Drug Discoveries and Therapeutics最新文献

Diminished ovarian reserve (DOR) refers to the decline in fertility caused by the loss of normal ovarian function. DOR is associated with adverse reactions to ovarian stimulation during in vitro fertilization and embryo transfer (IVF-ET), increasing cycle cancellation rates and reducing pregnancy rates. Although it is well known that dehydroepiandrosterone (DHEA) can be used as a dietary supplement for age-related diseases, its potential has gradually been shown for many diseases. In this review, we focus on the effects of DHEA on DOR, briefly analysing its clinical benefits and limitations and describing the mechanism of function and the clinical trials conducted. Therefore, we summarize the mechanisms and indications of DHEA for DOR.

We aimed to evaluate the effect of serum luteinizing hormone (LH) levels on human chorionic gonadotropin (HCG) injection day (LH_HCG) on outcomes of in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) patients. It is a retrospective cohort study involving 620 women who had an IVF cycle in Taizhou Hospital Affiliated to Wenzhou Medical University between 2018-2020. The participants were divided into different groups according to LH_HCG level and age. The clinical data and outcomes were compared between groups. The numbers of follicles (≥ 14 mm) on HCG day, retrieved oocytes, mature oocytes, and two pronuclei (2PN) embryos in women with LH_HCG < 2 IU/L were more than those with LH_HCG ≥ 2 IU/L. Women with LH_HCG < 2 IU/L had lower high-quality embryo rate (42.2% vs. 46.5%, p = 0.002) and implantation rate (40.0% vs. 58.8%, p = 0.044) compared to those with LH_HCG ≥ 2 IU/L. When LH_HCG < 2 IU/L, there was no significant difference in implantation rates in patients < 35 years compared to those ≥ 35 years. When LH_HCG ≥ 2 IU/L, patients < 35 years old had higher implantation rates (71.7% vs. 41.2%, p < 0.001) compared to those ≥ 35 years old. The success rates of IVF fertilization and ICSI fertilization and biochemical and clinical pregnancy rates were not significantly different between groups. Our results demonstrated that women undergoing IVF/ICSI-ET might benefit from maintaining LH_HCG levels at ≥ 2 IU/L. In addition, age might associate with LH_HCG levels and be a better determining factor of the transfer outcome than serum LH_HCG levels for IVF/ICSI-ET.

Tuberculosis (TB) is a major public health problem that causes millions of deaths in humans around the world, and the bacterial pathogen Mycobacterium tuberculosis (Mtb) is responsible for this disease. Evidence suggested that the inflammasome-pyroptosis pathway is crucial for preventing Mtb infection. Uncertainty exists regarding whether and how these infections can bypass this immune system by Mtb. A recent Science article by Chai et al. (doi: 10.1126/science.abq0132) revealed a novel role by a eukaryotic-like effector called PtpB during Mtb infection. The PtpB functions as a phospholipid phosphatase suppressing gasdermin D (GSDMD) dependent pyroptosis. And notably, the phospholipid phosphatase activity of PtpB is dependent on binding with mono-ubiquitin (Ub) of the host.

Staphylococcus aureus is a common clinical pathogen. Does every S. aureus infection require anti-MRSA drugs? Reported here are three cases of a community-acquired infection with S. aureus. The first case involveds a 45-year-old male who was admitted due to right ankle pain for 1 month; he was diagnosed with chronic suppurative osteomyelitis and an acute soft tissue infection of the ankle. S.aureus was cultured from the pus and was resistant to penicillin and sensitive to oxacillin and vancomycin. After receiving oxacillin, he was cured and discharged 45 days after admission. The second case involved a 44-year-old male who was admitted due to lumbar pain with right lower limb numbness for more than 1 month and fever for 1 day. S. aureus was cultured from blood specimens and was resistant to penicillin and sensitive to oxacillin and vancomycin. After receiving oxacillin, he as cured. The third case involved a 7-day-old newborn who was admitted due to skin jaundice for 6 days. S. aureus was cultured from skin secretions specimens and was resistant to penicillin and sensitive to oxacillin, erythromycin, and vancomycin. The newborn was treated with oxacillin for 4 days, and she was cured and discharged. Not all cases a suspected S. aureus infection require anti-MRSA drugs; instead, previous S. aureus susceptibility results in the area and hospital, as well as the patient's clinical profile, need to be taken into account.

Mycobacterium abscessus causes chronic skin infections, lung diseases, and systemic or disseminated infections. Although a silkworm infection model with M. abscessus has been established, pathological analysis of the infected silkworms has not been performed. In this study, we performed hematoxylin-eosin and Ziehl-Neelsen staining of silkworms infected with M. abscessus. Four days after infection with M. abscessus, M. abscessus accumulation was observed in the fat bodies of silkworms. The number of viable M. abscessus cells in the fat bodies of the infected silkworms increased over time. These results suggest that M. abscessus proliferates in the fat bodies of the infected silkworms.

Since nanoparticles are taken up into cells by endocytosis, phagocytosis, or pinocytosis, they have been studied as intracellular drug carriers. Janus particles have an anisotropic structure composed of two or more distinct domains and have been proposed for use in various applications, including use as imaging agents or nanosensors. This study aimed to clarify the influence of the type of nanoparticles on their distribution in a human Caucasian colon adenocarcinoma (Caco-2) cell monolayer. We fabricated Janus and conventional spherical nanoparticles composed of pharmaceutically applicable ingredients. Janus and spherical nanoparticles composed of a cationic polymer and surfactant lipids were prepared by controlling the solvent removal pattern from the oil phase in the solvent removal process using the solvent evaporation and solvent diffusion methods. The distribution of nanoparticles in the Caco-2 cell monolayer was then evaluated using confocal laser microscopy. The mean hydrodynamic size of the fabricated Janus nanoparticles was 119.2 ± 4.6 nm. Distribution analysis using Caco-2 cells suggested that Janus nanoparticles were localized around the adherens junctions located just below the tight junction. Clear localization was not observed in non-Janus nanoparticles with the same composition. The clear localization of the Janus nanoparticles around the adherens junction may be due to their positive charge and asymmetric structure. Our results suggest the considerable potential for the development of nanoparticulate drug carriers to target cellular gaps.

