-
Cellular Signalling Jan 2024Differentiation of induced pluripotent stem cells (iPSCs)-derived β-like cells is a novel strategy for treatment of type 1 diabetes. Elucidation of the regulatory...
BACKGROUND
Differentiation of induced pluripotent stem cells (iPSCs)-derived β-like cells is a novel strategy for treatment of type 1 diabetes. Elucidation of the regulatory mechanisms of long noncoding RNAs (lncRNAs) in β-like cells derived from iPSCs is important for understanding the development of the pancreas and pancreatic β-cells and may improve the quality of β-like cells for stem cell therapy.
METHODS
β-like cells were derived from iPSCs in a three-step protocol. RNA sequencing and bioinformatics analysis were carried out to screen the differentially expressed lncRNAs and identify the putative target genes separately. LncRNA Malat1 was chosen for further research. Series of loss and gain of functions experiments were performed to study the biological function of LncRNA Malat1. Quantitative real-time PCR (qRT-PCR), Western blot (WB) analysis and immunofluorescence (IF) staining were carried out to separately detect the functions of pancreatic β-cells at the mRNA and protein levels. Cytoplasmic and nuclear RNA fractionation and fluorescence in situ hybridization (FISH) were used to determine the subcellar location of lncRNA Malat1 in β-like cells. Enzyme-linked immunosorbent assays (ELISAs) were performed to examine the differentiation and insulin secretion of β-like cells after stimulation with different glucose concentrations. Structural interactions between lncRNA Malat1 and miR-15b-5p and between miR-15b-5p/Ihh were detected by dual luciferase reporter assays (LRAs).
RESULTS
We found that the expression of lncRNA Malat1 declined during differentiation, and overexpression (OE) of lncRNA Malat1 notably impaired the differentiation and maturation of β-like cells derived from iPSCs in vitro and in vivo. Most importantly, lncRNA Malat1 could function as a competing endogenous RNA (ceRNA) of miR-15b-5p to regulate the expression of Ihh according to bioinformatics prediction, mechanistic analysis and downstream experiments.
CONCLUSION
This study established an unreported regulatory network of lncRNA Malat1 and the miR-15b-5p/Ihh axis during the differentiation of iPSCs into β-like cells. In addition to acting as an oncogene promoting tumorigenesis, lncRNA Malat1 may be an effective and novel target for treatment of diabetes in the future.
Topics: MicroRNAs; RNA, Long Noncoding; Induced Pluripotent Stem Cells; In Situ Hybridization, Fluorescence; Cell Differentiation
PubMed: 37972802
DOI: 10.1016/j.cellsig.2023.110975 -
Frontiers in Endocrinology 2023To evaluate the effects of different ovarian stimulation protocols on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes in infertile women with...
OBJECTIVE
To evaluate the effects of different ovarian stimulation protocols on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes in infertile women with adenomyosis.
METHODS
We carried out a retrospective cohort study among infertile women with adenomyosis receiving IVF/ICSI treatment, including 257 fresh embryo transfer (ET) cycles and 305 frozen embryo transfer (FET) cycles. In fresh ET cycles, ultra-long, long, short, and antagonist protocols were adopted. In FET cycles, patients received long-acting GnRH agonist (GnRHa) pretreatment or not. The primary outcome was clinical pregnancy rate (CPR), and the secondary outcomes included implantation rate (IR), miscarriage rate (MR), and live birth rate (LBR).
