pGM-CSF as an adjuvant in DNA vaccination against SARS-CoV-2.

The emergence of SARS-CoV-2 presents a significant global public health dilemma. Vaccination has long been recognized as the most effective means of preventing the spread of infectious diseases. DNA vaccines have attracted attention due to their safety profile, cost-effectiveness, and ease of production. This study aims to assess the efficacy of plasmid-encoding GM-CSF (pGM-CSF) as an adjuvant to augment the specific humoral and cellular immune response elicited by DNA vaccines based on the receptor-binding domain (RBD) antigen. Compared to the use of plasmid-encoded RBD (pRBD) alone, mice that were immunized with a combination of pRBD and pGM-CSF exhibited significantly elevated levels of RBD-specific antibody titers in serum, BALF, and nasal wash. Furthermore, these mice generated more potent neutralization antibodies against both the wild-type and Omicron pseudovirus, as well as the ancestral virus. In addition, pGM-CSF enhanced pRBD-induced CD4+ and CD8+ T cell responses and promoted central memory T cells storage in the spleen. At the same time, tissue-resident memory T (Trm) cells in the lung also increased significantly, and higher levels of specific responses were maintained 60 days post the final immunization. pGM-CSF may play an adjuvant role by promoting antigen expression, immune cells recruitment and GC B cell responses. In conclusion, pGM-CSF may be an effective adjuvant candidate for the DNA vaccines against SARS-CoV-2.

Urothelial Calcium-Sensing Receptor Modulates Micturition Function via Mediating Detrusor Activity and Ameliorates Bladder Hyperactivity in Rats.

The urothelium displays mechano- and chemosensory functions via numerous receptors and channels. The calcium-sensing receptor (CaSR) detects extracellular calcium and modulates several physiological functions. Nonetheless, information about the expression and the role of CaSR in lower urinary tract has been absent. We aimed to determine the existence of urothelial CaSR in urinary bladder and its effect on micturition function. We utilized Western blot to confirm the expression of CaSR in bladder and used immunofluorescence to verify the location of the CaSR in the bladder urothelium via colocalization with uroplakin III A. The activation of urothelial CaSR via the CaSR agonist, AC-265347 (AC), decreased urinary bladder smooth muscle (detrusor) activity, whereas its inhibition via the CaSR antagonist, NPS-2143 hydrochloride (NPS), increased detrusor activity in in vitro myography experiments. Cystometry, bladder nerve activities recording, and bladder surface microcirculation detection were conducted to evaluate the effects of the urothelial CaSR via intravesical administrations. Intravesical AC inhibited micturition reflex, bladder afferent and efferent nerve activities, and reversed cystitis-induced bladder hyperactivity. The urothelial CaSR demonstrated a chemosensory function, and modulated micturition reflex via regulating detrusor activity. This study provided further evidence of how the urothelial CaSR mediated micturition and implicated the urothelial CaSR as a potential pharmacotherapeutic target in the intervention of bladder disorders.

Silicon-containing water intake confers antioxidant effect, gastrointestinal protection, and gut microbiota modulation in the rodents.

We explored the effects of silicon-containing water (BT) intake on gastrointestinal function and gut microbiota. BT was obtained by pressuring tap water through silicon minerals (mullite, Al6Si2O13) column. BT decreased H2O2 chemiluminescence counts, indicating its antioxidant activity. Four weeks of BT drinking increased H2O2 scavenging activity and glutathione peroxidase activity of plasma. BT drinking did not affect the body weight but significantly reduced the weight of feces and gastrointestinal motility. BT drinking significantly suppressed pylorus ligation enhanced gastric juice secretion, gastric reactive oxygen species amount, erythrocyte extravasation, IL-1ß production by infiltrating leukocyte, and lipid peroxidation within gastric mucosa. Data from 16S rRNA sequencing revealed BT drinking significantly increased beneficial flora including Ruminococcaceae UCG-005, Prevotellaceae NK3B31, Weissella paramesenteroides, Lactobacillus reuteri, and Lactobacillus murinus and decreased harmful flora including Mucispirillum, Rodentibacter, and Staphylococcus aureus. This study pioneerly provided scientific evidences for the potential effects of water-soluble forms of silicon intake on antioxidant activity, gastrointestinal function, and gut microbiota modulation.

Glycine tomentella hayata extract and its ingredient daidzin ameliorate cyclophosphamide-induced hemorrhagic cystitis and oxidative stress through the action of antioxidation, anti-fibrosis, and anti-inflammation.