The reverse transcription polymerase chain reaction (RT-PCR) offers high sensitivity, but has some drawbacks, such as the time required for the RNA extraction. Transcription reverse-transcription concerted reaction (TRC) Ready^® SARS-CoV-2 i is easy to use and can be performed in about 40 minutes. TRC Ready^® SARS-CoV-2 i and real-time one-step RT-PCR using the TaqMan probe tests of cryopreserved nasopharyngeal swab samples from patients diagnosed with COVID-19 were compared. The primary objective was to examine the positive and negative concordance rates. A total of 69 samples cryopreserved at -80° C were examined. Of the 37 frozen samples that were expected to be RT-PCR positive, 35 were positive by the RT-PCR method. TRC Ready^® SARS-CoV-2 i detected 33 positive cases and 2 negative cases. One frozen sample that was expected to be RT-PCR positive was negative on both TRC Ready^® SARS-CoV-2 i and RT-PCR. In addition, one frozen sample that was expected to be RT-PCR positive was positive by the RT-PCR method and negative by TRC Ready^® SARS-CoV-2 i. Of the 32 frozen samples that were expected to be RT-PCR negative, both the RT-PCR method and TRC Ready^® SARS-CoV-2 i yielded negative results for all 32 samples. Compared with RT-PCR, TRC Ready^® SARS-CoV-2 i had a positive concordance rate of 94.3% and a negative concordance rate of 97.1%. TRC Ready^® SARS-CoV-2 i can be utilized in a wide range of medical sites such as clinics and community hospitals due to its ease of operability, and is expected to be useful in infection control.

Transcription factor GATA6 stably expressed in Chinese hamster ovary (CHO)-K1 cells is exported from the nucleus to the cytoplasm and degraded there by proteasome upon treatment with dibutylyl-cyclic AMP (dbcAMP), which is a membrane-permeable cyclic AMP (cAMP) analogue. The cAMP-dependent proteolysis of GATA6 was characterized by dissection of the GATA6 protein into a zinc-finger domain (Zf) and the surrounding region (ΔZf). These segments were separately expressed in CHO-K1 cells stably, and followed by treatment with dbcAMP. The nuclear localized Zf was degraded by proteasome similarly to the full-length GATA6. Site-directed mutants of nuclear localizing signal (NLS) (³⁴⁵RKRKPK³⁵⁰ → AAAAPK and AAAAPA) and closely related GATA4 showed the same behavior. Although nuclear-localized ΔZf was degraded by proteasome, the cytoplasmic-located ΔZf was resistant to proteolysis in contrast to the NLS mutants. We also searched for a potential NLS and nuclear export signal (NES) with computational prediction programs and compared the results with ours. All these results suggest that the amino acid sequence(s) of the Zf of GATA6 is responsive to cAMP-dependent nuclear export and proteolysis.

We studied 95 patients with infantile hemangioma (IH) treated with propranolol at the Department of Dermatology, Kumamoto University Hospital, from November 2016 to January 2022, based on sex, site, clinical classification, duration of treatment, and residual lesions after treatment. Four of the 95 patients discontinued propranolol due to side effects, and 55 completed follow-ups at our hospital. We observed that 30.1% showed complete resolution of the skin rash, while the remaining 69.8% had erythema or atrophic scarring. Complete resolution occurred in 70% of the cases with the subcutaneous type but only in 15% with the tumor type. Seventeen of the 55 patients who completed follow-ups were treated with propranolol combined with laser therapy. Combined use of propranolol and laser therapy significantly reduced severe erythema compared to the propranolol monotherapy. These results suggest that propranolol therapy in IH often leaves erythema except in the subcutaneous type and that an improvement in erythema can be expected when propranolol is combined with laser therapy.

Increasing incidences of resistance to antibiotics by pathogenic bacteria is a worldwide concern and isolation of antibiotic-resistant strains of Niallia circulans (formerly known as Bacillus circulans), an opportunistic human pathogen, has been reported. Due to their lack of ethical constraints as well as their cost-effective rearing, invertebrates have been commonly used to study infection by bacteria pathogenic to humans. In this study, we demonstrate that a foodborne strain of N. circulans kills larvae of the silkworm, Bombyx mori within 48 h after hemolymph injection. The infected larvae turned black with an increase in the phenoloxidase (PO) activity in the hemolymph. Midgut injection of N. circulans resulted in the killing of larvae within 96 h. A significant increase in bacterial load was observed in the hemolymph 12 h after infection. The viable hemocyte number decreased to 48% within 12 h of injection. RT-qPCR analysis revealed that upon hemolymph infection with N. circulans the expression of the antimicrobial peptide (AMP) genes, Bmdefensin-B and Bmgloverin-3, were upregulated 2.5- and 1.8-fold, respectively, whereas 1.6-fold upregulation was observed for BmToll-2 in the larval fat body. Therapeutic effects of antibiotics like tetracycline, imipenem, ceftriaxone, ampicillin, and clindamycin were observed against N. circulans in the Bombyx larvae with varying efficacies. Results from this study suggest that larvae of B. mori can be used as infection models for screening therapeutics that are effective against N. circulans.