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Biomedical subjects

Albert Pinhasov

Publications and source records attributed to Albert Pinhasov.

10 recordsLinked to original sources

Precision Genomics: A Reality Having Universal Impact in a New Era of Psychiatry - Lessons Learned, Past and Present.

Addiction neuroscience explores the complex interplay between genetic, neurobiological, environmental, and socio-spiritual factors underlying substance and behavioral addictions. Over the past three decades, research in this domain has identified critical molecular and epigenetic mechanisms-particularly those affecting dopaminergic signaling and reward pathways-that contribute to both vulnerability and resilience to addictive behaviors. Central to this understanding is the concept of reward deficiency syndrome (RDS), first introduced by Kenneth Blum, which posits that hypodopaminergic functioning predisposes individuals to seek maladaptive rewards. Advances in neurogenetics, including the identification of key polymorphisms such as the DRD2 A1 allele, have paved the way for precision tools like the genetic addiction risk severity (GARS®) test. This test, alongside pro-dopaminergic nutraceutical interventions like KB220, demonstrates the potential for early detection and individualized treatment of "pre-addiction" risk states. Despite ongoing reliance on opioids for opioid use disorder (OUD), emerging paradigms advocate for dopamine homeostasis through non-addictive, integrative approaches. Furthermore, the integration of whole genome sequencing data can be used for Genome-Wide Association Studies (GWAS), multi-omics, and machine learning into clinical practice holds promise for advancing personalized medicine in addiction treatment. As the field progresses, addressing health equity and improving genomic representation across populations remain critical goals. This evolving framework underscores the importance of leveraging genomic insights to prevent, predict, and personalize interventions for addiction and mental illness at scale.

Disorder↗

Multi-Locus Pro-Dopaminergic Restoration of Reward Brain Circuitry in Reward Deficiency Rescinds Mono-Pharmaceutical Targeting.

Dopaminergic dysfunction in reward circuitry is well-documented as a contributor to addictive behaviors. Evidence indicates that changes in synchronous neural activity between brain regions mediating reward and cognitive functions may significantly contribute to substance-related disorders. In this commentary we highlight findings showing that the pro-dopaminergic nutraceutical (KB220) enhances functional connectivity between reward and cognitive brain areas in both animal and human studies. Animal studies demonstrate that KB220 activates important brain reward-related regions, including the nucleus accumbens, anterior cingulate gyrus, anterior thalamic nuclei, hippocampus, and prelimbic and infralimbic loci. Kb220 induced significant functional connectivity, enhanced neuroplasticity, and improved dopaminergic functionality within the brain reward circuitry with effects localized to these regions rather than broader distributed across the brain. In abstinent heroin-dependent individuals, acute KB220 administration significantly induced BOLD activation in caudate-accumbens dopaminergic pathways relative to placebo. Furthermore, data from 36 clinical trials and preclinical studies encompassing over 1,000 subjects, demonstrate that KB220 supports "dopamine homeostasis" across various reward deficiency behaviors. Clinical outcomes and quantitative electroencephalogy (qEEG) results underscore KB220's potential anti-craving/anti-relapse effects in addiction and other psychiatric disorders through direct or indirect dopaminergic modulation. Based on a review of the existing knowledge and further intensive investigation, we propose that instead of relying on mono-pharmaceutical approaches, the scientific community should endorse multi-loci dopaminergic restoration of reward brain circuitry as a fundamental paradigm for addressing mental illness.

Alcohol Use Disorder (AUD)↗

Protective peptides that are orally active and mechanistically nonchiral.

Previous reports identified two peptides that mimic the action of neuroprotective proteins derived from astrocytes. These peptides, NAPVSIPQ and SALLRSIPA, prevent neuronal cell death produced by electrical blockade, N-methyl-d-aspartate, and beta-amyloid peptide (25-35). In the present study, all d-amino acid peptides of NAPVSIPQ and SALLRSIPA were synthesized and compared respectively to the corresponding all l-amino acid peptides. In rat cerebral cortical test cultures cotreated with 1 microM tetrodotoxin, the d-amino acid peptides produced similar potency and efficacy for neuroprotection as that observed for their respective l-amino acid peptides. Since all these peptides tested individually exhibited attenuation of efficacy at concentrations of >10 pM, combinations of these peptides were tested for possible synergies. Equimolar d-NAPVSIPQ and d-SALLRSIPA combination treatment produced potent neuroprotection (EC(50), 0.03 fM) that did not attenuate with increasing concentrations. Similarly, the combination of l-NAPVSIPQ and d-SALLRSIPA also had high potency (EC(50), 0.07 fM) without attenuation of efficacy. Combined administration of peptides was tested in a model of fetal alcohol syndrome and in a model of learning impairment: apolipoprotein E knockout mice. Intraperitoneal administration of d-NAPVSIPQ plus d-SALLRSIPA to pregnant mice (embryonic day 8) attenuated fetal demise after treatment with an acute high dose of alcohol. Furthermore, oral administration of d-NAPVSIPQ plus d-SALLRSIPA significantly increased fetal survival after maternal alcohol treatment. Apolipoprotein E knockout mice injected with d-NAPVSIPQ plus d-SALLRSIPA showed improved performance in the Morris water maze. These studies suggest therapeutic potential for the combined administration of neuroprotective peptides that can act through a mechanism independent of chiral recognition.

