Aloe vera gel relieves cadmium triggered hepatic injury via antioxidative, anti-inflammatory, and anti-apoptotic routes.

Aloe vera (AV) gel extracted from fresh AV leaves was chosen in this study to evaluate its antioxidant, anti-inflammatory, and antiapoptotic activities against cadmium (Cd) -induced liver injury. Forty Wistar male adult rats were equally divided into four groups. Group I (standard control) ingested with 2.5 ml/kg b.w. of physiological saline. Group II (Cd-intoxicated) received 3 mg/kg b.w./day of CdCl2 dissolved in saline. Group III (AV) received 200 mg/kg b.w./day of AV gel dissolved in saline. Group IV (Cd+AV) ingested with 200 mg/kg b.w./day of AV gel solution along with 3 mg/kg b.w. CdCl2. All groups were ingested orally by gavage for 3 consecutive weeks. Paraoxonase-1 (PON-1) and HSP70 were measured in serum. The deposited Cd level, nitric oxide content, lipid peroxidation, collagen-1 (COL-1), and metalloproteinase-9 (MMP-9) levels were all determined in liver tissue homogenates. Gene expression of NF-κB and IL-6, Bax, and Bcl2, as well as immunohistochemistry analysis of activated caspase-3, was performed. Results showed that ingestion of AV gel greatly relieved all oxidative stress due to Cd exposure, modulated the NF-κB, IL-6, Bax, and Bcl2 expression levels, and improved the apoptotic state. In conclusion, AV gel confirmed its potential ameliorating effect against liver injury induced due to Cd exposure.

X-Linked Hydrocephalus with New L1CAM Pathogenic Variants: Review of the Most Prevalent Molecular and Phenotypic Features.

Introduction: The underlying molecular defects of congenital hydrocephalus are heterogeneous and many isolated forms of hydrocephalus remain unsolved at the molecular level. Congenital hydrocephalus in males associated with agenesis of the corpus callosum is a notable characteristic of L1CAM gene which is by far the most common genetic etiology of congenital hydrocephalus. Methods and Results: Sequencing of the L1CAM gene on 25 male patients/fetuses who had been presented with hydrocephalus revealed 6 patients and two fetuses with different hemizygous pathogenic variants. Our study identified 4 novel variants and 4 previously reported. The detection rate was 32%, and all the variants were shown to be maternally inherited. Nonsense variants were detected in 3 patients, while missense variants were detected in 2 patients. Frameshift, silent, and splicing variant, each was detected in 1 patient. The clinical manifestations of the patients are in line with those frequently observed including communicating hydrocephalus and agenesis of the corpus callosum. Moreover, rippled ventricles with subdural collection and asymmetry of ventricles after shunt operation were seen in 1 patient and 2 patients, respectively. In addition, abnormal basal ganglia were found in 4 patients which seems to be an additional distinct new finding. We also describe a patient with novel nonsense variant with the rare association of Hirschsprung's disease. This patient displayed additionally multiple porencephalic cysts and encephalomalacia secondary to hemorrhage due to repeated infections after shunt operation. The patients with the missense variants showed long survival, while those with truncating variants showed poor prognosis. Conclusion: This report adds knowledge of novel pathogenic variants to the L1CAM variant database. Furthermore, we evaluated the clinical and imaging data of these patients.

Berberine-loaded albumin nanoparticles reverse aflatoxin B1-induced liver hyperplasia.

Hepatocellular carcinoma (HCC) can be produced from aflatoxin B1 (AFB1) administration. Although berberine (BER) acts as an anticancer agent and can counteract the AFB1 effect, it has low bioavailability. Nanotechnology can overcome this problem. This research aimed to synthesize berberine nanoparticles (NPs) and then estimate their therapeutic effect compared to that of berberine against aflatoxin-induced hepatotoxicity. The desolvation method was used to prepare BER-NPs. Aflatoxicosis was induced by 5 consecutive intraperitoneal injections (IP) of 200 µg/kg/day AFB dissolved in dimethylsulfoxide (DMSO). After the induction period, two treatments were performed: the first with 100 mg/kg BER and the second with 10 mg/kg BER-NPs. Liver, kidney, and diabetic profiles were estimated by using standardized methods. Hepatic oxidative stress, inflammatory, cancer cell proliferation, and invasion markers were used by ELISA and qPCR techniques. The TEM image shows that both BSA NPs and BER-BSA NPs had spherical, regular, and uniform shapes. The BER encapsulation efficiency % was 78.5. The formed-BER-BSA NPs showed a loading capacity % of 7.71 and the synthesis yield % of 92.6. AFB1 increases pro-oxidant markers, decreases antioxidant systems, stimulates inflammatory enzymes, inhibits anti-inflammatory markers, decreases tumor suppressor enzymes, increases oncogenes, increases glycolytic activity, prevents cell death, and promotes cell growth. Most of the biochemical markers and hepatic architecture were normalized in the BER-BSA NP-treated group but not in the BER-treated group. Altogether, the obtained data proved that treatment with BER-NPs was more efficient than treatment with berberine against aflatoxicoses induced in rats.