RESULTS
In fresh ET cycles, compared with ultra-long and long protocols, IR (49.7%, 52.1% versus 28.2%, P=0.001) and CPR (64.3%, 57.4% versus 35.6%, P=0.004) significantly decreased in the short protocol. Similarly, compared with ultra-long and long protocols, a decreased inclination of IR (49.7%, 52.1% versus 33.3%) and CPR (57.4%, 64.3% versus 38.2%) existed in the antagonist protocol, although no statistical significance was detected because of strict P adjustment of Bonferroni method (P=0.008). Compared with long protocol, LBR in short protocol decreased obviously (48.2% versus 20.3%, P<0.001). In FET cycles, no matter which origin of embryos, there were no statistical differences in IR, CPR, and LBR. For women ≥35 years receiving fresh ET, CPR was higher in ultra-long and long protocols (52.1%, 50.0% versus 20.0%, 27.5%, P=0.031) compared to antagonist and short protocols. For women ≥35 years receiving FET, compared with ultra-long and antagonist protocols, cycles with embryos originating from long and short protocols had higher proportions of long-acting GnRHa pretreatment (30.4%,30.00 versus 63.9%, 51.4%, P=0.009). IR (61.1%, 48.6% versus 32.6%, 25.0%, P=0.020) and CPR (58.3%, 48.6% versus 30.4%, 25.0%, P=0.024) in long and short protocols were higher than rates of ultra-long and antagonist protocols, but no statistical differences were supported because of strict Bonferroni method (P=0.008).
CONCLUSION
In infertile women with adenomyosis, if a fresh embryo was planned for transfer, an ultra-long or long protocol might be beneficial. If antagonist and short protocols were used, whole embryos frozen followed by FET was recommended. In FET cycles, embryos derived from different protocols had no impact on pregnancy outcomes.
Topics: Male; Pregnancy; Humans; Female; Adenomyosis; Infertility, Female; Retrospective Studies; Semen; Reproductive Techniques, Assisted; Ovulation Induction
PubMed: 37664864
DOI: 10.3389/fendo.2023.1198779 -
British Journal of Clinical Pharmacology Jun 2024Long-acting injectable (LAI) cabotegravir and rilpivirine for HIV treatment and LAI cabotegravir for pre-exposure HIV prophylaxis are being rolled out in a multitude of... (Review)
Review
Long-acting injectable (LAI) cabotegravir and rilpivirine for HIV treatment and LAI cabotegravir for pre-exposure HIV prophylaxis are being rolled out in a multitude of countries worldwide. Due to the prolonged exposure, it can be challenging to undertake 'traditional' pharmacokinetic studies and current guidance is derived from their oral equivalents or physiologically based pharmacokinetic studies. This review aims to consider pharmacokinetic characteristics of cabotegravir and rilpivirine and describe anticipated drug-drug interactions (DDIs) with frequent concomitant medications in African settings. Relevant co-medications were identified from the WHO 2021 List of Essential Medicines. All original human and physiologically based pharmacokinetic studies published in English on PubMed, discussing DDIs with LAI cabotegravir and rilpivirine prior to April 2023, were reviewed. The Liverpool HIV interaction database was also reviewed (https://www.hiv-druginteractions.org/checker). LAI cabotegravir and rilpivirine have half-lives of 6-12 and 13-28 weeks, respectively. Cabotegravir is primarily metabolized by UDP-glucuronyltransferase (UGT)-1A1 and rilpivirine by cytochrome P450 (CYP)-3A4. LAI cabotegravir and rilpivirine themselves exhibit low risk of perpetrating interactions with co-medications as they do not induce or inhibit the major drug metabolizing enzymes. However, they are victims of DDIs relating to the induction of their metabolizing enzymes by concomitantly administered medication. Noteworthy contraindicated co-medications include rifamycins, carbamazepine, phenytoin, flucloxacillin and griseofulvin, which induce CYP3A4 and/or UGT1A1, causing clinically significant reduced concentrations of rilpivirine and/or cabotegravir. In addition to virologic failure, subtherapeutic concentrations resulting from DDIs can lead to emergent drug resistance. Clinicians should be aware of potential DDIs and counsel people receiving LAI cabotegravir/rilpivirine appropriately to minimize risk.