We explored the therapeutic potential of intragastric administration of traditional Chinese medicine Glycine tomentella Hayata (I-Tiao-Gung [ITG]) extract and its major component Daidzin on cyclophosphamide (CYP)-induced cystitis, oxidative stress, fibrosis, inflammation, and bladder hyperactivity in rats. Female Wistar rats were divided into control, CYP (200 mg/kg), CYP+ITG (1.17 g/kg/day), and CYP+Daidzin (12.5 mg/kg/day) groups. We measured the voiding function by the transcystometrogram and evaluated the pathology with the hematoxylin and eosin and Masson stain. We determined the bladder reactive oxygen species (ROS) amount by an ultrasensitive chemiluminescence analyzer, the expression of 3-nitrotyrosine (3-NT) and NADPH oxidase 4 (NOX4) by Western blot and the expression of multiple cytokine profiles, including matrix metalloproteinase (MMP)-8 and tissue inhibitor of metalloproteinase (TIMP)-1 through a cytokine array. ITG extract contains 1.07% of Daidzin through high-performance liquid chromatography. The effect of ITG extract and Daidzin in scavenging hydrogen peroxide activity was more efficient than distilled water. CYP-induced higher urination frequency, shorter intercontraction interval, and lower maximal voiding pressure in the bladders and these symptoms were significantly ameliorated in CYP+ITG and CYP+Daidzin groups. The amount of in vivo bladder ROS and the expression of 3-NT and NOX4 expressions were significantly increased in CYP group but were efficiently decreased in the CYP+ITG and CYP+Daidzin groups. CYP-induced fibrosis, hemorrhage, leukocyte infiltration, and edema in the bladders were significantly attenuated in the CYP+ITG and CYP+Daidzin groups. These results suggested that ITG extract and its active component Daidzin effectively improved CYP-induced oxidative stress, inflammation, and fibrosis through inhibiting the MMP-8, TIMP-1, and oxidative stress.

Aromatherapy: Activating olfactory calcium-sensing receptors impairs renal hemodynamics via sympathetic nerve-mediated vasoconstriction.

AIM: This study determines whether the activation of olfactory calcium-sensing receptor initiates a sympathetic activation-dependent neurovascular reflex subsequently contributing to renal hemodynamic depression. METHODS: Immunohistochemistry and nose-loading calcium-sensitive dye were used to explore the location and function of calcium-sensing receptor on the olfactory sensory neuron. The renal sympathetic nervous activity, renal hemodynamics and the microcirculation of kidney, liver and intestine were evaluated after liquid-phase intranasal administrations of saline, lidocaine, calcium-sensing receptor agonists and antagonist in sham and bilateral renal denervated rats. Real-time renal glomerular filtration rate was measured by a magnetic resonance renography. RESULTS: Calcium-sensing receptors were expressed on the cilia the olfactory sensory neuron and their activation depolarized olfactory sensory neuron and induced the calcium influx in the terminal side on olfactory glomeruli. Activating olfactory calcium-sensing receptors significantly increased arterial blood pressure and renal sympathetic nervous activities and subsequently decreased renal blood flow, renal, hepatic and enteral microcirculation. Cotreatments with calcium-sensing receptor antagonist or lidocaine inhibited these physiological alterations. The renal hemodynamic depressions by olfactory calcium-sensing receptor activation were significantly blocked by bilateral renal denervation. The intranasal manganese administration decreased the glomerular filtration rate. CONCLUSION: Calcium-sensing receptor acts as a functional chemosensory receptor on olfactory sensory neuron, and its activation causes the global sympathetic enhancement contributing to systematic vasoconstriction and subsequently depresses renal blood flow and glomerular filtration rate. These data implicate a possibly clinical aspect that several environmental stimuli may activate olfactory calcium-sensing receptors to evoke a sympathetic nervous system-mediated neurovascular reflex to depress renal hemodynamics.

A Highly Efficient and Reusable Palladium(II)/Cationic 2,2'-Bipyridyl-Catalyzed Stille Coupling in Water.

A water-soluble PdCl2(NH3)2/cationic 2,2'-bipyridyl system was found to be a highly efficient catalyst for Stille coupling of aryl iodides and bromides with organostannanes. The coupling reaction was conducted at 110 °C in water, under aerobic conditions, in the presence of NaHCO3 as a base to afford corresponding Stille coupling products in good to high yields. When aryltributylstannanes were employed, the reactions proceeded smoothly under a very low catalyst loading (as little as 0.0001 mol %). After simple extraction, the residual aqueous phase could be reused in subsequent runs, making this Stille coupling economical. In the case of tetramethylstannane, however, a greater catalyst loading (1 mol %) and the use of tetraethylammonium iodide as a phase-transfer agent were required in order to obtain satisfactory yields.

Enantioselective synthesis of macrocyclic heterobiaryl derivatives of molecular asymmetry by molybdenum-catalyzed asymmetric ring-closing metathesis.

Winding vine-shaped molecular asymmetry is induced by enantioselective ring-closing metathesis with a chiral molybdenum catalyst. The reaction proceeds under mild conditions through an E-selective ring-closing metathesis leading to macrocyclic bisazoles with enantioselectivities of up to 96% ee.

Simultaneous induction of axial and planar chirality in arene-chromium complexes by molybdenum-catalyzed enantioselective ring-closing metathesis.

The molybdenum-catalyzed asymmetric ring-closing metathesis of the various Cs -symmetric (π-arene)chromium substrates provides the corresponding bridged planar-chiral (π-arene)chromium complexes in excellent yields with up to >99 % ee. With a bulky and unsymmetrical substituent, such as N-indolyl or 1-naphthyl, at the 2-positions of the η(6) -1,3-diisopropenylbenzene ligands, both biaryl-based axial chirality and π-arene-based planar chirality are simultaneously induced in the products. The axial chirality is retained even after the removal of the dicarbonylchromium fragment, and the chiral biaryl/heterobiaryl compounds are obtained with complete retention of the enantiopurity.

