Nanoengineered Red Blood Cells Loaded with TMPRSS2 and Cathepsin L Inhibitors Block SARS-CoV-2 Pseudovirus Entry into Lung ACE2+ Cells.

The enzymatic activities of Furin, Transmembrane serine proteinase 2 (TMPRSS2), Cathepsin L (CTSL), and Angiotensin-converting enzyme 2 (ACE2) receptor binding are necessary for the entry of coronaviruses into host cells. Precise inhibition of these key proteases in ACE2+ lung cells during a viral infection cycle shall prevent viral Spike (S) protein activation and its fusion with a host cell membrane, consequently averting virus entry to the cells. In this study, dual-drug-combined (TMPRSS2 inhibitor Camostat and CTSL inhibitor E-64d) nanocarriers (NCs) are constructed conjugated with an anti-human ACE2 (hACE2) antibody and employ Red Blood Cell (RBC)-hitchhiking, termed "Nanoengineered RBCs," for targeting lung cells. The significant therapeutic efficacy of the dual-drug-loaded nanoengineered RBCs in pseudovirus-infected K18-hACE2 transgenic mice is reported. Notably, the modular nanoengineered RBCs (anti-receptor antibody+NCs+RBCs) precisely target key proteases of host cells in the lungs to block the entry of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), regardless of virus variations. These findings are anticipated to benefit the development of a series of novel and safe host-cell-protecting antiviral therapies.

Ovariectomy induces hyperalgesia accompanied by upregulated estrogen receptor α and protein kinase B in the rat spinal cord.

Hormone supplementation is one of the common therapies for menopause-related disorders. Among different tools, the ovariectomy (OVX) rodents are widely accepted as an appropriate menopausal pain model. Our previous study has showed that OVX produces a significant pain facilitation in both acute pain and tonic pain, however, the underlying mechanisms remain unclear. In this study, we examined the effects of OVX treatment and estradiol (E2) supplementation on formalin-induced nociceptive responses, and explored the associated spinal mechanisms. Female Sprague-Dawley rats underwent bilateral OVX, and E2 supplementation was given subcutaneously from the 5th week after surgery (30 µg/day for 7 days). Our results showed that formalin-induced nociceptive behaviors did not differ between diestrus and proestrus stages of the estrous in intact rats. However, OVX exacerbated formalin-evoked inflammatory pain, especially in the late phase at 4-5 weeks but not 2 weeks post-surgery. E2 supplementation significantly reversed the OVX-triggered hyperalgesia. Double immunofluorescence staining revealed that both ERα and ERß in the spinal dorsal horn were co-labeled with the neuronal markers, but not with markers of astrocytes or microglia. The spinal ERα (but not ERß) expression significantly increased in the OVX group, which was reversed by E2 supplementation. Moreover, the OVX individuals showed an increased protein kinase B (AKT) level in lumbar spinal cord, and E2 supplementation diminished the AKT expression in OVX rats. Finally, intrathecal injection Wortmannin, an inhibitor for AKT signaling, effectively reduced the nociceptive behaviors in the late phase and the number of c-fos positive cells. Together, our findings indicate that E2 supplementation alleviates the OVX-induced hyperalgesia, which might be involved in spinal ERα and AKT mechanisms.

Two different placement paths in popliteal fossa with a novel nerve block needle for postoperative analgesia after foot and ankle surgery.

BACKGROUND: Previous studies have documented that single injection nearby the sciatic nerve bifurcation would influence the anesthesia and analgesia effect. But this is uncertain for preoperative continuous popliteal sciatic nerve block. This trial was conducted to compare two paths (proximal to the bifurcation and at the bifurcation) of ultrasound-guided continuous popliteal sciatic nerve block in foot and ankle surgery. METHODS: Forty recruited objects were randomly assigned to receive ultrasound-guided continuous popliteal sciatic nerve block at the puncture path proximal to the nerve bifurcation either at the nerve bifurcation. Subjects received an injection using a novel nerve block needle with external indwelling cannula guided by ultrasound invented by the corresponding author. The external indwelling cannula was inserted for postoperative analgesia. The primary outcome was NRS scores (at rest and during movement) times at 24 hours after surgery. The secondary outcomes included the measurements related to the performance of the nerve block and efficacy of analgesia, such as anesthesia effect grade, grade of nausea and vomiting, case number of patients with cannula leaking, occlusion or slipping, patient satisfaction, etc. RESULTS: During the surgery, six subjects in the proximal group needed additional analgesic, significantly different from one in the at bifurcation group (P<0.05). There was significant difference on anesthesia effect rating, 1.6±0.8 in the proximal group and 1.1±0.4 in another (P<0.05). The proximal group got 2.1±1.6 of NRS on rest at 24 hours and 1.7±1.5 at 48 hours, and the at bifurcation group got 0.9±1.4 at 24 hours and 0.7±1.1 at 48 hours (P<0.05). The proximal group got more PCA times during 6-24 hours and 24-48 hours and lower satisfaction scores. CONCLUSIONS: Continuous popliteal sciatic nerve block at nerve bifurcation could receive better analgesia effect and more patients' satisfaction, rather than proximal to the bifurcation.