PubMed: 38923554
DOI: 10.1111/bcp.16154 -
Cancers Dec 2023Anticancer peptides are short and structurally heterogeneous aminoacidic chains, which display selective cytotoxicity mostly against tumor cells, but not healthy cells,... (Review)
Review
Anticancer peptides are short and structurally heterogeneous aminoacidic chains, which display selective cytotoxicity mostly against tumor cells, but not healthy cells, based on their different cell surface properties. Their anti-tumoral activity is carried out through interference with intracellular homeostasis, such as plasmalemma integrity, cell cycle control, enzymatic activities and mitochondrial functions, ultimately acting as angiogenesis-, drug resistance- and metastasis-inhibiting agents, immune stimulators, differentiation inducers and necrosis or extrinsic/intrinsic apoptosis promoters. The marine environment features an ever-growing level of biodiversity, and seas and oceans are poorly exploited mines in terms of natural products of biomedical interest. Adaptation processes to extreme and competitive environmental conditions led marine species to produce unique metabolites as a chemical strategy to allow inter-individual signalization and ensure survival against predators, infectious agents or UV radiation. These natural metabolites have found broad use in various applications in healthcare management, due to their anticancer, anti-angiogenic, anti-inflammatory and regeneration abilities. The aim of this review is to pick selected studies that report on the isolation of marine animal-derived peptides and the identification of their anticancer activity in in vitro cultures of cancer cells, and list them with respect to the taxonomical hierarchy of the source organism.
PubMed: 38201464
DOI: 10.3390/cancers16010036 -
International Journal of Molecular... Dec 2023The pathophysiology of depression is related to the reduced volume of the hippocampus and amygdala and hypertrophy of the nucleus accumbens. The mechanism of these...
The pathophysiology of depression is related to the reduced volume of the hippocampus and amygdala and hypertrophy of the nucleus accumbens. The mechanism of these changes is not well understood; however, clinical studies have shown that the administration of the fast-acting antidepressant ketamine reversed the decrease in hippocampus and amygdala volume in depressed patients, and the magnitude of this effect correlated with the reduction in depressive symptoms. In the present study, we attempted to find out whether the psychedelic substance psilocybin affects neurotransmission in the limbic system in comparison to ketamine. Psilocybin and ketamine increased the release of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of naive rats as demonstrated using microdialysis. Both drugs influenced glutamate and GABA release in the nucleus accumbens, hippocampus and amygdala and increased ACh levels in the hippocampus. The changes in D2, 5-HT1A and 5-HT2A receptor density in the nucleus accumbens and hippocampus were observed as a long-lasting effect. A marked anxiolytic effect of psilocybin in the acute phase and 24 h post-treatment was shown in the open field test. These data provide the neurobiological background for psilocybin's effect on stress, anxiety and structural changes in the limbic system and translate into the antidepressant effect of psilocybin in depressed patients.
Topics: Humans; Animals; Rats; Psilocybin; Ketamine; Limbic System; Glutamic Acid; Antidepressive Agents
PubMed: 38203271
DOI: 10.3390/ijms25010100 -
Consortium Psychiatricum Jul 2023A substantial increase in the prevalence of eating disorders has been noticed over the past decades. Priority in the treatment of eating disorders is justifiably given... (Review)
Review
BACKGROUND
A substantial increase in the prevalence of eating disorders has been noticed over the past decades. Priority in the treatment of eating disorders is justifiably given to psychosocial interventions. However, it is also well known that centrally acting drugs can significantly affect appetite and food consumption.
AIM
To narratively review the available neurobiological data on the mechanisms of central regulation of eating behavior as a rationale to summarize pharmacological strategies for appetite modulation in eating disorders.
METHODS
The authors have carried out a narrative review of scientific papers published from January 2013 to March 2023 in the PubMed and Web of Science electronic databases. Studies were considered eligible if they included data on the neurobiological mechanisms of appetite regulation or the results of clinical trials of centrally acting drugs in eating disorders. Relevant studies were included regardless of their design. Descriptive analysis was used to summarize the obtained data.
RESULTS
The review included 51 studies. The available neurobiological and clinical data allowed us to identify the following pharmacological strategies for appetite modulation in eating disorders: serotonergic, catecholaminergic, amino acidergic and peptidergic. However, implementation of these data into clinical practice difficult due to an insufficient number of good-quality studies, which is particularly relevant for adolescents as there is a research gap in this population.
