SLC4A4 is a novel driver of enzalutamide resistance in prostate cancer.

The androgen receptor signaling inhibitor (ARSI) enzalutamide (Enz) has shown critical efficacy in the treatment of advanced prostate cancer (PCa). However, the development of drug resistance is a significant factor contributing to mortality in PCa patients. We aimed to explore the key mechanisms of Enz-resistance. Through analysis of GEO databases, we identified SLC4A4 as a novel driver in Enz resistance. Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-κB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo. Hence, our results suggest that targeting SLC4A4 could be a promising therapeutic strategy for Enz resistance. STATEMENT OF SIGNIFICANCE: SLC4A4 is a novel driver of enzalutamide resistance.

The association and underlying mechanism of the digit ratio (2D:4D) in hypospadias.

The second-to-fourth digit (2D:4D) ratio is thought to be associated with prenatal androgen exposure. However, the relationship between the 2D:4D ratio and hypospadias is poorly understood, and its molecular mechanism is not clear. In this study, by analyzing the hand digit length of 142 boys with hypospadias (23 distal, 68 middle, and 51 proximal) and 196 controls enrolled in Shanghai Children's Hospital (Shanghai, China) from December 2020 to December 2021, we found that the 2D:4D ratio was significantly increased in boys with hypospadias ( P < 0.001) and it was positively correlated with the severity of the hypospadias. This was further verified by the comparison of control mice and prenatal low testosterone mice model obtained by knocking out the risk gene (dynein axonemal heavy chain 8 [ DNAH8 ]) associated with hypospadias. Furthermore, the discrepancy was mainly caused by a shift in 4D. Proteomic characterization of a mouse model validated that low testosterone levels during pregnancy can impair the growth and development of 4D. Comprehensive mechanistic explorations revealed that during the androgen-sensitive window, the downregulation of the androgen receptor (AR) caused by low testosterone levels, as well as the suppressed expression of chondrocyte proliferation-related genes such as Wnt family member 5a ( Wnt5a ), Wnt5b , Smad family member 2 ( Smad2 ), and Smad3 ; mitochondrial function-related genes in cartilage such as AMP-activated protein kinase ( AMPK ) and nuclear respiratory factor 1 ( Nrf-1 ); and vascular development-related genes such as myosin light chain ( MLC ), notch receptor 3 ( Notch3 ), and sphingosine kinase 1 ( Sphk1 ), are responsible for the limitation of 4D growth, which results in a higher 2D:4D ratio in boys with hypospadias via decreased endochondral ossification. This study indicates that the ratio of 2D:4D is a risk marker of hypospadias and provides a potential molecular mechanism.

Using Piezosurgery in Anterior Cervical Discectomy and Fusion to Treat Complex Cervical Spondylotic Myelopathy Is Safe and Effective.

Objective: To investigate the safety and efficacy of piezosurgery in anterior cervical discectomy and fusion (ACDF) for cervical spondylotic myelopathy (CSM). Methods: 47 patients with complex CSM (cCSM) underwent ACDF surgery from 2014 to 2017. Among these patients, 26 underwent ACDF using piezosurgery (group A) and 21 underwent ACDF by using traditional tools such as high-speed air drill, bone curette, and Kerrison bone punch (group B). Average surgical time, intraoperative blood loss, surgical complications, preoperative and postoperative Japanese Orthopaedic Association (JOA) scores, and improvement rate were measured. Results: Average surgical time and intraoperative blood loss were significantly lower in group A than those in group B (P < 0.01). The incidences of surgical complications were 3.8% and 23.8% in the A and B groups (P < 0.05), respectively. There were no significant differences in JOA scores and improvement rates between data collection periods at preoperative, 3-day postoperative, and 1-year postoperative follow-ups (P > 0.05). Conclusion: For treating cCSM, both the piezosurgery and traditional tools led to significant neurological improvement. However, the piezosurgery was superior to the traditional tools in terms of surgical time, blood loss, and complication rate. Hence, piezosurgery was a safe and effective adjunct for ACDF treating cCSM.

Evaluating the Role of Morphological Parameters in the Prostate Transition Zone in PHI-Based Predictive Models for Detecting Gray Zone Prostate Cancer.