Neuroprotective effect of sodium alginate against chromium-induced brain damage in rats.

Oral exposure to chromium hexavalent [Cr(VI)] has disastrous impacts and affects many people worldwide. Cr(VI) triggers neurotoxicity via its high oxidation potential by generating high amount of ROS. Meanwhile, alginates are known by their chelating activity and ability to bind heavy metals and toxins, in addition to their antioxidant, anti-inflammatory, and anti-apoptotic activities. So, this study aimed to explore the neuroprotective potential of sodium alginate (SA) against cellular injury, DNA damage, macromolecule alterations, and apoptosis induced by oral ingestion of Cr. Forty Wistar male rats were divided into 4 groups; group I: standard control ingested with the vehicle solution, group II: Cr-intoxicated group received 10 mg/kg b.w. of potassium dichromate orally by gavage and kept without treatment, group III: SA group in which rats were orally exposed to 200 mg/kg b.w. of SA only, and group IV: SA-treated group that received 200 mg/kg b.w. of SA along with Cr for 28 consecutive days. Neurotransmitters such as Acetyl choline esterase (AchE), Monoamine oxidase A (MAOA) concentrations, Dopamine (DA) and 5-Hydroxytryptamine (5-HT) levels were assessed in brain homogenate tissues. Neurobiochemical markers; NAD+ and S100B protein were investigated in the brain tissues and serum, respectively. Levels of HSP70, caspase-3, protein profiling were evaluated. DNA damage was determined using the Comet assay. Results revealed a significant reduction in the AchE and MAOA concentrations, DA, 5-HT, and NAD+ levels, with an increase in the S100B protein levels. Cr(VI) altered protein pattern and caused DNA damage. High levels of HSP70 and caspase-3 proteins were observed. Fortunately, oral administration of SA prevented the accumulation of Cr in brain homogenates and significantly improved all investigated parameters. SA attenuated the ROS production and relieved the oxidative stress by its active constituents. SA can protect against cellular and DNA damage and limit apoptosis. SA could be a promising neuroprotective agent against Cr(VI)-inducing toxicity.

TLR3\TLR7 as Differentially Expressed Markers Among Viral, Nonviral, and Autoimmune Diseases in Egyptian Patients.

Toll-like receptors (TLRs) represent the immune link between the innate and the adaptive immune signals against various pathogens. This study aimed to evaluate the TLRs3 and 7 as immune-markers in differentiating between hepatitis C virus (HCV)-infected and -uninfected patients. Also, the use of the TLR3 and TLR7 as immune markers was compared with the prevalent bio and immune markers for autoimmune diseases in HCV-infected or -uninfected patients. The levels of GPT, GOT, B cell activated factors, tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-10 were measured in plasma, while the levels of TLR3 and TLR7 were quantified in lysates of peripheral blood mononuclear cells from healthy donors, HCV-infected patients, nonalcoholic fatty liver (NAFL) patients without autoimmune diseases and with autoimmune diseases (HCV-infected patients with autoimmune diseases [HCV+auto], nonalcoholic fatty liver patients with autoimmune diseases [NAFL+auto]), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) patients. The relative expression of TLR3, TLR7, TNF, and IL-10 in cell lysates was assessed against glyceraldehyde 3-phosphate dehydrogenase (GAPDH) by quantitative real time-polymerase chain reaction (qRT-PCR). Results showed that TLRs 3 and 7 levels were significantly higher in SLE, RA, HCV, HCV+auto, and the NAFL patients compared to the normal control. The cell lysates from SLE patients expressed TLR3 at relatively significantly higher mRNA levels compared to normal subjects or other patient groups. The NAFL+auto patients expressed TLR7 at relatively significantly high mRNA levels compared to normal subjects or other patients. The RA patients expressed TLR7 at relatively significantly higher mRNA levels when compared to HCV, HCV+auto, and NAFL+auto patients. Conclusions: At the protein level, TLR7 can differentiate between HCV and NAFL patients. In addition, both TLRs3 and 7 can serve as potent markers in differentiating between NAFL and NAFL+auto.