CONCLUSION
The progress in neurobiological understanding of the mechanisms of central regulation of appetite opens opportunities for new pharmacotherapeutic approaches aimed at changing the patterns of eating behavior. Obviously, treatment of eating disorders is a much broader problem and cannot be reduced to the correction of eating patterns. Nevertheless, at certain stages of treatment, drug-induced modulation of appetite can play an important role among multi-targeted biological and psychosocial interventions. Translation of neurobiological data into clinical practice requires a large number of clinical studies to confirm the long-term efficacy and safety of pharmacotherapeutic approaches and to develop personalized algorithms for the treatment of various forms of eating disorders in different age groups.
PubMed: 38250648
DOI: 10.17816/CP6150 -
Frontiers in Plant Science 2023Silicon-based defenses deter insect herbivores in many cultivated and wild grass species. Furthermore, in some of these species, silicon (Si) uptake and defense can be...
Silicon-based defenses deter insect herbivores in many cultivated and wild grass species. Furthermore, in some of these species, silicon (Si) uptake and defense can be induced by herbivory. Tropical trees also take up Si and leaf Si concentrations vary greatly across and within species. As herbivory is a major driver of seedling mortality and niche differentiation of tropical tree species, understanding anti-herbivore defenses is pivotal. Yet, whether silicon is a constitutive and inducible herbivory defense in tropical forest tree species remains unknown. We grew seedlings of eight tropical tree species in a full factorial experiment, including two levels of plant-available soil Si concentrations (-Si/+Si) and a simulated herbivory treatment (-H/+H). The simulated herbivory treatment was a combination of clipping and application of methyl jasmonate. We then carried out multiple-choice feeding trials, separately for each tree species, in which leaves of each treatment combination were offered to a generalist caterpillar (). Leaf damage was assessed. Three species showed a significant decrease in leaf damage under high compared to low Si conditions (by up to 72%), consistent with our expectation of Si-based defenses acting in tropical tree species. In one species, leaf damage was increased by increasing soil Si and in four species, no effect of soil Si on leaf damage was observed. Opposite to our expectation of Si uptake and defense being inducible by herbivory damage, simulated herbivory increased leaf damage in two species. Furthermore, simulated herbivory reduced Si concentrations in one species. Our results showed that tropical tree seedlings can be better defended when growing in Si-rich compared to Si-poor soils, and that the effects of Si on plant defense vary strongly across species. Furthermore, Si-based defenses may not be inducible in tropical tree species. Overall, constitutive Si-based defense should be considered part of the vast array of anti-herbivore defenses of tropical tree species. Our finding that Si-based defenses are highly species-specific combined with the fact that herbivory is a major driver of mortality in tropical tree seedling, suggests that variation in soil Si concentrations may have pervasive consequences for regeneration and performance across tropical tree species.
PubMed: 37900768
DOI: 10.3389/fpls.2023.1250868 -
Pharmaceutics May 2024According to the latest World Health Organization (WHO) report, an estimated 10.6 million people were diagnosed with tuberculosis (TB) in 2022, and 1.30 million died. A... (Review)
Review
According to the latest World Health Organization (WHO) report, an estimated 10.6 million people were diagnosed with tuberculosis (TB) in 2022, and 1.30 million died. A major concern is the emergence of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) strains, fueled by the length of anti-TB treatment and HIV comorbidity. Innovative anti-TB agents acting with new modes of action are the only solution to counteract the spread of resistant infections. To escape starvation and survive inside macrophages, has evolved to become independent of the host by synthesizing its own amino acids. Therefore, targeting amino acid biosynthesis could subvert the ability of the mycobacterium to evade the host immune system, providing innovative avenues for drug discovery. The aim of this review is to give an overview of the most recent progress in the discovery of amino acid biosynthesis inhibitors. Among the hits discovered over the past five years, tryptophan (Trp) inhibitors stand out as the most advanced and have significantly contributed to demonstrating the feasibility of this approach for future TB drug discovery. Future efforts should be directed at prioritizing the chemical optimization of these hits to enrich the TB drug pipeline with high-quality leads.