Administration, Oral↗

High-throughput siRNA-based functional target validation.

The drug discovery process pursued by major pharmaceutical companies for many years starts with target identification followed by high-throughput screening (HTS) with the goal of identifying lead compounds. To accomplish this goal, significant resources are invested into automation of the screening process or HTS. Robotic systems capable of handling thousands of data points per day are implemented across the pharmaceutical sector. Many of these systems are amenable to handling cell-based screening protocols as well. On the other hand, as companies strive to develop innovative products based on novel mechanisms of action(s), one of the current bottlenecks of the industry is the target validation process. Traditionally, bioinformatics and HTS groups operate separately at different stages of the drug discovery process. The authors describe the convergence and integration of HTS and bioinformatics to perform high-throughput target functional identification and validation. As an example of this approach, they initiated a project with a functional cell-based screen for a biological process of interest using libraries of small interfering RNA (siRNA) molecules. In this protocol, siRNAs function as potent gene-specific inhibitors. siRNA-mediated knockdown of the target genes is confirmed by TaqMan analysis, and genes with impacts on biological functions of interest are selected for further analysis. Once the genes are confirmed and further validated, they may be used for HTS to yield lead compounds.

Base Sequence↗

Gene expression analysis for high throughput screening applications.

To meet growing needs for high throughput gene expression profiling, we established a new automated high throughput TaqMan RT-PCR method for quantitative mRNA expression analysis. In this method, the Allegro( trade mark ) (Zymark) system conducts all sample tracking and liquid handling steps, and ABI PRISM 7900 HT (Applied Biosystems) is used to conduct real-time determination of the C(t) value when amplification of PCR products is first detected and accumulation of inhibitory PCR products is unlikely to occur. The ABI PRISM 7900 HT Sequence Detection System features a real-time PCR instrument with 384-well-plate compatibility and robotic loading, and continuous wavelength detection, which enables the use of multiple fluorophores in a single reaction. The Allegro System offers an assembly line approach with a modular design that allows reconfiguration of the components to accommodate variations in the assay flow. In the present study, we have established and validated a new automated High Throughput (HT) TaqMan RT-PCR- based method for quantitative mRNA expression analysis. The data demonstrate that HT-Taqman PCR is a powerful tool that can be used for measuring low concentrations of mRNA, and is highly accurate, reproducible, and amenable to high throughput analysis. Results suggest that HT-TaqMan is a reliable method for the quantification of low-expression genes and a powerful tool with HT capability for target identification/validation, structure-activity relationship (SAR) study, compound selection for efficacy studies, and biomarker identification in drug discovery and development.

Drug Design↗

Activity-dependent neuroprotective protein: a novel gene essential for brain formation.

We have recently cloned the novel homeobox-containing activity-dependent neuroprotective protein (ADNP). In the current study, mouse ADNP was shown to be expressed at the time of neural tube closure, detected at E7.5 and increased on E9.5. Expression was augmented in the brain (E12.5), sustained throughout embryogenesis and regulated by VIP. To assess the function of ADNP, knockout mice were established. Detailed analysis revealed cranial neural tube closure failure and death on E8.5-9.0 of the ADNP-knockout embryos. The expression of Oct4, a gene associated with germ-line maintenance was markedly augmented in the knockout embryos. In contrast, the expression of Pax6, a gene crucial for cerebral cortex formation, was abolished in the brain primordial tissue of the knockout embryos. Thus, Pax6 and Oct4 constitute a part of the mechanism of action of ADNP on brain formation, inhibiting germ-line division while activating morphogenesis. In conclusion, ADNP is identified here as a new key gene essential for organogenesis in the developing embryo and may be implicated as a clinical target associated with proper neurodevelopment.