Background: The early detection of clinically significant prostate cancer (csPCa) through the integration of multidimensional parameters presents a promising avenue for improving survival outcomes for this fatal disease. This study aimed to assess the contribution of prostate transition zone (TZ) to predictive models based on the prostate health index (PHI), with the goal of enhancing early detection of csPCa in the prostate-specific antigen (PSA) gray zone. Methods: In this observational cross-sectional study, a total of 177 PSA gray zone patients (total prostate-specific antigen [tPSA] level ranging from 4.0 to 10.0 ng/mL) were recruited and received PHI detections from August 2020 to March 2022. Prostatic morphologies especially the TZ morphological parameters were measured by transrectal ultrasound (TRUS). Results: Univariable logistic regression indicated prostatic morphological parameters including total prostate volume (PV) indexes and transitional zone volume indexes were all associated with csPCa (P < .05), while the multivariable analysis demonstrated that C-reactive protein (CRP), PHI, PHI density (PHID), and PHI transition zone density (PHI-TZD) were the 4 independent risk factors. The receiver-operating characteristic (ROC) curve analysis suggested that integrated predictive models (PHID, PHI-TZD) yield area under the curves (AUCs) of 0.9135 and 0.9105 in csPCa prediction, which shows a relatively satisfactory predictive capability compared with other predictors. Moreover, the PHI-TZD outperformed PHID by avoiding 30 patients' unnecessary biopsies while maintaining 74.36% specificity at a sensitivity of 90%. Decision-curve analysis (DCA) confirmed the comparable performance of the multivariable full-risk prediction models, without the inclusion of the net benefit, thereby highlighting the superior diagnostic efficacy of PHID and PHI-TZD in comparison with other diagnostic models, in both univariable and multivariable models. Conclusion: Our data confirmed the value of prostate TZ morphological parameters and suggested a significant advantage for the TZ-adjusted PHI predictive model (PHI-TZD) compared with PHI and PHID in the early detection of gray zone csPCa under specific conditions.

Endogenous hydrogen sulfide inhibition suppresses tumor growth by promoting apoptosis and pyroptosis in esophageal cancer cells.

BACKGROUND: Hydrogen sulfide (H2S) has been identified as the third gaseous signaling molecule. Endogenous H2S plays a key role in the progression of various types of cancer. However, the effect of endogenous H2S on the growth of esophageal cancer (EC) remains unknown. METHODS: In this study, three kinds of H2S-producing enzymes inhibitors, DL-propargylglycine (PAG, inhibitor of cystathionine-γ-lyase), aminooxyacetic acid (AOAA, inhibitor of cystathionine-ß-synthase), and L-aspartic acid (L-Asp, inhibitor of 3-mercaptopyruvate sulfurtransferase) were used to determine the role of endogenous H2S in the growth of EC9706 and K450 human EC cells. RESULTS: The results indicated that the combination (PAG+AOAA+L-Asp) group showed higher inhibitory effects on the viability, proliferation, migration, and invasion of EC cells than PAG, AOAA, and L-Asp group. Inhibition of endogenous H2S promoted apoptosis via activation of mitogen-activated protein kinase pathway in EC cells. Endogenous H2S suppression triggered pyroptosis of EC cells by activating reactive oxygen species-mediated nuclear factor-κB signaling pathway. In addition, the combine group showed its more powerful growth-inhibitory effect on the growth of human EC xenograft tumors in nude mice without obvious toxicity. CONCLUSION: Our results indicate that inhibition of endogenous H2S production can significantly inhibit human EC cell growth via promotion of apoptosis and pyroptosis. Endogenous H2S may be a promising therapeutic target in EC cells. Novel inhibitors for H2S-producing enzymes can be designed and developed for EC treatment.

Hydrogen sulfide-induced post-translational modification as a potential drug target.

Hydrogen sulfide (H2S) is one of the three known gas signal transducers, and since its potential physiological role was reported, the literature on H2S has been increasing. H2S is involved in processes such as vasodilation, neurotransmission, angiogenesis, inflammation, and the prevention of ischemia-reperfusion injury, and its mechanism remains to be further studied. At present, the role of post-translational processing of proteins has been considered as a possible mechanism for the involvement of H2S in a variety of physiological processes. Current studies have shown that H2S is involved in S-sulfhydration, phosphorylation, and S-nitrosylation of proteins, etc. This paper focuses on the effects of protein modification involving H2S on physiological and pathological processes, looking forward to providing guidance for subsequent research.