PubMed: 38931847
DOI: 10.3390/pharmaceutics16060725 -
Psychiatric Services (Washington, D.C.) Apr 2024The authors sought to describe out-of-pocket (OOP) costs among beneficiaries with schizophrenia differing in Medicare Part D low-income subsidy (LIS) status.
OBJECTIVE
The authors sought to describe out-of-pocket (OOP) costs among beneficiaries with schizophrenia differing in Medicare Part D low-income subsidy (LIS) status.
METHODS
National 100% Medicare claims were used to identify all adult fee-for-service Medicare Part D beneficiaries with schizophrenia who used antipsychotics in 2019 (N=283,813). Proportions of patients by LIS status, OOP costs per prescription, and annual OOP costs were reported. Results were stratified by type of antipsychotic received (oral antipsychotic [OAP], first-generation long-acting injectable [FGA-LAI], or second-generation long-acting injectable [SGA-LAI]).
RESULTS
In the final sample, 90.3% of beneficiaries had full LIS status, paying minimal copayments (29.6% institutionalized full LIS, paying $0; 42.2% noninstitutionalized full LIS, ≤100% federal poverty level [FPL], paying $1.25-$3.80; and 18.5% noninstitutionalized full LIS, >100% FPL, paying $3.40-$8.50). Only 0.9% of the sample received partial LIS status, and 8.8% had a non-LIS status. Non-LIS beneficiaries had the highest OOP costs, followed by partial LIS beneficiaries. Before entering catastrophic coverage, median OOP costs per prescription for generic OAPs, brand-name OAPs, FGA-LAIs, and SGA-LAIs were $10.85, $171.97, $26.09, and $394.28, respectively, for non-LIS beneficiaries and $3.69, $105.82, $9.35, and $229.20, respectively, for partial LIS beneficiaries. The annual total OOP costs varied substantially by LIS status (full LIS, $0-$130.79; partial LIS, $458.96; non-LIS, $998.81).
CONCLUSIONS
Most Medicare beneficiaries with schizophrenia qualified for full LIS and faced minimal OOP costs for both OAPs and LAIs. The remainder (i.e., partial LIS and non-LIS beneficiaries) faced substantial OOP costs, both per prescription and annually, especially for SGA-LAIs.
Topics: Aged; Adult; Humans; United States; Antipsychotic Agents; Schizophrenia; Health Expenditures; Medicare Part D; Poverty
PubMed: 37960866
DOI: 10.1176/appi.ps.20230142 -
Frontiers in Endocrinology 2024Managing reactive hypoglycaemia (RH) poses challenges due to limited and often ineffective treatment options. We report a case series and draw on this to propose a...
BACKGROUND/AIM
Managing reactive hypoglycaemia (RH) poses challenges due to limited and often ineffective treatment options. We report a case series and draw on this to propose a stepwise treatment approach consisting of lifestyle modifications, metformin, GLP-1 analogues, and the use of flash glucose monitoring technology.
METHOD
A retrospective review was conducted to analyse the management of 11 cases presenting with recurrent RH symptoms.
RESULT
Two patients experienced successful resolution of symptoms through lifestyle modifications. Metformin alone was effective in treating seven out of nine patients who received pharmacological treatment. Two patients with previous upper gastrointestinal surgery showed a partial response to metformin and benefited further from additional long-acting GLP-1 analogue. Pharmacological intervention led to significant reductions in insulin and C-peptide levels in repeat mixed meal tolerance tests (P-values 0.043 for insulin and 0.006 for C-peptide). Finally, flash glucose monitoring technology was useful in early detection and preventing episodes of hypoglycaemia in one of these patients with persistent symptoms.
CONCLUSION
These findings highlight the potential efficacy of escalated treatment strategies for RH, including the use of metformin, GLP-1 analogues, and flash glucose monitoring technology.
Topics: Humans; Hypoglycemic Agents; Diabetes Mellitus, Type 2; C-Peptide; Blood Glucose Self-Monitoring; Blood Glucose; Hypoglycemia; Metformin
PubMed: 38370356
DOI: 10.3389/fendo.2024.1332702