Association between gut microbiota and menstrual disorders: a two-sample Mendelian randomization study.

Background: Evidence from observational studies and clinical trials suggests that the gut microbiota is associated with gynecological diseases. However, the causal relationship between gut microbiota and menstrual disorders remains to be determined. Methods: We obtained summary data of gut microbiota from the global consortium MiBio-Gen's genome-wide association study (GWAS) dataset and data on menstrual disorders from the IEU Open GWAS project. MR-Egger, weighted median, inverse variance weighted, simple mode, and weighted mode were used to examine the causal association between gut microbiota and menstrual disorders. Thorough sensitivity studies were performed to confirm the data's horizontal pleiotropy, heterogeneity, and robustness. Results: Through MR analysis of 119 kinds of gut microbiota and 4 kinds of clinical phenotypes, it was discovered that 23 different kinds of gut microbiota were loosely connected to menstrual disorders. After FDR correction, the results showed that only Escherichia/Shigella (p = 0.00032, PFDR = 0.0382, OR = 1.004, 95%CI = 1.002-1.006) is related to menstrual disorders. Conclusion: According to our MR Analysis, there are indications of a causal relationship between menstrual disorders and gut microbiota. This finding could lead to new discoveries into the mechanisms behind menstrual disorders and clinical research involving the microbiota.

Design of pH-responsive antimicrobial peptide melittin analog-camptothecin conjugates for tumor therapy.

Melittin, a classical antimicrobial peptide, is a highly potent antitumor agent. However, its significant toxicity seriously hampers its application in tumor therapy. In this study, we developed novel melittin analogs with pH-responsive, cell-penetrating and membrane-lytic activities by replacing arginine and lysine with histidine. After conjugation with camptothecin (CPT), CPT-AAM-1 and CPT-AAM-2 were capable of killing tumor cells by releasing CPT at low concentrations and disrupting cell membranes at high concentrations under acidic conditions. Notably, we found that the C-terminus of the melittin analogs was more suitable for drug conjugation than the N-terminus. CPT-AAM-1 significantly suppressed melanoma growth in vivo with relatively low toxicity. Collectively, the present study demonstrates that the development of antitumor drugs based on pH-responsive antimicrobial peptide-drug conjugates is a promising strategy.

Evaluating the cytotoxicity mechanism of the cell-penetrating peptide TP10 on Jurkat cells.

TP10, a classic cell-penetrating peptide, shows a high degree of similarity to AMPs in structure. Although TP10 has been widely used in drug delivery, the mechanism underlying its cytotoxicity is yet to be elucidated. Herein, we explored the cell-killing mechanism of TP10 against human leukemia Jurkat cells. TP10 induced necrosis in Jurkat cells via rapid disruption of cell membranes, particularly at high concentrations. Although mitochondria in Jurkat cells were damaged by TP10, mitochondria-mediated apoptosis did not occur, possibly due to intracellular ATP depletion. Necroptosis in TP10-treated Jurkat cells became an alternative route of apoptosis. Our results demonstrate that necrosis and necroptosis rather than apoptosis are involved in the cell-killing mechanism of TP10, which contributes to the understanding of its toxicity.

Development of Neuropeptide Hemokinin-1 Analogues with Antimicrobial and Wound-Healing Activity.

Wound healing is a complex process that can be delayed in some pathological conditions, such as infection and diabetes. Following skin injury, the neuropeptide substance P (SP) is released from peripheral neurons to promote wound healing by multiple mechanisms. Human hemokinin-1 (hHK-1) has been identified as an SP-like tachykinin peptide. Surprisingly, hHK-1 shares similar structural features with antimicrobial peptides (AMPs), but it does not display efficient antimicrobial activity. Therefore, a series of hHK-1 analogues were designed and synthesized. Among these analogues, AH-4 was found to display the greatest antimicrobial activity against a broad spectrum of bacteria. Furthermore, AH-4 rapidly killed bacteria by membrane disruption, similar to most AMPs. More importantly, AH-4 showed favorable healing activity in all tested mouse full-thickness excisional wound models. Overall, this study suggests that the neuropeptide hHK-1 can be used as a desirable template for developing promising therapeutics with multiple functions for wound healing.