Recent advances in the role of endogenous hydrogen sulphide in cancer cells.

Hydrogen sulphide (H2 S) is a gaseous neurotransmitter that can be self-synthesized by living organisms. With the deepening of research, the pathophysiological mechanisms of endogenous H2 S in cancer have been increasingly elucidated: (1) promote angiogenesis, (2) stimulate cell bioenergetics, (3) promote migration and proliferation thereby invasion, (4) inhibit apoptosis and (5) activate abnormal cell cycle. However, the increasing H2 S levels via exogenous sources show the opposite trend. This phenomenon can be explained by the bell-shaped pharmacological model of H2 S, that is, the production of endogenous (low concentration) H2 S promotes tumour growth while the exogenous (high concentration) H2 S inhibits tumour growth. Here, we review the impact of endogenous H2 S synthesis and metabolism on tumour progression, summarize the mechanism of action of H2 S in tumour growth, and discuss the possibility of H2 S as a potential target for tumour treatment.

Inhibition of endogenous hydrogen sulfide production suppresses the growth of nasopharyngeal carcinoma cells.

Hydrogen sulfide (H2 S) has been widely recognized as one of gasotransmitters. Endogenous H2 S plays a crucial role in the progression of cancer. However, the effect of endogenous H2 S on the development of nasopharyngeal carcinoma (NPC) is still unknown. In this study, aminooxyacetic acid (AOAA, an inhibitor of cystathionine-ß-synthase), dl-propargylglycine (PAG, an inhibitor of cystathionine-γ-lyase), and l-aspartic acid (l-Asp, an inhibitor of 3-mercaptopyruvate sulfurtransferase) were adopted to detect the role of endogenous H2 S in NPC growth. The results indicated that the combine (PAG + AOAA + l-Asp) group had higher inhibitory effect on the growth of NPC cells than the PAG, AOAA, and l-Asp groups. There were similar trends in the levels of apoptosis and reactive oxygen species (ROS). In addition, the combine group exhibited lower levels of phospho (p)-extracellular signal-regulated protein kinase but higher expressions of p-p38 and p-c-Jun N-terminal kinase than those in the AOAA, PAG, and l-Asp groups. Furthermore, the combine group exerted more potent inhibitory effect on NPC xenograft tumor growth without obvious toxicity. In summary, suppression of endogenous H2 S generation could dramatically inhibit NPC growth via the ROS/mitogen-activated protein kinase pathway. Endogenous H2 S may be a novel therapeutic target in human NPC cells. Effective inhibitors for H2 S-producing enzymes could be designed and developed for NPC treatment.

Procollagen C-proteinase enhancer 1 promotes physiologic retinal angiogenesis via regulating the process of collagen.

AIM: To investigate the role of procollagen C-proteinase enhancer 1 (PCPE1) in retinal angiogenesis and relevant mechanisms. METHODS: The Pcolce1-knockout (KO) mice were used to explore the effect of PCPE1 on retinal angiogenesis in vivo. Pcolce1 siRNA were designed, cell count kit 8 (CCK8) assays and tube formation assays were performed to investigate the cell proliferation and tube formation abilities of retinal microvascular endothelial cells (hRMECs) in vitro. Mouse embryo fibroblasts (MEF) cells were isolated and cultured to analyze the effect of PCPE1 on enhancing procollagen cleavage. RESULTS: In vivo studies showed that the retinal vascular density of Pcolce1-/- mice was significantly lower than that of the control group. Furthermore, silencing of Pcolce1 inhibited cell proliferation and tube formation abilities of hRMECs in vitro. Additionally, much more pro-collagen was found in Pcolce1-/- MEF cells, compared to wild type MEF cells. CONCLUSION: PCPE1 may promote physiological retinal angiogenesis by regulating the processing of collagen, which may provide a potential therapeutic target of retinal vascular disease.

Hydrogen Sulfide Biology and Its Role in Cancer.

