPB caused by neonatal ketamine exposure makes functional synapses. Importantly, patch-clamp electrophysiology for miniature excitatory postsynaptic currents (mEPSCs) in acute brain slices ex vivo revealed increased frequency and amplitudes of mEPSCs in hippocampal CA3 neurons in ketamine-treated groups when compared to vehicle controls. We conclude that neonatal ketamine exposure interferes with normal neural circuit development and that this interference leads to lasting increase in excitatory synaptic transmission in hippocampus.

Integrated analysis of the expression profiles of the lncRNA-miRNA-mRNA ceRNA network in granulosa and cumulus cells from yak ovaries

BackgroundGrowing oocytes acquire the ability to mature through two-way communication between gametes and surrounding somatic cumulus cells (CCs). Granulosa cells (GCs) support oocyte growth, regulate meiosis progression, and modulate global oocyte transcription activity. However, the proliferation and differentiation of the yak ovary in GCs and CCs remain unclear. To characterize the important roles of long non-coding RNA, (lncRNA), microRNA (miRNA), and messenger RNA (mRNA), whole-transcriptome analysis was performed. Real-time quantitative fluorescence PCR was performed to verify the selected RNA sequences.ResultsImportant gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways related to differentiation and oocyte development were identified for the target genes of differentially expressed lncRNAs, miRNAs, and mRNAs. In total,6223 mRNAs (2197 upregulated, 4026 downregulated), 643 lncRNAs (204 upregulated, 479 downregulated), and 559 miRNAs (311 upregulated, 248 downregulated) were significantly altered between the two groups. Target genes involved in cell adhesion, cell differentiation, regulation of developmental processes, cell proliferation, embryo development, signal transduction, apoptosis, and aromatic compound biosynthetic processes were significantly enriched. These RNAs were involved in ECM-receptor interaction, MAPK signaling, Hippo signaling, PI3K-Akt signaling, cell cycle, cell adhesion, leukocyte trans-endothelial migration, and actin cytoskeleton regulation.ConclusionsA comprehensive analysis of the co-expression network of competing endogenous RNAs (ceRNAs) will facilitate the understanding of the process of granulosa cell proliferation and differentiation and offer a theoretical basis for the development of oocytes.

Investigation of the cell structure and organelles during autolytic PCD of Antirrhinum majus "Legend White" petals.

One of the classes of the plant developmental programmed cell death (PCD) is vacuolar cell death or autolysis. The results of the transmission electron microscope (TEM) studies indicated that this type of PCD occurs during the petal senescence of Antirrhinum majus "Legend White" flowers. The major hallmarks of the process related to the ultrastructure of the cells involved chloroplast degradation, vacuolation, chromatin condensation, cell wall swelling, degradation of Golgi apparatus, protoplasmic shrinkage, degradation of the endoplasmic reticulum, nuclear fragmentation, rupture of tonoplast, and plasma membrane. Macroautophagy and microautophagy processes were also clearly observed during vacuole formation. As in yeasts, in the present study, Golgi apparatus became autophagosome-like structures during degradation that had autophagy activity and then disappeared. Our results revealed a type of selective microautophagy, piecemeal microautophagy of the nucleus (PMN), in nuclear degradation during PCD of petals that has not previously been reported in plants. Moreover, vesicular structures, such as paramural and multilamellar bodies, were observed in some stages.

Revealing the Impact of Mitochondrial Fitness During Early Neural Development Using Human Brain Organoids.

Mitochondrial homeostasis -including function, morphology, and inter-organelle communication- provides guidance to the intrinsic developmental programs of corticogenesis, while also being responsive to environmental and intercellular signals. Two- and three-dimensional platforms have become useful tools to interrogate the capacity of cells to generate neuronal and glia progeny in a background of metabolic dysregulation, but the mechanistic underpinnings underlying the role of mitochondria during human neurogenesis remain unexplored. Here we provide a concise overview of cortical development and the use of pluripotent stem cell models that have contributed to our understanding of mitochondrial and metabolic regulation of early human brain development. We finally discuss the effects of mitochondrial fitness dysregulation seen under stress conditions such as metabolic dysregulation, absence of developmental apoptosis, and hypoxia; and the avenues of research that can be explored with the use of brain organoids.