Influence of chain length on the anticancer activity of the antimicrobial peptide CAMEL with fatty acid modification.

Antimicrobial peptides (AMPs) display promising potential in cancer therapy. Modification with fatty acids is a simple and effective approach to improve the activity of AMPs. In the present study, we investigated the effects of fatty acid chain lengths on the anticancer activity, self-assembly and mechanism of action of CAMEL (CM15, KWKLFKKIGAVLKVL-NH2), an amphipathic AMP with 15 amino acids. Conjugation of fatty acids could obviously improve the in vitro anticancer activity of CAMEL. Among the tested peptides, C12-CAMEL showed the highest anticancer activity, while C16-CAMEL killed cancer cells with the slowest kinetics. This may be related to the self-assembly of C12-CAMEL and C16-CAMEL, which could form spherical nanoparticles and tightened nanofibers, respectively. In addition, necrosis and necroptosis rather than apoptosis were the major mechanisms underlying the anticancer activity of CAMEL, C12-CAMEL and C16-CAMEL, implying that modification with fatty acids did not obviously alter the mechanism of action of CAMEL. Notably, C12-CAMEL, with high and rapid cell-killing activity, exhibited significantly stronger in vivo anticancer activity than CAMEL and C16-CAMEL. Overall, the present work suggests that the choice of a suitable fatty acid for structural modification is necessary for improving the anticancer activity of AMPs.

Case Distribution, Sources, and Breeds of Dogs Presenting to a Veterinary Behavior Clinic in the United States from 1997 to 2017.

The purpose of this retrospective case study was to evaluate trends over time in case distribution, sources, and breeds of dogs presenting to the behavioral medicine service at a veterinary college referral hospital in the United States. For case distribution and sources, the available records from the behavior service (n = 1923) from 1997 to 2017 were evaluated. Breeds of dogs presenting to all services (n = 51,052) were compared to behavior cases (n = 822) from 2007 to 2016. Over twenty years, 72.2% of dogs presented for aggression, 20.1% for anxieties/fears/phobias, and 7.4% for miscellaneous behavioral problems. Dogs acquired from breeders decreased and dogs from shelters, rescues, or adopted as a stray increased over twenty years (p < 0.0001). The Herding (p = 0.0124) and Terrier (p < 0.0001) groups were overrepresented for behavior problems as compared to all other services over ten years. Variations in terminology and diagnostic approach made comparisons with earlier studies difficult, which underscores a need for a more consistent methodology in veterinary behavioral medicine. Understanding trends in sources of dogs could direct resources aimed at guiding owners when acquiring a pet dog and preventing behavioral problems. Findings related to breeds could help guide research focused on the genetic contributions to behavior.

Antimicrobial and anti-inflammatory activities of the neuropeptide antagonist SPA.

Antimicrobial peptides have received increased attention due to the increasing prevalence of antibiotic-resistant bacteria. However, the development of antimicrobial peptides for clinical applications remains a huge challenge. SPA ([D-rg1 , D-Trp5,7,9 , Leu11 ]SP), an analog of substance P, is a broad-spectrum neuropeptide antagonist. In this study, we found that SPA could efficiently kill Gram-positive and Gram-negative bacteria by membrane disruption, similar to antimicrobial peptides. In addition, SPA showed high killing activity toward bacteria rather than mammalian cells. Our results also demonstrated that SPA could significantly decrease the expression of proinflammatory cytokines and rescue mice from lethal septic shock induced by lipopolysaccharide (LPS). The impressive therapeutic potential of SPA, as indicated in this study, makes it a good template for developing effective antibiotics. Meanwhile, our study provides a new idea for developing multifunctional therapeutic agents to combat bacterial infections.