Animals↗

Injections of the neuroprotective peptide NAP to newborn mice attenuate head-injury-related dysfunction in adults.

The prophylactic neuroprotective effects of NAP, a femtomolar-acting neuroprotective peptide were tested in a mouse model of head trauma. NAP was injected for the first 3 weeks of life and head injury was initiated at 4 months. After trauma, mice were tested for their performance by evaluating damaged motor ability, balance and alertness. Comparison of the performance 1 h and 1 week after injury indicated that NAP treatment resulted in faster and enhanced recovery. In a 5-day Morris water maze test with mice suffering moderate to severe injuries, only the NAP-treated group learned to find the hidden platform in the maze. Furthermore, NAP treatment resulted in decreased mRNA expression of the inflammation marker, Mac-1. Thus, a potentially new prophylactic treatment against neurodegeneration is suggested.

Aging↗

A vasoactive intestinal peptide receptor analog alters the expression of homeobox genes.

A lipophilic analog of vasoactive intestinal peptide (VIP), stearyl-Nle(17)-neurotensin(6-11)VIP(7-28) (SNH), that inhibited lung cancer growth, has been previously described. The mechanism of SNH inhibition of cancer growth is still being elucidated. The present study examined the effects of SNH on homeobox genes in the colon cancer cell line HT 29 that expresses VIP receptors. Homeobox genes contain a characteristic DNA sequence, coding for a stretch of 61 amino acid homeodomain that binds specific DNA motifs. While the HOX gene family contains a single homeodomain, the POU gene family contains an additional DNA binding homeodomain. HT 29 cells were incubated with SNH; RNA was extracted and subjected to reverse-transcription-polymerase chain reaction (RT-PCR) with primers that matched the conserved area of the various HOX or POU genes. The PCR products that were altered by SNH treatment were sequenced. Three candidate SNH-responsive genes, the HOX A4, the HOX B5 and the PUO V transcription factor I (Oct-3) were identified. Semi-quantitative RT-PCR with specific primers confirmed the increase in HOX A4 and the decrease in Oct-3 expression levels following SNH treatment. Thus, the HOX A4 and the Oct-3 homeobox genes may partially mediate SNH activity on cancer cells.

DNA Primers↗

Differential expression of embryonic and maternal activity-dependent neuroprotective protein during mouse development.

OBJECTIVE: Activity-dependent neuroprotective protein (ADNP) potently enhances the survival of neurons and is regulated by vasoactive intestinal peptide, which also mediates postimplantation mouse embryonic growth. The objective of this study was to characterize ADNP in mouse embryonic tissues throughout development. STUDY DESIGN: Developmental tissues (embryo, decidua, placenta) from timed pregnant C57B16/J mice were harvested on days 6 though 18. To evaluate ADNP expression, RNA was extracted from at least three samples from three different mice per day. Five micrograms of total RNA from each sample was used per reverse transcriptase-polymerase chain reaction. Immunocytochemistry with anti-ADNP-derived peptide immunoglobulin and anti-gammadelta T-cell receptor was performed on 20 microm thick fixed sections of day 9.5 uteri. RESULTS: Embryonic ADNP messenger RNA (mRNA) has a temporal pattern with greater amounts present from gestational days 9 to 16. Placental ADNP mRNA was uniformly expressed on gestational days 11 to 18. Levels of decidual ADNP mRNA were greatest early in gestation and declined until delivery. Within the decidua, ADNP and gammadelta T-cell receptor immunoreactivity was present in the same cells. CONCLUSION: The expression of ADNP during pregnancy supports a developmental role for this protein. These data indicate both embryonic and maternal sources of ADNP during the critical period of organogenesis.

Animals↗

NAP accelerates the performance of normal rats in the water maze.

NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) has neuroprotective, memory enhancing, and neurotrophic properties. NAP is a short peptide sequence derived from the recently cloned, activity-dependent neuroprotective protein. The current study was designed to evaluate NAP activity in normal middle-aged animals to further assess NAP's breadth of neuroprotection. NAP was administered by inhalation. Results showed that in the paradigm of the Morris water maze, assessing short-term memory, only the NAP-treated middle-aged rats and not placebo-treated rats showed significant improvements by the end of the testing period. These results suggest efficacy for NAP in normal aging that is associated with accumulating environmental and genetic toxic factors.

Aging↗