Anxiolytic effect of the homeopathic complex Tepeex®

Aims: Homeopathic complex Tepeex® is a compound of Actaea racemosa 4cH, Natrum muriaticum 2cH, Pulsatilla nigricans 3cH, Chamomilla 3cH and Sepia succus5cH. This study evaluated the effect of Tepeex® in pre-clinical models of depression and anxiety. Methods: the following tests were performed: elevated plus maze test (EPM); forced swimming test (FST); open field test (OFT) and Rotarod test (RRT). Results: In EPM, animals treated with Tepeex® on days 20 and 30 stayed longer in the open arms of the maze than the control group (p < 0.05, Dunnett test). In FST, treatment with Tepeex® did not increase swimming time compared to the control group in any phase of treatment. In OFT, crossing increased significantly with treatment with amfepramone, and also with 30-day treatment with Tepeex® (p < 0.05, Dunnette test). In RRT, treatment with amfepramone significantly reduced latency time. 30-day treatment with Tepeex® did not affect motor coordination when compared to the control group. Conclusion: results suggest that homeopathic complex Tepeex® has anxiolytic properties without affecting motor coordination.

Supplementing a blend of magnesium oxide to feedlot cattle: effects on ruminal, physiological, and productive responses

This experiment evaluated ruminal, physiological, and productive responses of feedlot cattle consuming a corn-based finishing diet that included different levels of a magnesium oxide (MG) blend. Yearling cattle (58 heifers and 62 steers) were ranked by sex and initial body weight (BW; 407 ± 3.1 kg), and allocated to 4 groups of 30 animals each. Groups were housed in 1 of 4 drylot pens (30 × 12 m) equipped with GrowSafe automated feeding systems (Model 6000E, 4 bunks/pen) during the experiment (d -14 to 117). On d 0, groups were randomly assigned to receive a total-mixed ration without (CON; n = 30) or with the inclusion (as-fed basis) of MG at 0.25% (MG25; n = 30), 0.50% (MG50; n = 30), or 0.75% (MG75; n = 30) until slaughter on d 118. Individual feed intake was recorded daily, and BW were recorded every 14 d and prior to slaughter (d 117). Blood samples were collected on d 0, 28, 56, 84 and 112, and hair samples were collected on d 0, 56 and 112 from the tail-switch. On d 42, 8 rumen-cannulated steers (BW = 492 ± 8.0 kg) were housed with yearling cattle (1 pair/pen). Pairs rotated among groups every 14 d, resulting in a replicated 4 × 4 Latin square design (n = 8/treatment; d 42 to 98). Rumen pH was measured on d 7 and 14 of each period (0800, 1200, 1600 and 2000 h). Orthogonal contrasts were used to determine if inclusion of MG (0, 0.25, 0.50, or 0.75% of the diet) yielded linear or quadratic effects, and to explore overall effect of MG supplementation (CON vs. MG25 + MG50 + MG75). No treatment differences were noted (P ≥ 0.31) for BW gain, feed intake, or feed efficiency. Cattle supplemented with MG tended have less carcass marbling (P = 0.07) compared with CON. Inclusion of MG linearly increased (P &lt; 0.01) mean plasma concentrations of magnesium, and tended to linearly decrease (P = 0.09) mean plasma concentrations of haptoglobin. Cattle supplemented with MG had greater (P &lt; 0.01) mean plasma concentrations of cortisol compared with CON. Hair cortisol concentration did not differ between treatments on d 56 (P ≥ 0.25), and linearly decreased (P &lt; 0.01) with MG inclusion on d 112 (treatment × day; P = 0.02). Inclusion of MG linearly increased (P = 0.03) mean rumen pH, but these outcomes were mostly noted during the last two sampling of the day (treatment × hour; P = 0.02). Collectively, supplemental MG was effective in controlling rumen pH in cattle receiving a corn-based finishing diet, but without improvements in feedlot performance and carcass merit.