Suppression of antipsychotic-induced tardive dyskinesia with aripiprazole in an elderly patient with bipolar I disorder.

INTRODUCTION: Aripiprazole has a low risk for causing extrapyramidal syndrome and can remit neuroleptic-induced tardive dyskinesia (TD). Here, we presented a case in which TD was suppressed, but not cured, by long-term aripiprazole treatment. CASE: This 74-year-old male patient had bipolar I disorder and had developed TD many times after several antipsychotic treatments. The lowest chlorpromazine dose equivalent among the previous antipsychotic treatments was 25 mg/day of quetiapine. His TD always improved immediately after the dosage was shifted to aripiprazole. However, his insomnia or other psychiatric symptoms worsened the first three times when the treatment was shifted to aripiprazole, making the transition a failure. Before the fourth attempt of aripiprazole transition, the patient was in a euthymic state but again developed TD under olanzapine 10 mg/day treatment. During the fourth attempt of aripiprazole transition, his TD had remained in complete remission for more than 1 year after the dosage shifted to 10 mg/day of aripiprazole. He developed TD again when we tapered the aripiprazole dose to 5 mg/day, but his TD remitted when we restored his aripiprazole dose to 10 mg/day. CONCLUSION: Aripiprazole could be an effective drug in elderly bipolar patients with antipsychotic-induced TD while the patients are in a euthymic state. However, aripiprazole may only suppress TD rather than cure it.

Phosphine-olefin ligands based on a planar-chiral (π-arene)chromium scaffold: design, synthesis, and application in asymmetric catalysis.

The NMR and X-ray crystallographic studies clarified that planar-chiral alkenylene-bridged (phosphino-π-arene)(phosphine)chromium complexes 3 were capable of coordinating to a rhodium(I) cation in a bidentate fashion at the (π-arene)-bound phosphorus atom and at the olefin moiety. The P-olefin chelate coordination of 3 constructs the effective chiral environment at the metal center, and thus, these rhodium complexes display high performances in various rhodium-catalyzed asymmetric 1,4- and 1,2-addition reactions with arylboron nucleophiles. The control experiments demonstrated that the (η(2)-olefin)-Rh interaction as well as the bridging structure in 3 played the pivotal roles in the high enantioselectivity of the Rh-catalyzed asymmetric reactions. To enhance the synthetic utilities of these phosphine-olefin ligands, an enantiospecific and scalable synthetic method was developed. The novel synthetic method is flexible in terms of the substituent variation, and a library of the planar-chiral (arene)chromium-based phosphine-olefin ligands was established by the combinatorial approach. Among the newly prepared ligand library, compound 3g, which is with a bis(3,5-dimethylphenyl)phosphino group on the η(6)-arene ring, was found to be a far better chiral ligand in the rhodium-catalyzed asymmetric reactions showing excellent enantioselectivity and high yields.

Atropisomeric chiral dienes in asymmetric catalysis: C(2) -symmetric (Z,Z)-2,3-bis[1-(diphenylphosphinyl)ethylidene]tetralin as a highly active Lewis base organocatalyst.

Diene catalysts with a twist: The title C2 -symmetric tetralin-fused 1,3-butadiene derivative is atropisomeric and can be resolved into the two helical enantiomers. The optically pure compound showed excellent enantioselectivity as well as unusually high catalytic activity as a chiral Lewis basic organocatalyst in the asymmetric allylation of various aldehydes with ß-substituted allyltrichlorosilanes.

A fluorescent organic nanotube assembled from novel p-phenylene ethynylene-based dicationic amphiphiles.

Novel π-extended conjugated amphiphiles composed of a hydrophilic section of two quaternary ammonium groups and p-phenylene ethynylene with adjustable alkyl chain hydrophobic section were prepared by a multistep synthesis. These dicationic amphiphiles showed good water solubility and formed a tubular assembly in water. The evidence for the nanotubular comes from direct optical and TEM observations. A strong π-π stacking interaction between neighboring molecules, as evidenced by the red-shift and self-quenching in fluorescence, is proposed for the self-assembly. At the same time, dehydration of the bromide led to strong counterion condensation in headgroups, which resulted in the small curvature structure of the nanotubes. A bilayer lamellar structural model for the organic nanotube is proposed, and a reasonable structural model based on the experimental XRD pattern, as well as cell constants, is proposed.

Sonogashira reaction of aryl and heteroaryl halides with terminal alkynes catalyzed by a highly efficient and recyclable nanosized MCM-41 anchored palladium bipyridyl complex.

A heterogeneous catalyst, nanosized MCM-41-Pd, was used to catalyze the Sonogashira coupling of aryl and heteroaryl halides with terminal alkynes in the presence of CuI and triphenylphosphine. The coupling products were obtained in high yields using low Pd loadings to 0.01 mol%, and the nanosized MCM-41-Pd catalyst was recovered by centrifugation of the reaction solution and re-used in further runs without significant loss of reactivity.