Hydrogen sulfide (H2S) is an endogenous biologically active gas produced in mammalian tissues. It plays a very critical role in many pathophysiological processes in the body. It can be endogenously produced through many enzymes analogous to the cysteine family, while the exogenous source may involve inorganic sulfide salts. H2S has recently been well investigated with regard to the onset of various carcinogenic diseases such as lung, breast, ovaries, colon cancer, and neurodegenerative disorders. H2S is considered an oncogenic gas, and a potential therapeutic target for treating and diagnosing cancers, due to its role in mediating the development of tumorigenesis. Here in this review, an in-detail up-to-date explanation of the potential role of H2S in different malignancies has been reported. The study summarizes the synthesis of H2S, its roles, signaling routes, expressions, and H2S release in various malignancies. Considering the critical importance of this active biological molecule, we believe this review in this esteemed journal will highlight the oncogenic role of H2S in the scientific community.

Targeting circDGKD Intercepts TKI's Effects on Up-Regulation of Estrogen Receptor ß and Vasculogenic Mimicry in Renal Cell Carcinoma.

Vasculogenic mimicry (VM) has been reported as an alternative channel to increase tumor nutrient supplies and accelerate tumor progression, and is associated with poor survival prognosis in multiple cancers, including renal cell carcinoma (RCC). The currently used anti-angiogenic treatment for metastatic RCC, sunitinib, a tyrosine kinase inhibitor (TKI), has been reported to induce VM formation. Previously we identified that the estrogen receptor ß (ERß) functions as an oncogenic factor to promote RCC progression, supported by the analytic results from The Cancer Genome Atlas (TCGA) database. We have also found evidence that sunitinib induces RCC VM formation by up-regulating ERß expression. In this study, we further demonstrated that treatment with sunitinib, as well as axitinib, another TKI, could induce ERß expression in RCC cell lines. Clinical clear cell RCC (ccRCC) patients with higher ERß expression are more likely to be found VE-cadherin positive and VM positive. Mechanism dissection showed that TKI- induced ERß transcriptionally up-regulates the circular RNA of DGKD (circDGKD, hsa_circ_0058763), which enhances VE-cadherin expression by sponging the microRNA miR-125-5p family. Targeting circDGKD intercepts sunitinib-pretreatment-induced RCC VM formation, reduces metastases and improves survival in an experimental orthotopic animal model. Targeting ERß/circDGKD signals may improve the TKI efficacy and provide novel combination therapies for metastatic RCC.

Biology of PEST-Containing Nuclear Protein: A Potential Molecular Target for Cancer Research.

PEST-containing nuclear protein (PCNP), a novel nuclear protein, is involved in vital cellular processes like cell proliferation and mediates tumorigenesis. PCNP is a short-living, small nuclear protein of only 178 amino acids with two remarkable PEST sequences that are rich in proline (P), glutamic acid (E), serine (S), and threonine (T). The current understanding of PCNP reveals that PCNP has the ability to interact with cell cycle regulatory proteins; tumor suppressors (p53 and pRB), and promoters (cyclin E and cyclin D) to determine the fate of tissues to facilitate the process of either apoptosis or cell proliferation. In many preclinical studies, it has been evaluated that PCNP expression has associations with the development and progression of various cancers like neuroblastoma, lung adenocarcinoma, and ovarian cancer. Based on these depicted novel roles of PCNP in cell cycleregulation and of PCNP in tumorigenesis, it is logical to consider PCNP as a potential molecular target for cancer research. The aim of the current communication is to present an update on PCNP research and discussion on the potential role of PCNP in cancer development with challenges and opportunities perspectives. Considering the available evidence as a baseline for our statement, we anticipate that in the future, new research insights will strengthen the aim to develop PCNP-based diagnostic and therapeutic approaches that will move the PCNP from the laboratory to the cancer clinic.

[A case-control study of minimally invasive transforaminal interbody fusion with the assistance of robot and traditional fluoroscopy in the treatment of single-space lumbar disc herniation].