Therapeutic potential of targeted-gold nanospheres on collagen-induced arthritis in rats.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes functional disability due to bone destruction and severe joint pain. Current anti-rheumatic treatments develop severe complications and do not provide complete remission. Gold nanoparticles (AuNPs) have garnered attention because of their unique physical and chemical properties. In this study, we have evaluated the therapeutic effects of gold nanospheres (AuNSs) with two different ligands (targeted-nanoparticles) against collagen-induced arthritis (CIA) and compared the outcomes with conventional methotrexate (MTX) and biological (infliximab) treatments. Clinical evaluation was performed by radiographic and histological examinations. The bioaccumulation of AuNSs in vital organs was assessed. The mechanistic studies targeting pro-inflammatory/anti-inflammatory and angiogenic mediators' expressions were performed. Radiographic examination showed that the targeted AuNSs reduced joint space narrowing and bone erosion. Moreover, histopathological examination of rat ankle joints demonstrated that targeted AuNSs reduce bone and cartilage degeneration/inflammation. Gold nanospheres-conjugated with nucleus localized peptide (nuclear membrane-targeted) (AuNSs@NLS) has resolved bone destruction and inflammation compared to gold nanospheres-conjugated at polyethylene glycol (AuNSs@PEG). Although the AuNSs accumulated in different organs in both cases, they did not induce any toxicity or tissue damage. The two different targeted AuNSs significantly suppress inflammatory and angiogenic mediators' expression and induced anti-inflammatory cytokine production, but the AuNSs@NLS had superior therapeutic efficacy. In conclusion, these results suggested that nuclear membrane-targeted AuNSs effectively attenuated arthritis progression without systemic side effects.

Cytotoxic and Apoptotic Effects of Luffa Cylindrica Leaves Extract against Acute Lymphoblastic Leukemic Stem Cells.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is an aggressive malignancy defined by accumulation of lymphoblasts in the bone marrow. Leukemic stem cells (LSCs) are the major cause of the recurrence and metastasis of ALL. This study aimed to develop an effective anti-cancer agent targeting these LSCs. Luffa Cylindrica (L.C.) leaves extract was selected to evaluate its effect on ALL via eradicating the LSCs as it contains many active anti-cancer flavonoids. METHODS: Thirty-two bone marrow samples of ALL patients were used in this study. LSCs population was identified in the selected samples. Cell viability was measured by MTT assay and flow cytometry. Cell cycle, apoptosis, proliferation marker; ki-67 and colony forming assay were further analyzed. RESULTS: This study revealed the expression of CD34+/CD38+ cells in addition to CD34+/CD38- population and the extract was effective against the two LSCs populations. MTT assay showed that treated leukemic cells exhibited significant reduction in the viable cells in a dose dependent manner with IC50 of 3 µg/µl which was then confirmed by flow cytometry. Cell cycle analysis results showed significant reduction in the percentage of cells treated with L.C. extract in both the S and G0/G1 phases, with concomitant increase in the G2/M phase. Also, L.C. extract could effectively induce apoptosis, inhibit proliferation and suppress colonogenecity of leukemic cells. CONCLUSION: This study validated the medicinal potential of L.C. leaves extract as a promising anti-leukemic agent targeting both LSCs and blasts in ALL patients, which may be explained by the synergy found between its potent flavonoids especially apigenin, luteolin and kaempferol.

Plasma levels of gamma-aminobutyric acid and panic disorder.

Low levels of gamma-aminobutyric acid (GABA) in plasma have been associated with the presence of mood disorders in patients with major depressive disorder. We examined plasma GABA in patients with panic disorder, a disorder that is often comorbid with major depression, and in a group of control subjects. Patients with panic disorder had plasma GABA levels that did not differ significantly from levels in controls subjects. These data support the specificity of low plasma GABA as a marker for mood disorders.

Effects of tryptophan depletion on responses to yohimbine in healthy human subjects.