Evaluating mono and combination therapy of meropenem and amikacin against Pseudomonas aeruginosa bacteremia in the Hollow-Fiber Infection Model

Debate continues as to the role of combination antibiotic therapy for the management of Pseudomonas aeruginosa infections. We studied extent of bacterial killing and resistance emergence of meropenem and amikacin as monotherapy and as a combination therapy against susceptible and resistant P. aeruginosa isolates from bacteremic patients using the dynamic in vitro hollow-fiber infection model. Three P. aeruginosa isolates (meropenem MICs 0.125, 0.25 & 64 mg/L) were used simulating bacteremia with an initial inoculum ~ 1×105 CFU/mL and the expected pharmacokinetics of meropenem and amikacin in critically ill patients. For isolates susceptible to amikacin and meropenem (isolates 1 and 2), the rate of bacterial killing was increased with the combination regimen when compared with monotherapy of either antibiotic. Both the combination and meropenem monotherapy were able to sustain bacterial killing throughout the seven-day treatment course, whereas regrowth of bacteria occurred with amikacin monotherapy after 12 hours. For the meropenem-resistant P. aeruginosa isolate (isolate 3), only the combination regimen demonstrated bacterial killing. Given that tailored antibiotic regimens can maximize potential synergy against some isolates, future studies should explore the benefit of combination therapy against resistant P. aeruginosa.

Discovery Potent of Thiazolidinedione Derivatives as Antioxidant, α-Amylase Inhibitor, and Antidiabetic Agent

This work aimed to synthesize safe antihyperglycemic derivatives bearing thiazolidinedione fragment based on spectral data. The DFT theory discussed the frontier molecular orbitals (FMOs), chemical reactivity of compounds, and molecular electrostatic potential (MEP) to explain interaction between thiazolidinediones and the biological receptor. α-amylase is known as the initiator-hydrolysis of the of polysaccharides; therefore, developing α-amylase inhibitors can open the way for a potential diabetes mellitus drug. The molecular docking simulation was performed into the active site of PPAR-γ and α-amylase. We evaluated in vitro α-amylase’s potency and radical scavenging ability. The compound 6 has the highest potency against α-amylase and radical scavenging compared to the reference drug and other members. They have been applied against anti-diabetic and anti-hyperlipidemic activity (in vivo) based on an alloxan-induced diabetic rat model during a 30-day treatment protocol. The most potent anti hyperglycemic members are 6 and 11 with reduction percentage of blood glucose level by 69.55% and 66.95%, respectively; compared with the normal control. Other members exhibited moderate to low anti-diabetic potency. All compounds showed a normal value against the tested biochemical parameters (CH, LDL, and HDL). The ADMET profile showed good oral bioavailability without any observed carcinogenesis effect.

Anxiolytic and antidepressive effects of the homeopathic complex Homeo-pax® (pre-clinical study)

Background: The homeopathic complex Homeo-Pax® has been used as an antidepressant and anxiolytic homeopathic medicine available in Brazil. It is a complex mixture prepared with Aconitum nap. 6cH, Aurum met. 6cH, Phosphorus 6cH, Argentum nitricum 6cH, Arsenicum alb. 6cH, and Valeriana officinalis 3cH. Aims: This study had evaluated the behavior in rats after treatment with Homeo-Pax® in pre-clinical models of depression and anxiety. Mathods: Elevated Plus Maze Test (EPM), Forced Swimming Test (FST), Open Field Test (OFT) and the Rota Rod Test (RRT) behavior assays were used to confirm its activity. In the EPM, the animals treated with Homeo-pax® on the 1st day and until the 20th day of treatment remained longer in the open arms of the maze than on 30th day. This result was statistically significant compared with the control group (p < 0.05). In the FST, the treatment with Homeo-pax® (0.5 ml, p.o) increased the swimming time, compared to the control group. This effect was dependent on treatment time, resulting in a similar effect to that presented by amfepramone (10 mg/kg, p.o). In the OFT, crossing by the animals was significantly increased by the treatment with amfepramone (10mg/kg, p.o), and also with the 30-day treatment with Homeo-pax®. In the RRT, the 30-day treatment with Homeo-pax® (0.5 ml, p.o) did not affect the animals’ motor coordination, compared with the control group, which presented the same behavior. Conclusion: Based on the results obtained, it can be suggested that the homeopathic complex Homeo-pax® has anxiolytic and antidepressant properties without affecting motor coordination capacity.