Neuroprotective efficacy of berberine following developmental exposure to chlorpyrifos in F1 generation of Wistar rats: Apoptosis-autophagy interplay

Chlorpyrifos (CPF), an organophosphate insecticide commonly used in agriculture and household applications, is considered a developmental neurotoxicant. This study aimed to explain the neuroprotective role of Berberine (BBR) against CPF-induced autophagy dysfunction and apoptotic neurodegeneration in the developing hippocampus. F1 generation of Wistar rats was exposed to CPF (3 mg/kg b.wt.) and co-treated with BBR (10 mg/kg b.wt) in two different exposure regimens, gestational (GD9–12 and GD17–21) and lactational (PND1–20). Our results demonstrated that CPF intoxication instigated cognitive and neurobehavioral impairment, oxidant-antioxidant imbalance, and histomorphological alterations in CA1, CA3, and DG regions of the offsprings. Furthermore, mRNA expression of pro-apoptotic genes (caspase3 and Bax) was upregulated, and that of anti-apoptotic BCl2 was downregulated. In addition, exposure to CPF also activated the autophagy inhibitor (mTOR) transcription and subsequently downregulated the expression of autophagy markers beclin1 and LC3-II. In contrast, gestational and lactational co-treatment of BBR significantly upregulated the enzymatic anti-oxidant bar of the hippocampus and attenuated histological alterations. Moreover, BBR co-treatments reduced apoptotic neurodegeneration in the hippocampal region by regulating the expression of apoptotic genes and upregulated the levels of autophagy, confirmed by ultrastructural studies, decreased gene expression and immunostaining of mTOR and increased, and increased expression gene expression and immunostaining of LC3-II positive cells. Our results confirm that treatment with BBR induces autophagy, which plays a neuroprotective role in CPF-induced developmental neuronal apoptosis in the F1 generation of Wistar rats by regulating the balance between autophagy and apoptosis.

Charge-specific adverse effects of polystyrene nanoplastics on zebrafish (Danio rerio) development and behavior

Nanoplastics are being detected with increasing frequency in aquatic environments. Although evidence suggests that nanoplastics can cause overt toxicity to biota across different trophic levels, but there is little understanding of how materials such as differently charged polystyrene nanoplastics (PS-NP) impact fish development and behavior. Following exposure to amino-modified (positive charge) PS-NP, fluorescence accumulation was observed in the zebrafish brain and gastrointestinal tract. Positively charged PS-NP induced stronger developmental toxicity (decreased spontaneous movement, heartbeat, hatching rate, and length) and cell apoptosis in the brain and induced greater neurobehavioral impairment as compared to carboxyl-modified (negative charge) PS-NP. These findings correlated well with fluorescence differences indicating PS-NP presence. Targeted neuro-metabolite analysis by UHPLC-MS/MS reveals that positively charged PS-NP decreased levels of glycine, cysteine, glutathione, and glutamic acid, while the increased levels of spermine, spermidine, and tyramine were induced by negatively charged PS-NP. Positively charged PS-NP interacted with the neurotransmitter receptor N-methyl-D-aspartate receptor 2B (NMDA2B), whereas negatively charged PS-NP impacted the G-protein-coupled receptor 1 (GPR1), each with different binding energies that led to behavioral differences. These findings reveal the charge-specific toxicity of nanoplastics to fish and provide new perspective for understanding PS-NP neurotoxicity that is needed to accurately assess potential environmental and health risks of these emerging contaminants.

Three-axis classification of mouse lung mesenchymal cells reveals two populations of myofibroblasts.

The mesenchyme consists of heterogeneous cell populations that support neighboring structures and are integral to intercellular signaling, but are poorly defined morphologically and molecularly. Leveraging single-cell RNA-sequencing, 3D imaging and lineage tracing, we classify the mouse lung mesenchyme into three proximal-distal axes that are associated with the endothelium, epithelium and interstitium, respectively. From proximal to distal: the vascular axis includes vascular smooth muscle cells and pericytes that transition as arterioles and venules ramify into capillaries; the epithelial axis includes airway smooth muscle cells and two populations of myofibroblasts - ductal myofibroblasts, surrounding alveolar ducts and marked by CDH4, HHIP and LGR6, which persist post-alveologenesis, and alveolar myofibroblasts, surrounding alveoli and marked by high expression of PDGFRA, which undergo developmental apoptosis; and the interstitial axis, residing between the epithelial and vascular trees and sharing the marker MEOX2, includes fibroblasts in the bronchovascular bundle and the alveolar interstitium, which are marked by IL33/DNER/PI16 and Wnt2, respectively. Single-cell imaging reveals a distinct morphology of mesenchymal cell populations. This classification provides a conceptual and experimental framework applicable to other organs.