There is considerable evidence that both the norepinephrine (NE) and serotonin (5-HT) systems are involved in the regulation of human anxiety and fear responses. To assess the modulating effects of central 5-HT levels on NE function, 11 healthy human subjects were studied with placebo-controlled challenge tests involving tryptophan depletion followed by administration of the alpha-2-adrenergic antagonist yohimbine 0.4 mg/kg IV. Five of the 11 subjects reported a marked increase in feelings of nervousness (> or = 25 mm on a 100 mm analog scale) following the combination test, while 1/11 had this response to yohimbine alone. No subjects had an increase in nervousness during other control tests. The increase in nervousness after the tryptophan depletion-yohimbine test was statistically significant for the whole group, but there were no other unique changes in behavioral, physiologic or biochemical (MHPG, cortisol) variables with this test. These data are discussed in terms of possible functional interactions between the 5-HT and NE neurotransmitter systems.

Response to meta-chlorophenylpiperazine in panic disorder patients and healthy subjects: influence of reduction in intravenous dosage.

As a further test of the hypothesis of serotonin hypersensitivity in panic disorder (PD), the serotonin agonist meta-chlorophenylpiperazine (MCPP) was administered intravenously in a dose of 0.05 mg/kg to 27 PD patients and 22 normal control subjects. This is one-half the dose used in our previous study of PD patients, where the dose may have been too high to provide evidence of hypersensitivity to the agent. Responses of anxiety and nervousness were statistically indistinguishable by analysis of variance in the two groups, replicating our previous findings. Panic attack symptom score (PASS) ratings were significantly higher in the PD group, compared with a trend toward higher PASS ratings in the 0.1 mg/kg study. Cortisol, human growth hormone, and male prolactin responses showed no significant differences in the two groups by analysis of variance. Prolactin responses were significantly blunted in the female patients. The unexpected blunted prolactin response to MCPP in female PD patients may reflect a nonspecific blunting of prolactin response to stress. The PASS data provide some evidence of serotonergic hypersensitivity in PD.

Information and psychopathology.

Our current understanding of mental processes in health and disease is limited by the absence of a practical model describing the physiology of the mind as an informational system. The mind is described here as a physical system with four functional dimensions that can be interrelated mathematically on the basis of information theory. These variables describe the information processing activities of the mind, and include: a) a state function (g), which is the number of potential states that the system can occupy at a given time and relates to the complexity and activity of the brain; b) a power function (P), the number of state changes per unit time; c) time (t); and d) the relative entropy of the system (R), which describes the ordering of mental states in time. Using these variables, the evolution of states of mind can be described as a trajectory in a multidimensional phase space representing all possible mental states. Ego functions constrain the field of brain states within this space, thereby giving rise to the information content of consciousness and to the individual psyche. Functional mental disorders, as disorders of the psyche, are dysfunctions in the ordering processes that give rise to conscious information.

Dynamic SPECT imaging of dopamine D2 receptors in human subjects with iodine-123-IBZM.

We studied the uptake, distribution, metabolism and washout of the dopamine D2 receptor ligand [123I]IBZM in healthy subjects (n = 12) with dynamic brain SPECT. The highest radioactivity level was detected in the striatum. Operationally-defined striatal "specific" uptake peaked at 69 min postinjection of radioligand and showed a gradual decline of 15% per hour thereafter. "Specific" uptake at maximal counts represented 53% of the total striatal radioactivity. Two subjects received haloperidol (20 micrograms/kg i.v.) 80 min postinjection of radioligand. Haloperidol caused a 2.6-fold increase in the rate of washout of specific striatal activity in comparison to that in the 10 control subjects and was consistent with drug-induced displacement of radioligand from the dopamine D2 receptor. Two classes of metabolites were detected in plasma and urine: a polar fraction, not extracted by ethyl acetate, and a nonpolar, extractable fraction consisting of parent compound and two compounds having shorter retention times on reversed-phase HPLC. Greater than half the plasma parent was metabolized within 10-15 min after administration. The volume of distribution, estimated from the peak arterial plasma concentration at 50-75 sec, was 7.7-10.2 l; the free (nonprotein bound) fraction of [123I]IBZM after in vitro incubation with blood or plasma was 4.4% +/- 0.4%. These results suggest that [123I]IBZM exhibits uptake in brain regions with high D2 receptor density and shows a relatively stable washout during which drugs affecting dopaminergic transmission may be administered.