OBJECTIVE: To compare the safety and nail placement accuracy of fluoroscopy-assisted and robot-assisted minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) in the treatment of single-space lumbar disc herniation. METHODS: The clinical data of 52 patients with single-space lumbar disc herniation treated by MIS-TLIF from March 2019 to February 2020 were retrospectively analyzed. Among them, 24 patients were treated by robot-assisted MIS-TLIF(group A) and 28 patients were treated by fluoroscopy-assisted MIS-TLIF (group B). The intraoperative blood loss, operation time, intraoperative fluoroscopy times, preoperative and postoperative visual analogue scale(VAS), Japanese Orthopaedic Association(JOA) scores and operation-related complications were recorded in two groups. Gertzbein-Robbins grade according to CT scan was used to evaluate the nail placement after operation. Grade A and B were evaluated as satisfactory nail placement, and grade C, D, and E were evaluated as error placement. Babu's method was used to evaluate the screw's invasion to the superior articular process. RESULTS: The operation time, intraoperative blood loss and intraoperative fluoroscopy times in group A were less than those in group B(P<0.05).VAS and JOA scores of all patients at the final follow-up were significantly improved compared with those before operation(P<0.05), but there was no statistically significant difference between the groups(P>0.05). There were 96 and 112 screws in group A and group B, respectively. Three days after operation, according to the Gertzbein-Robbins grade to evaluate the nail placement accuracy, there were 90 screws of grade A, 5 of grade B, 1 of grade C, no grade D and E in group A;there were 84 screws of grade A, 16 of grade B, 8 of grade C, 4 of grade D, no grade E in group B;the difference between two groups was statistically significant(Z=-3.709, P=0.000). The satisfactory rate of screw placement in group A was 98.96% (95/96), and that of group B was 89.29% (100/112), the difference between two groups was statistically significant (χ2=8.254, P=0.004). Three days after operation, the invasion of superior facet joints by pedicle screws was evaluated according to Babu's method, including 90 screws in grade 0, 4 in grade 1, 2 in grade 2, and 0 in grade 3 in group A;86 in grade 0, 12 in grade 1, 10 in grade 2 and 4 in grade 3 in group B, and the difference was statistically significant(Z=-3.433, P=0.001). There were no serious spinal cord, nerve and vascular injuries and other operation-related complications caused by screw implantation failure in both groups. All patients were followed up from 6 to 12(9.06±1.60) months. The neurological symptoms improved well after operation. During the follow-up period, there was no recurrence of symptoms, loosening or breakage of the internal fixation. CONCLUSION: Compared with the traditional fluoroscopy-assisted MIS-TLIF, the spinal robot-assisted MIS-TLIF not only has more minimally invasive and safer, but also has higher accuracy in nail placement, lower incidence of upper articular process invasion, and more accurate decompression targets, which can be used for minimally invasive treatment of single-space lumbar disc herniation.

Five novel copy number variations detected in patients with familial exudative vitreoretinopathy.

Purpose: Familial exudative vitreoretinopathy (FEVR) is an inherited retinal vascular disease genetically heterogeneous with multiple causative genes. The aim of this study is to report five novel copy number variation (CNV) regions in FEVR patients and to investigate the possible contributions of novel CNVs to FEVR. Methods: In this study, 824 FEVR families were collected. All cases were performed using the targeted next generation sequencing (NGS) assay, and families with no definite pathogenic mutations in FEVR genes were screened for CNVs according to the NGS results. Droplet digital polymerase chain reaction (ddPCR) testing was introduced to validate the screened CNV regions. We also reviewed the clinical presentations of the probands and affected family members associated with the novel CNVs and conducted segregation analysis. Results: Five CNVs in five patients were detected in this study: heterozygous deletions of kinesin family member 11 (KIF11) exons 2-4, KIF11 exon 11, KIF11 exons 1-10, tetraspanin-12 (TSPAN12) exons 1-3, and low-density lipoprotein receptor-related protein 5 (LRP5) exons 19-21. Among the five affected families, TSPAN12 exons 1-3 heterozygous deletion and LRP5 exons 19-21 heterozygous deletion originate from the mother and the father of the proband, respectively. No other family members manifested as FEVR except for the probands. The correlation between disease severity and CNV loci seems uncertain. Conclusions: Five novel CNV loci in FEVR patients were uncovered in this study, including one maternally-inherited and one paternally-inherited CNV region. Though there is no evidence of co-segregation between these CNVs and FEVR, our findings suggest novel genetic risk factors for FEVR.

Hierarchical microstructure constructed with graphitic carbon-coated Ni3S2 nanoparticles anchored on N-doped mesoporous carbon nanoflakes for optimized sodium storage.