MiRNA-155 inhibition enhances porcine embryo preimplantation developmental competence by upregulating ZEB2 and downregulating ATF4

The in vitro embryo's competence is lower than in vivo counterparts and miRNAs found to affect the developmental competence, affecting pluripotency, stress level and apoptosis in embryos. We aimed to investigate the effect of miRNA-155 on parthenogenically activated early development porcine embryos at the preimplantation blastocyst stage. We designed miRNA-155 mimics and inhibitors and microinjected them into post-activated oocytes. The embryonic cleavage rate, blastocyst rate, and embryo development quality in terms of stress and apoptosis levels were investigated by confocal microscopy. Furthermore, we selected target genes, analyzed gene interaction and prediction networks, and compared the gene expression level in treatments and controls. miRNA-155 inhibition improved in vitro developmental competence by increasing cell numbers and reducing stress and apoptosis levels. The cleavage rate in the miRNA-155 inhibitor group was significantly higher (P < 0.05) than that in the miRNA-155 mimic group, but not in the control, whereas the blastocyst rate of the miRNA-155 inhibitor group was statistically significantly higher (P < 0.05) than in both control and miRNA-155 mimic groups. The relative gene expression level analysis showed downregulation of mRNAs related to stress and apoptosis, BAX, and the stress-induced autophagy gene ATF4, and TNF-ɑ in the miRNA-155 inhibitor group. Moreover, miRNA-155 inhibition showed upregulation of the relative expression of OCT4, ZEB2, BCL2, and IL-1 mRNA compared to control and mimic groups. However, the miRNA-155 mimic-injected group showed lower cleavage rates and blastocyst development rates than the other two groups. In conclusion, miRNA-155 inhibition in porcine in vitro embryos improved their preimplantation developmental competence and in vitro embryo production.

Environmental Risk Assessment of Oxaliplatin Exposure on Early Life Stages of Zebrafish (Danio rerio).

Pharmaceuticals are actually identified as a threat to the ecosystem. Nowadays, the growing consumption of antineoplastic agents has been related to their continuous input in natural environments. These substances can interfere with physiological and biochemical processes of aquatic species over their entire life cycle. Oxaliplatin (OXA) is a widely used chemotherapeutic agent to treat colon or rectal cancer. This study was aimed to evaluate the developmental toxicity of the OXA exposure. To this end, zebrafish embryos were incubated with 0.001, 0.1, 0.5 mg/L OXA. At different timepoints mortality rate, hatching rate, developmental abnormalities, histological analysis, oxidative stress and mRNA expression of gene related to oxidative stress were evaluated. Our results showed that OXA exposure can induce increased mortality and developmental abnormalities reducing the hatching rate. Histological analysis demonstrated that OXA induced liver, intestine, muscle and heart injury. Superoxide dismutase and catalase activities were significantly increased after OXA exposure demonstrating its oxidative effects. The mRNA expression levels of apoptosis-related genes (caspase-3, bax and bcl-2) were significantly upregulated by OXA exposure. In conclusion, we highlighted that OXA exposure led to a dose-related developmental toxicity, oxidative stress and apoptosis.

Environmental relevant concentrations of triclosan affected developmental toxicity, oxidative stress, and apoptosis in zebrafish embryos.

Triclosan (TCS), as a broad-spectrum antibacterial agent, is widely used in various pharmaceutical and personal care products. However, the details of ecological environmental health risks of TCS are not clear. In this study, zebrafish embryos/larval were exposed to environmentally relevant concentrations of TCS to evaluate the developmental toxicity. Four-hour post-fertilization (hpf) zebrafish embryos were exposed to 0, 2, 10, 50, and 250μg/L TCS until 96 h. The heart beats at 72 hpf were significantly increased in 2μg/L TCS group, while significantly decreased in 250μg/L TCS treated group compared with control. The results of acridine orange staining, terminal deoxynucleotide transferase-mediated UTPnick end labeling assay, and detection of mitochondrial membrane potential showed that 50 and 250μg/L TCS resulted in apoptosis. Meanwhile, reactive oxygen species (ROS) and DNA damage were induced, but SOD activity was significantly decreased in 250μg/L TCS treated group. In addition, SOD(Mn) and GPx gene mRNA expressions were significantly down-regulated in 50 and 250μg/L TCS treated groups, while Casp3, Casp9, Puma, Casp8, Apaf1, and Bid genes in 250μg/L TCS and Mdm2 gene in 50μg/L treated groups were significantly up-regulated. P53 protein was significantly up-regulated in 250μg/L TCS treated group. The overall results showed that TCS can cause oxidative stress and result in apoptosis via the involvement of ROS-p53-caspase-dependent apoptotic pathway in zebrafish embryos. The present findings suggest the potential mechanisms of TCS-induced developmental toxicity appears to be the generation of ROS and the consequent triggering of apoptosis genes.

Programmed Cell Death Recruits Macrophages Into the Developing Mouse Cochlea.