Dynamic SPECT imaging after injection of the benzodiazepine receptor ligand [123I]iomazenil in healthy human subjects.

Previous work suggests that iomazenil (formerly known as Ro 16-0154) is a useful ligand for static imaging of the benzodiazepine (BZ) receptor with single photon emission computed tomography (SPECT). The present study evaluated the feasibility of dynamic SPECT imaging of cerebral radioactivity following intravenous [123I]iomazenil injection in healthy human subjects, in preparation for future receptor quantitation studies. Maximal brain uptake was reached approximately 25-30 minutes after i.v. administration of the radioligand and represented approximately 12% of the injected dose. The regional distribution of radioactive densities was consistent with the known distribution of BZ receptors in human brain, with highest uptake localized over the occipital area. Washout of cortical radioactivity was regionally variable but relatively slow, with a half-life of approximately 4 hours after the time of peak radioactivity. In summary, [123I]iomazenil is a promising SPECT radioligand for the BZ receptor, with high brain uptake, relatively slow washout of radioactivity, and appropriate regional distribution.

Consciousness and synchronicity.

The brain is described as a system whose states are subject to quantum uncertainty. Conscious observation brings individual states into being from the multiple states possible at a given instant. This gives rise to information, which is the content of consciousness. Synchronicity is the principle by which a single state is generated by conscious observation throughout the brain at a given instant. It is the equivalent of the non-local interaction in quantum theory. Both psychodynamic and cognitive applications of the proposed model are described.

Deconvoluted X-ray diffraction analysis of bone and mixtures of bone and particulate hydroxyapatite.

Recent evidence suggests that bone phosphate exists almost entirely as hydroxyapatite (HA). The relative deficiency of calcium and presence of substantial HPO2-4 in bone phosphate indicates modification of the ideal HA structure, however. An inability to resolve closely spaced lines in fine grained materials, coupled with the limited periodicity of the thin mineral crystals of bone have prevented definitive characterization of the structure of bone mineral using standard X-ray diffraction (XRD) techniques. We have applied computer deconvolution XRD techniques to aid in the resolution of component overlapped profiles from bone, synthetic hydroxyapatite (HA) and mixtures of bone and synthetic HA resulting from implantation studies. In the course of this resolution process separate profiles were resolved from the (002) profile of bone derived HA. The ratio of integrated intensities of these profiles to the intensity of the profile of synthetic HA appears to provide an approximate measure of the ratio of bone to synthetic HA in a given sample. The finding of shoulders on the (002) peak of bone provides the basis for resolution into separate profiles. The asymmetry of these shoulders in mature bone cannot be attributed to crystallinity, particle size, or computer artifact. The same finding has been previously reported in hydrolyzed, deproteinated bone. Further work will be needed to resolve the question of whether the structural heterogeneity implied by profile geometry is the result of multiple HA phases, surface layer structure involving hydrolysis and calcium absences, or some other factor.

Sepiolite asbestos from Franklin, New Jersey: a case study in medical geology.

Asbestiform sepiolite has been found in a zinc deposit at Franklin, New Jersey. The host rock is Precambrian Franklin marble. Pseudomorphous foliated texture and cross-cutting relationships indicate replacement of talc by sepiolite. Sepiolite is manganoan, while talc contains little manganese, suggesting differences in manganese substitution in these minerals and providing evidence against solid-state replacement. Sepiolite from Franklin is of moderate crystallinity and consists of soft, flexible mass-fiber. Comparison with other sepiolite samples suggests that increased crystallinity among sepiolites parallels increased fiber length, while disorder appears to be associated with flexibility. Length and aspect ratio (length/width) distributions support toxicological equation of asbestiform sepiolite with the regulated asbestos minerals. The data presented here suggest that talc can be unstable in a low-temperature hydrothermal environment, altering under certain conditions to form sepiolite. In a wider context, sepiolite may be expected to precipitate at the end-stages of hydrothermal mineralization in some talc deposits and in carbonate and calc-silicate rocks. Many occurrences of sepiolite in these rocks may have been overlooked due to similarities with other minerals. The fact that sepiolite has been previously unrecognized and misidentified at Franklin is a case in point. Since there is evidence suggesting that sepiolite is fibrogenic and carcinogenic, its potential occurrence in consumer talcs and crushed-stone products has environmental health implications. Similarities in composition and other analytical parameters may cause sepiolite to be mistaken for fibrous talc or chrysotile in environmental samples.