Molnupiravir Extends COVID-19 Viral Phase, Evidenced by the High Frequency of Rare and Dangerous Mutations in SARS-COV-2

This paper analyzes SARS-COV-2 mutations data from Merck’s Molnupiravir trials, in the larger context. •5-day treatment with Molnupiravir caused the appearance and selection (to a frequency &gt;5%) of two of the most dangerous spike mutations – E484K and P681H – in multiple patients of a very small group (2/202 and 4/202, respectively).•Molnupiravir disproportionately increases the frequency of dangerous and unusual mutations•Molnupiravir worsens COVID-19 in patients, especially those who start treatment within 3 days of symptom onset. Some theoretically possible mechanisms causing this include acute bone marrow disorder and/or the generation of immune-evasive or even immunosuppressive viral genomes. •These mechanisms are likely to extend the virus shedding period in a substantial number of patients. The virus shed by these patients would be highly mutated and likely selected toward virulence.•Molnupiravir allows for virus diversification in the treated minority and purification in the untreated, a luxury rarely experienced by any virus in the nature. •Merck failed to collect enough data about Molnupiravir driven mutations. •For each important safety event, the collected data represents a few realizations of a random variable with unknown heavy tailed statistical distribution. Merck incorrectly treated this data as worst-case scenarios.

Prior exposure to microcystin alters host gut resistome and is associated with dysregulated immune homeostasis in translatable mouse models

The increased propensity of harmful algal blooms (HABs) and exposure from HABs-cyanotoxin causes human toxicity. It has been associated with the progression of several diseases that encompass the liver, kidneys, and immune system. Recently, a strong association of cyano-HAB toxicity with the altered host gut microbiome has been shown. We tested the hypothesis that prior exposure to cyanotoxin microcystin may alter the microbiome and induce microbiome-host-resistome crosstalk. Using both wild-type and humanized mice, we show that the mice exposed to microcystin had an altered microbiome signature that harbored antimicrobial resistance genes. Host resistome phenotypes such as mefA, msrD, mel, ant6, and tet40 increased in diversity and relative abundance following microcystin exposure. Interestingly, the increased abundance of these genes was traced to resistance to common antibiotics such as tetracycline, macrolides, glycopeptide, and aminoglycosides, crucial for modern-day treatment for several diseases. Increased abundance of these genes was positively associated with increased expression of PD1, a T-cell homeostasis marker, and pleiotropic inflammatory cytokine IL-6 with a concomitant negative association with immunosurveillance markers IL7 and TLR2. Microcystin exposure also caused decreased TLR2, TLR4, and REG3G expressions, increased immunosenescence, and higher systemic levels of IL-6 in both wild-type and humanized mice. In conclusion, the results show a first-ever characterization of the host resistome of microcystin exposure and its connection to host immune status and antibiotic resistance. The results may be crucial for understanding the ability of exposed subjects to fight future bacterial infections and the progression of the debilitating disease in hospital settings.

Mirtazapine treatment in a young female mouse model of Rett syndrome identifies time windows for the rescue of early phenotypes during development

Rett Syndrome (RTT) is a rare X-linked neurodevelopmental disorder, mainly caused by mutations in the MECP2 gene. Reduction in monoamine levels in RTT patients and mouse models suggested the possibility to rescue clinical phenotypes through antidepressants. Accordingly, we tested mirtazapine (MTZ), a noradrenergic and specific-serotonergic tetracyclic antidepressant (NaSSA). In previous studies, we showed high tolerability and significant positive effects of MTZ in male Mecp21m1.1Bird-knock-out mice, adult female Mecp2tm1.1Bird-heterozygous (Mecp2+/-) mice, and adult female RTT patients. However, it remained to explore MTZ efficacy in female Mecp2+/- mice at young ages. As RTT-like phenotypes in young Mecp2+/- mice have been less investigated, we carried out a behavioural characterization to analyze Mecp2+/- mice in "early adolescence" (6 weeks) and "late adolescence/young adulthood" (11 weeks) and identified several progressive phenotypes. Then, we evaluated the effects of either a 15- or a 30-day MTZ treatment on body weight and impaired motor behaviours in 11-week-old Mecp2+/- mice. Finally, since defective cortical development is a hallmark of RTT, we performed a histological study on the maturation of perineuronal nets (PNNs) and parvalbuminergic (PV) neurons in the primary motor cortex. The 30-day MTZ treatment was more effective than the shorter 15-day treatment, leading to the significant rescue of body weight, hindlimb clasping and motor learning in the accelerating rotarod test. Behavioral improvement was associated with normalized PV immunoreactivity levels and PNN thickness. These results support the use of MTZ as a new potential treatment for adolescent girls affected by RTT and suggest a possible mechanism of action.