A hierarchical microstructure constructed with graphitic-carbon-coated Ni3S2 nanoparticles anchored on N-doped mesoporous carbon nanoflakes was fabricated using a nickel-based micro-nano structure as a precursor and polydopamine as a carbon source. By optimizing the microstructure, the obtained Ni3S2/carbon composite compounded with the thickest carbon nanoflakes delivers ultrafast and stable Na-ion storage performance, and can maintain a reversible charge capacity of 372 mA h g-1 at a current density of 5 A g-1 over 250 cycles, and 316 mA h g-1 even at a current density of 20 A g-1 for 2000 cycles. These remarkable electrochemical properties can be attributed to its hierarchical microstructure of graphitic-carbon-coated Ni3S2 particles and N-doped mesoporous carbon nanoflakes, which provide easy accessibility to the electrolyte, fast electron transport and Na+ diffusion, and even relieve the strain caused by the volume expansion upon cycling.

Role of Hydrogen Sulfide in the Endocrine System.

Hydrogen sulfide (H2S), as one of the three known gaseous signal transduction molecules in organisms, has attracted a surging amount of attention. H2S is involved in a variety of physiological and pathological processes in the body, such as dilating blood vessels (regulating blood pressure), protecting tissue from ischemia-reperfusion injury, anti-inflammation, carcinogenesis, or inhibition of cancer, as well as acting on the hypothalamus and pancreas to regulate hormonal metabolism. The change of H2S concentration is related to a variety of endocrine disorders, and the change of hormone concentration also affects the synthesis of H2S. Understanding the effect of biosynthesis and the concentration of H2S on the endocrine system is useful to develop drugs for the treatment of hypertension, diabetes, and other diseases.

Cytotoxic polyhydroxylated pregnane glycosides from Cissampelos pareira var. hirsuta.

Fourteen new polyhydroxylated pregnane glycosides, cissasteroid A-N (1-14), and five known analogues (15-19), were isolated from the dried whole plant of Cissampelos pareira var. hirsuta. Their structures and stereochemistry were elucidated by extensive spectroscopic data, chemical hydrolysis, and ECD measurements. All the compounds were tested for their cytotoxicity against five human cancer cell lines, and inhibitory activity against NO release in LPS-induced RAW 264.7 cells. Compared with cisplatin, compound 7 showed more potent cytotoxicities against the HL-60, A549, SMMC-7721, MCF-7, and SW480 cell lines, with IC50 values of 2.19, 14.38, 2.00, 7.58, and 7.44 µM, respectively. The preliminary study of structure-activity relationship indicated that benzoic acid esterification at C-20 may have a negative effect on the cytotoxic activity of polyhydroxylated pregnane derivatives in these five human cancer cell lines. These results revealed the potential of compound 7 as an ideal antitumor lead compound.

Two new flavonoid glucosides from the fruits of Sinopodophyllum hexandrum.

Two new flavonoid glucosides, sinoflavonoidgs A (1) and B (2), along with three known analogues 3-5, were isolated from the fruits of Sinopodophyllum hexandrum. Their structures were established on the basis of extensive spectroscopic (UV, IR, HR-ESI-MS, 1H-NMR, 13C-NMR, HSQC, HMBC) and chromatographic (HPLC) analysis. The isolation of compounds 1-2 represents the first report of ring B-glucosided flavonoids from the genus Sinopodophyllum. The cytotoxic activities of all isolated compounds were evaluated in comparison with etoposide against four cell lines (MCF-7, HepG2, HeLa, KB). The antioxidant activities of all isolated compounds were examined by DPPH free radical-scavenging assay. The preliminary structure-activity relationships showed that the glycosilation of 3-methoxyquercetin at C-3' resulted in a greater decrease of cytotoxic and antioxidant activity.

Tunable Cascade Reactions of Alkynols with Alkynes under Combined Sc(OTf)3 and Rhodium Catalysis.

Two tunable cascade reactions of alkynols and alkynes have been developed by combining Sc(OTf)3 and rhodium catalysis. In the absence of H2O, an endo-cycloisomerization/C-H activation cascade reaction provided 2,3-dihydronaphtho[1,2-b]furans in good to high yields. In the presence of H2O, the product of alkynol hydration underwent an addition/C-H activation cascade reaction with an alkyne, which led to the formation of 4,5-dihydro-3H-spiro[furan-2,1'-isochromene] derivatives in good yields under mild reaction conditions. Mechanistic studies of the cascade reactions indicated that the rate-determining step involves C-H bond cleavage and that the hydration of the alkynol plays a key role in switching between the two reaction pathways.