Programmed cell death (PCD) plays a critical role in the development and maturation of the cochlea. Significant remodeling occurs among cells of the greater epithelial ridge (GER) of Kölliker’s organ, leading to tissue regression and formation of the inner sulcus. In mice, this event normally occurs between postnatal days 5–15 (P5-15) and is regulated by thyroid hormone (T3). During this developmental time period, the cochlea also contains a large population of macrophages. Macrophages are frequently involved in the phagocytic clearance of dead cells, both during development and after injury, but the role of macrophages in the developing cochlea is unknown. This study examined the link between developmental cell death in the GER and the recruitment of macrophages into this region. Cell death in the basal GER begins at P5 and enhanced numbers of macrophages were observed at P7. This pattern of macrophage recruitment was unchanged in mice that were genetically deficient for CX3CR1, the receptor for fractalkine (a known macrophage chemoattractant). We found that injection of T3 at P0 and P1 caused GER cell death to begin at P3, and this premature PCD was accompanied by earlier recruitment of macrophages. We further found that depletion of macrophages from the developing cochlea (using CX3CR1DTR/+ mice and treatment with the CSF1R antagonist BLZ945) had no effect on the pattern of GER regression. Together, these findings suggest that macrophages are recruited into the GER region after initiation of developmental PCD, but that they are not essential for GER regression during cochlear remodeling.

Differences in Neuronal Numbers, Morphology, and Developmental Apoptosis in Mice Nigra Provide Experimental Evidence of Ontogenic Origin of Vulnerability to Parkinson's Disease.

Parkinson disease (PD) prevalence varies by ethnicity. In an earlier study, we replicated the reduced vulnerability to PD in an admixed population, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-susceptible C57BL/6J, MPTP-resistant CD-1 and their F1 crossbreds. In the present study, we investigated if the differences have a developmental origin. Substantia nigra was evaluated at postnatal days 2 (P2), P6, P10, P14, P18, and P22. C57BL/6J mice had smaller nigra and fewer dopaminergic neurons than the CD-1 and crossbreds at P2, which persisted through development. A significant increase in numbers and nigral volume was observed across strains until P14. A drastic decline thereafter was specific to C57BL/6J. CD-1 and crossbreds retained their numbers from P14 to stabilize with supernumerary neurons at adulthood. The neuronal size increased gradually to attain adult morphology at P10 in the resistant strains, vis-à-vis at P22 in C57BL/6J. Accordingly, in comparison to C57BL/6J, the nigra of CD-1 and reciprocal crossbreds possessed cytomorphological features of resilience, since birth. The considerably lesser dopaminergic neuronal loss in the CD-1 and crossbreds was seen at P2 and P14 and thereafter was complemented by attenuated developmental cell death. The differences in programmed cell death were confirmed by reduced TUNEL labelling, AIF, and caspase-3 expression. GDNF expression aligned with the cell death pattern at P2 and P14 in both nigra and striatum. Earlier maturity of nigra and its neurons appears to be better features that reflect as MPTP resistance at adulthood. Thus, variable MPTP vulnerability in mice and also differential susceptibility to PD in humans may arise early during nigral development.

Critical appraisal of epigenetic regulation of galectins in cancer.

Galectins are defined as the glycan-binding protein containing either one or two carbohydrate-binding domains and participate in various biological functions such as developmental processes, vascularisation programs, cell migration, and immune-regulation and apoptosis. Galectins are also linked to many diseases, including cancer. They are widely spread in extracellular and intracellular spaces, and their altered expression in cancer leads to tumor progression, metastasis, angiogenesis and stemness through different signalling pathways. Promoter methylation, microRNA, and histone modification constitute the epigenetic changes that regulate galectin activity in cancer. Our review discusses the concept of epigenetics in cancer and how the aforementioned factors i.e., promoter methylation, histone modification, change in miRNAs expression affect the glycomic changes in malignancies.

Perinatal phthalate exposure increases developmental apoptosis in the rat medial prefrontal cortex

Phthalates are a class of endocrine disruptors found in a variety of consumer goods, and offspring can be exposed to these compounds during gestation and lactation. Our laboratory has found that perinatal exposure to an environmentally relevant mixture of phthalates resulted in a decrease in cognitive flexibility and in neuron number in the adult rat medial prefrontal cortex (mPFC). Here, we examine effects of phthalate treatment on prenatal cellular proliferation and perinatal apoptosis in the mPFC. To examine the phthalate effects on cellular proliferation, dams consumed 0, 1, or 5 mg/kg of the phthalate mixture daily from embryonic day 2 (E2) through the day of birth (P0), and on E16 and E17, they were injected with BrdU. The mPFC of offspring was analyzed on P5 and showed a decrease in labelled cells in the phthalate exposed groups. To examine whether changes in BrdU density observed on P5 were due to altered cell survival, cell death was measured on E18, P0, and P5 using a TUNEL assay in a separate cohort of prenatally exposed offspring. There was an increase in TUNEL labelled cells at E18 in the phthalate exposed groups. In the final experiment, dams consumed the phthalate mixture from E2 through P10, at which time mPFC tissue was stained with TUNEL. Phthalate treated subjects showed a higher density of apoptotic cells at P10. These results indicate both pre- and postnatal phthalate exposure increases apoptosis in the male and female rat mPFC. While the impact of phthalates on proliferation cannot be ruled out, these data do not allow for definitive conclusions.